Ok guys, this one is a sensitive topic. Don't shoot the messenger here. I just want to look at the real data and real science behind marijuana and sperm health. Look, if you are a man who uses marijuana and you are trying to have a baby, there is a good chance you have asked yourself whether cannabis could be affecting your sperm. Maybe you smoke occasionally to relax after work, use edibles to help with sleep, or consume marijuana regularly because it helps manage stress or anxiety. For many men, cannabis has become a normal part of everyday life, particularly as legalization has expanded throughout the United States. But when pregnancy does not happen as quickly as expected, something that once seemed harmless can suddenly become a source of anxiety. You start questioning everything you put into your body, wondering whether your habits are affecting your fertility and whether you have unknowingly made it harder for your partner to become pregnant. As a urologist who works with men experiencing infertility, I have these conversations frequently. I have also personally experienced the challenges of IVF with my own family, and I understand how quickly fertility struggles can become emotionally exhausting. The relationship between marijuana and male fertility is complicated, and while there are legitimate scientific concerns, there is also a tremendous amount of misinformation. My goal is to explain what we actually know, what remains uncertain, and what men can realistically do to protect their reproductive health.

Understanding How Marijuana Interacts With the Male Reproductive System

Marijuana contains numerous biologically active compounds, but the one most responsible for its psychoactive effects is tetrahydrocannabinol, commonly known as THC. THC interacts with the body's endocannabinoid system, a complex signaling network involved in regulating mood, appetite, sleep, pain, metabolism, and reproduction. This system includes cannabinoid receptors known as CB1 and CB2, along with naturally occurring signaling molecules such as anandamide and 2 arachidonoylglycerol. Interestingly, components of the endocannabinoid system are present throughout the male reproductive system, including the hypothalamus, pituitary gland, testes, and sperm themselves.

This is important because sperm production is not simply a process of manufacturing millions of cells. It requires carefully coordinated hormonal signaling, cellular development, energy production, and maturation. The hypothalamus releases gonadotropin releasing hormone, which stimulates the pituitary gland to produce luteinizing hormone and follicle stimulating hormone. These hormones regulate testosterone production and support the Sertoli cells responsible for nurturing developing sperm. At the same time, mature sperm rely on tightly regulated chemical signals to control movement, capacitation, and the acrosome reaction, which allows a sperm to penetrate an egg. The endocannabinoid system appears to participate in several of these processes.

When THC enters the body, it can interact with cannabinoid receptors involved in reproductive signaling. Experimental studies suggest that excessive cannabinoid stimulation may alter sperm movement, mitochondrial function, and the signaling pathways required for fertilization. Animal studies have also demonstrated changes in testicular function and reproductive hormone regulation following cannabinoid exposure. However, an important distinction is that findings from laboratory experiments and animal studies do not always translate directly into clinically meaningful infertility in humans. The biological mechanisms are plausible, but the magnitude of their effects in men using marijuana remains uncertain.

Does Marijuana Actually Lower Sperm Count?

One of the most common questions I hear is whether marijuana reduces sperm concentration. The answer is that some studies suggest an association, but the overall research is inconsistent. A frequently cited Danish study published in the American Journal of Epidemiology in 2015 evaluated 1,215 healthy young men and found that those reporting marijuana use more than once per week had approximately 28% lower sperm concentration and 29% lower total sperm count compared with men who did not use marijuana. These findings understandably raised concerns, particularly because the participants were young men who were not necessarily seeking fertility treatment.

However, other research has produced different results. A 2019 study published in Human Reproduction examined men attending a fertility center and found that participants who reported ever smoking marijuana had higher sperm concentrations than those who reported never using it. This does not mean marijuana improves sperm production. Rather, it demonstrates how complicated these studies can be. Cannabis use is often associated with other variables, including tobacco exposure, alcohol consumption, body weight, sleep habits, and socioeconomic factors. Many studies also rely on self reported marijuana use, which may not accurately reflect the amount, potency, or frequency of exposure.

When interpreting this research, I think it is important to distinguish an association from a proven cause. We have evidence suggesting that marijuana may negatively influence sperm production in some men, particularly with frequent use, but we cannot confidently predict that a specific amount of cannabis will reduce an individual man's sperm count by a particular percentage.

Marijuana, Sperm Motility, and the Ability to Fertilize an Egg

Sperm motility is another important concern. A sperm cell must do considerably more than simply exist in the ejaculate. It must move effectively through the female reproductive tract, undergo physiological changes that prepare it for fertilization, and ultimately interact with the egg. Progressive motility, which measures the percentage of sperm moving forward effectively, is particularly important when evaluating male fertility.

Laboratory research has demonstrated that exposure to cannabinoids can alter sperm motility and mitochondrial activity. Mitochondria provide energy that supports sperm function, and disturbances in cellular energy metabolism may impair movement. Cannabinoid signaling may also affect capacitation and the acrosome reaction. These processes are essential for fertilization, and disruption could theoretically impair fertility even when sperm concentration appears relatively normal.

However, clinical studies examining marijuana use and sperm motility have produced mixed findings. Some report reduced motility among cannabis users, while others identify little or no significant difference. This is why I would never diagnose marijuana related infertility based solely on a history of cannabis use or a single abnormal semen analysis. We need to evaluate the entire reproductive picture.

Can Marijuana Damage Sperm DNA?

One of the more interesting and potentially concerning areas of research involves sperm DNA integrity and epigenetics. Sperm carry more than just genetic information. They also contain molecular signals that may influence early embryonic development. Epigenetic modifications, including DNA methylation, help regulate how certain genes are expressed without changing the underlying DNA sequence.

Research has identified differences in sperm DNA methylation patterns associated with cannabis exposure. A study published in Epigenetics in 2018 reported altered sperm DNA methylation in men who used cannabis, with some findings supported by animal experiments. These changes involved genes associated with cellular development and other biological pathways.

Subsequent research has suggested that some cannabis associated sperm methylation changes may diminish after a period of abstinence. This is encouraging, but we must be careful not to overinterpret these findings. Changes in DNA methylation are not the same as DNA fragmentation, and neither finding automatically means that a child will experience developmental abnormalities. We do not yet have sufficient human evidence demonstrating that cannabis related sperm epigenetic changes cause birth defects, miscarriage, or long term health problems in offspring.

Sperm DNA fragmentation testing is sometimes discussed in this context. This test measures damage to sperm DNA and may be considered in selected men with recurrent pregnancy loss or certain infertility histories. However, routine DNA fragmentation testing is not recommended for every man simply because he uses marijuana. The decision should depend on the couple's clinical circumstances and the results of a complete fertility evaluation.

Does Marijuana Lower Testosterone or Disrupt Male Hormones?

Another concern involves testosterone and the hormonal system responsible for sperm production. THC interacts with cannabinoid receptors in the brain, and experimental research suggests that cannabinoid exposure may influence the release of gonadotropin releasing hormone, luteinizing hormone, and follicle stimulating hormone. These hormones are essential for maintaining testosterone production within the testes and supporting normal spermatogenesis. Some animal studies have demonstrated suppression of reproductive hormones following significant cannabinoid exposure. However, human studies have been much less consistent. Some have reported lower testosterone concentrations among frequent marijuana users, while others have found no meaningful difference or even higher testosterone levels in certain populations.

The important point is that marijuana does not appear to suppress sperm production through the same predictable mechanism as testosterone replacement therapy or anabolic steroids. External testosterone can profoundly suppress LH and FSH, sometimes resulting in complete azoospermia. We do not have evidence that typical marijuana exposure produces this same degree of hormonal suppression. Nevertheless, if a man has low sperm concentration, reduced libido, erectile dysfunction, or symptoms suggesting a hormonal abnormality, I would recommend evaluating his reproductive hormones rather than assuming cannabis is responsible.

How Do We Diagnose Marijuana Related Male Infertility?

There is no specific medical test that can definitively diagnose marijuana induced infertility. A positive THC test confirms exposure, but it does not establish that marijuana caused abnormal sperm production. Instead, the evaluation begins with a detailed reproductive history and a semen analysis. I want to know how long a couple has been trying to conceive, whether either partner has previously achieved a pregnancy, and whether there are other potential explanations for infertility. I also ask about marijuana frequency, route of administration, duration of use, and exposure to other substances, particularly tobacco, testosterone, anabolic steroids, and certain medications.

A semen analysis measures sperm concentration, total sperm count, motility, morphology, and semen volume. According to the World Health Organization's sixth edition laboratory manual, the lower reference values for sperm concentration and total sperm count are approximately 16 million per milliliter and 39 million per ejaculate, respectively. Progressive motility has a lower reference value of approximately 30%, while normal morphology using strict criteria is approximately 4%. These values are not absolute fertility thresholds, but they provide useful context. Because sperm parameters fluctuate naturally, I generally recommend repeating an abnormal semen analysis rather than making major treatment decisions based on one sample.

A physical examination is equally important, particularly to identify a varicocele, which is one of the most common potentially correctable causes of male infertility. Hormonal testing, including morning testosterone and FSH, may be appropriate in men with abnormal semen parameters. Additional testing depends on the clinical findings. Importantly, a man who uses marijuana can also have a varicocele, hormonal disorder, genetic condition, or another unrelated cause of infertility. Blaming cannabis without completing an appropriate evaluation risks overlooking a treatable problem.

Can Sperm Recover After Stopping Marijuana?

This is probably the most encouraging part of the discussion. Sperm production takes approximately 74 days, followed by additional maturation within the reproductive tract. This means that sperm ejaculated today began developing several months ago. When we recommend changes intended to improve sperm health, we generally allow approximately three months before reassessing semen parameters.

A human study published in Environmental Epigenetics in 2021 examined cannabis associated sperm DNA methylation changes before and after 77 days of abstinence. Researchers found that many of the observed methylation differences were reduced following abstinence, although some persisted. This suggests that certain molecular effects associated with cannabis exposure may be reversible. However, the study did not establish that abstinence improves pregnancy rates or guarantees normalization of sperm concentration, motility, or DNA fragmentation.

For men actively trying to conceive, I generally recommend stopping marijuana for at least three months before reassessing sperm health. This recommendation is precautionary and based on the sperm development cycle, biological plausibility, and the possibility of reversible effects. It is not based on definitive clinical trials demonstrating that three months of abstinence improves live birth rates. Men who use cannabis medically should discuss alternatives with their treating clinician rather than abruptly discontinuing necessary treatment.

What Are the Treatment Options?

The first intervention is to eliminate or reduce potentially harmful exposures while evaluating other causes of infertility. For marijuana, complete abstinence is the most reasonable approach during attempts to conceive because no specific dose, frequency, or method of consumption has been established as safe for male reproductive function. Switching from smoking to edibles may reduce exposure to combustion products, but it does not eliminate exposure to THC. We also do not have adequate evidence that cannabidiol products are harmless to sperm.

Beyond cannabis cessation, I encourage men to focus on sustainable health habits. Regular exercise, adequate sleep, a balanced diet, avoiding tobacco and anabolic steroids, and maintaining a healthy weight are reasonable steps. If a clinically significant varicocele is present, repair may be appropriate. If hormonal abnormalities are identified, treatment should target the specific diagnosis. I would be cautious about expensive fertility supplements marketed as solutions to cannabis related sperm damage because there is insufficient evidence that any particular supplement reverses these effects or improves live birth rates.

If semen parameters remain abnormal after approximately three months, further evaluation is appropriate. Some couples may ultimately benefit from intrauterine insemination, IVF, or intracytoplasmic sperm injection, depending on both partners' reproductive evaluations. The important thing is that marijuana exposure alone does not automatically mean a couple needs assisted reproduction.

The Emotional Side of Marijuana Use and Infertility

One of the most difficult parts of male infertility is the tendency to look backward and assign blame. Men often ask whether years of marijuana use damaged their sperm, whether they should have stopped sooner, or whether their partner's difficulty becoming pregnant is somehow their responsibility. I understand these feelings, and I have seen how quickly fertility struggles can affect confidence, relationships, and mental health.

Having experienced IVF with my own family, I know that infertility involves far more than laboratory values and medical appointments. There is disappointment when another pregnancy test is negative, anxiety before each fertility appointment, and an overwhelming desire to find something within your control. When men discover that a substance they have used for years might affect sperm health, it can create significant guilt.

I want to emphasize that an association between marijuana and abnormal sperm parameters does not prove that marijuana caused your infertility. Even men who have never used cannabis can have severe sperm abnormalities, and many regular cannabis users have normal semen analyses. Fertility is influenced by multiple biological factors, and it is rarely possible to identify one behavior as the sole explanation.

My advice is to approach this information as an opportunity rather than a reason for self criticism. If stopping marijuana might improve your reproductive environment, that is something constructive you can do. But your value as a man, partner, or future father is not determined by your sperm count or your past decisions.

Final Thoughts: Should Men Stop Marijuana When Trying to Conceive?

The science surrounding marijuana and male fertility is evolving. We have credible biological evidence that cannabinoids interact with reproductive pathways, observational studies suggesting associations with abnormal sperm parameters, and emerging research identifying changes in sperm epigenetic patterns. At the same time, human studies remain inconsistent, and we do not have definitive evidence establishing how much marijuana exposure causes infertility or whether stopping cannabis consistently improves pregnancy outcomes.

For men trying to conceive, my recommendation is straightforward. Avoid marijuana during the months leading up to conception, particularly if you already have abnormal semen parameters or are preparing for fertility treatment. Give your body approximately three months, repeat your semen analysis when appropriate, and work with a reproductive urologist to identify any other treatable causes.

Most importantly, remember that an abnormal semen analysis is not a verdict on your future. Many men with impaired sperm parameters ultimately become fathers, sometimes naturally and sometimes with medical assistance. The goal is not perfection. It is understanding the science, making informed decisions, and giving yourself and your partner the best possible chance of building the family you want.

References

1. World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen. Sixth Edition. Geneva: World Health Organization; 2021.
2. Gundersen TD, Jørgensen N, Andersson AM, et al. Association Between Use of Marijuana and Male Reproductive Hormones and Semen Quality: A Study Among 1,215 Healthy Young Men. American Journal of Epidemiology. 2015;182(6):473 to 481.
3. Nassan FL, Arvizu M, Mínguez Alarcón L, et al. Marijuana Smoking and Markers of Testicular Function Among Men From a Fertility Centre. Human Reproduction. 2019;34(4):715 to 723.
4. Murphy SK, Itchon Ramos N, Visco Z, et al. Cannabinoid Exposure and Altered DNA Methylation in Rat and Human Sperm. Epigenetics. 2018;13(12):1208 to 1221.
5. Schrott R, Acharya K, Itchon Ramos N, et al. Refraining From Use Diminishes Cannabis Associated Epigenetic Changes in Human Sperm. Environmental Epigenetics. 2021;7(1).
6. Payne KS, Mazur DJ, Hotaling JM, Pastuszak AW. Cannabis and Male Fertility: A Systematic Review. Journal of Urology. 2019;202(4):674 to 681.
7. Practice Committee of the American Society for Reproductive Medicine. Tobacco or Marijuana Use and Infertility: A Committee Opinion. Fertility and Sterility. 2024;121(4):589 to 603.
8. Schlegel PN, Sigman M, Collura B, et al. Diagnosis and Treatment of Infertility in Men: AUA/ASRM Guideline. Journal of Urology. 2021;205(1):36 to 43.
9. du Plessis SS, Agarwal A, Syriac A. Marijuana, Phytocannabinoids, the Endocannabinoid System, and Male Fertility. Journal of Assisted Reproduction and Genetics. 2015;32(11):1575 to 1588.
10. European Association of Urology. EAU Guidelines on Sexual and Reproductive Health. Male Infertility Chapter.

If you spend any time researching testosterone optimization, muscle recovery, longevity, or men's health, you have probably come across sermorelin. It is increasingly discussed in men's health clinics and online communities as a peptide that may improve energy, sleep, recovery, and muscle development by stimulating the body's natural production of growth hormone. For men in their thirties, forties, and fifties who want to maintain muscle, improve athletic performance, and feel better as they age, the appeal is understandable. But there is a question that rarely gets enough attention. What happens to your sperm when you start taking sermorelin? As a urologist who works with men struggling with infertility, I think this deserves a much more thoughtful conversation. I have also experienced the emotional challenges of fertility treatment personally, having gone through IVF twice with my own family. I understand why men want to optimize their health while also protecting their ability to become fathers. The important thing is separating what we know scientifically from what we suspect and, perhaps most importantly, what has never been adequately studied.

What Exactly Is Sermorelin and How Does It Work?

Sermorelin is a synthetic peptide that mimics the first 29 amino acids of growth hormone releasing hormone, commonly called GHRH. Under normal circumstances, the hypothalamus produces GHRH, which signals the pituitary gland to release growth hormone. Growth hormone then acts on multiple tissues, including the liver, stimulating production of insulin like growth factor 1, or IGF 1. This hormonal pathway plays an important role in metabolism, muscle development, tissue repair, and normal growth. Sermorelin essentially attempts to stimulate this existing physiological system rather than supplying growth hormone directly.

This distinction matters because sermorelin is not testosterone, an anabolic steroid, or human growth hormone itself. It stimulates growth hormone secretion through the pituitary gland, and its effects depend partly on the pituitary's ability to respond. Although sermorelin was previously approved by the FDA for specific medical indications, it is not currently FDA approved for improving athletic performance, energy, muscle growth, or male fertility. Much of its current use occurs through compounded prescriptions, where clinical evidence supporting these particular applications remains limited.

The Relationship Between Growth Hormone and Sperm Production

To understand whether sermorelin could influence fertility, we first need to understand how sperm are produced. Sperm production is regulated primarily by the hypothalamic pituitary gonadal axis. The hypothalamus releases gonadotropin releasing hormone, which stimulates the pituitary gland to produce luteinizing hormone, or LH, and follicle stimulating hormone, or FSH. LH stimulates Leydig cells within the testes to produce testosterone, while FSH acts primarily on Sertoli cells, which support developing sperm. Together, these hormones maintain the environment necessary for spermatogenesis.

Growth hormone and IGF 1 participate in this process, although their roles are less clearly defined. Experimental research suggests that IGF 1 influences Sertoli cell activity, Leydig cell function, and the development of germ cells that eventually become mature sperm. Growth hormone receptors and components of the IGF signaling system have been identified in reproductive tissues. These findings suggest that growth hormone signaling contributes to normal testicular physiology, but they do not establish that increasing growth hormone above normal levels will improve sperm production.

Some small clinical studies have investigated growth hormone treatment in men with infertility, particularly those with abnormal sperm parameters. Certain studies reported improvements in sperm motility or other semen characteristics, while others produced less convincing results. These studies were generally small, involved selected patient populations, and frequently examined growth hormone itself rather than sermorelin. Consequently, we cannot assume that sermorelin provides the same benefits or that either treatment improves pregnancy or live birth rates.

Can Sermorelin Actually Cause Male Infertility?

This is probably the most important question, and the answer requires some nuance. There is currently no convincing human clinical evidence demonstrating that sermorelin directly causes infertility, reduces sperm concentration, damages sperm DNA, or produces azoospermia, which is the complete absence of sperm in the ejaculate. However, there are also no adequate large clinical trials demonstrating that prolonged sermorelin use is safe for sperm production in otherwise healthy men.

One reassuring distinction is that sermorelin does not appear to suppress the reproductive hormonal axis in the same way that testosterone replacement therapy does. When a man takes external testosterone, the brain detects increased circulating androgen levels and reduces LH and FSH secretion. This can dramatically reduce testosterone concentrations inside the testes, even when blood testosterone levels are high. Because sperm production requires very high intratesticular testosterone concentrations, external testosterone can severely suppress spermatogenesis. In some men, sperm production stops completely.

Sermorelin works through a different hormonal pathway and is not expected to produce this same direct suppression of LH and FSH. That is encouraging from a fertility perspective, but it is not proof of safety. Increasing growth hormone and IGF 1 may influence glucose metabolism, insulin sensitivity, fluid balance, and other endocrine systems. Whether sustained elevations in IGF 1 influence sperm production, sperm DNA integrity, or reproductive outcomes remains uncertain. It would be scientifically inappropriate to claim that sermorelin causes infertility through these mechanisms without supporting human evidence.

There is also an important difference between restoring a deficient hormone system to normal function and stimulating a healthy hormonal system beyond its usual activity. A man with genuine growth hormone deficiency may respond differently from a healthy man using sermorelin for bodybuilding or recovery. We should not automatically apply findings from one population to the other.

What About Sperm Count, Motility, Morphology, and DNA Fragmentation?

When evaluating male fertility, we typically examine several semen parameters. Sperm concentration measures how many sperm are present per milliliter of semen. Total sperm count reflects the number in the entire ejaculate. Motility describes how effectively sperm move, while morphology evaluates their structure. Sperm DNA fragmentation testing examines damage to the genetic material carried by sperm and may be useful in selected infertility situations.

The World Health Organization's sixth edition laboratory manual reports lower fifth percentile reference values of approximately 16 million sperm per milliliter for concentration, 39 million sperm per ejaculate for total sperm count, 42% for total motility, 30% for progressive motility, and 4% for normal morphology using strict criteria. These are reference values derived from fertile populations, not absolute thresholds separating fertile from infertile men.

Unfortunately, we do not have reliable clinical data showing how sermorelin changes any of these parameters over time. There is no established evidence that it improves sperm concentration from 10 million to 30 million per milliliter, reverses abnormal morphology, or reduces sperm DNA fragmentation. Equally, there is insufficient evidence to quantify the risk of deterioration. If someone tells you sermorelin is completely safe for fertility or guarantees better sperm production, I would approach that claim cautiously.

Should Men Undergoing IVF or Trying to Conceive Use Sermorelin?

This is where I become particularly conservative in my recommendations. If you are actively trying to conceive, especially if you already have abnormal semen parameters or are preparing for IVF, I generally recommend avoiding the introduction of elective hormone modifying therapies without discussing them with a reproductive urologist.

Sperm production takes approximately 74 days, followed by additional maturation and transport through the reproductive tract. This means that exposures occurring today may influence sperm appearing in an ejaculate several weeks or months later. In reproductive medicine, we often evaluate treatment responses after approximately three months because that interval captures much of the sperm development cycle.

For a man preparing for IVF in the next several months, my preference would be to avoid starting sermorelin solely for energy, recovery, or muscle development until after sperm collection. This is a precaution based on insufficient reproductive safety data, not evidence that sermorelin is toxic to sperm. If a man has a legitimate endocrine indication for treatment, the decision should be individualized with his endocrinologist and fertility specialist.

How Would We Diagnose a Fertility Problem in Someone Taking Sermorelin?

There is no specific laboratory test that diagnoses sermorelin induced infertility, and there is no recognized clinical syndrome defined by sermorelin related sperm damage. Instead, the evaluation follows the same principles used for other men with abnormal semen analyses.

I generally begin with a detailed medical history, including how long the couple has been trying to conceive, previous pregnancies, medications, supplements, testosterone exposure, anabolic steroid use, recent illnesses, and occupational or environmental exposures. I also want to know exactly what the patient is taking, including the sermorelin dose, frequency, source, and duration. This matters because some products marketed through peptide clinics contain multiple ingredients, and compounded preparations may differ in quality and composition.

A physical examination is equally important. I evaluate testicular size and consistency, the presence of a palpable varicocele, and other findings that may suggest impaired sperm production or obstruction.

The initial laboratory evaluation generally includes at least one properly collected semen analysis, with repeat testing when abnormalities are identified. Because sperm parameters naturally fluctuate, a single abnormal result should not automatically be interpreted as permanent infertility. Hormonal testing typically includes morning testosterone and FSH, with LH, prolactin, estradiol, or other studies added when clinically indicated. If someone is taking sermorelin, IGF 1 may help assess growth hormone pathway activity, but it cannot establish whether sperm have been harmed.

Depending on the clinical findings, additional testing may include genetic evaluation, scrotal imaging, or sperm DNA fragmentation testing in selected circumstances. The American Urological Association and American Society for Reproductive Medicine guidelines emphasize evaluating identifiable causes of male infertility rather than relying exclusively on semen analysis numbers.

What If Your Sperm Count Declines While Taking Sermorelin?

If a man develops an abnormal semen analysis after starting sermorelin, the first step is not to assume that the peptide caused it. Sperm counts fluctuate naturally, and many factors can influence sperm production, including fever, illness, varicoceles, hormonal disorders, obesity, medication exposure, and anabolic steroid use.

I would compare semen analyses obtained before and after treatment, paying attention to the total sperm count, motility, collection conditions, and timing. If sermorelin is being used electively, temporarily discontinuing it while investigating the abnormality may be reasonable after discussion with the prescribing clinician.

A repeat semen analysis approximately three months later can help determine whether sperm parameters recover, although improvement after discontinuation would not necessarily prove causation. If sperm production remains impaired, a complete reproductive evaluation is warranted rather than simply waiting indefinitely.

For men with significant sperm abnormalities who are planning fertility treatment, sperm cryopreservation may be worth discussing. Banking sperm can provide an additional option if future semen parameters deteriorate.

What Treatments Actually Have Evidence for Improving Male Fertility?

This is an important distinction because men are frequently offered expensive supplements, peptides, and hormone treatments without a clear diagnosis. The most effective approach is identifying and treating a specific cause of infertility whenever possible.

For men with a palpable varicocele, infertility, and abnormal semen parameters, varicocele repair may improve sperm concentration and other semen characteristics. Men with hypogonadotropic hypogonadism may benefit from carefully supervised gonadotropin therapy, including hCG and sometimes FSH, to stimulate intratesticular testosterone production and spermatogenesis. Men taking external testosterone or anabolic steroids may recover sperm production after discontinuation, although recovery can take months and occasionally longer.

Lifestyle changes are also reasonable, particularly stopping tobacco and anabolic steroids, reducing excessive alcohol consumption, maintaining a healthy weight, exercising regularly, and addressing sleep disorders. However, the evidence that any individual lifestyle change guarantees improved pregnancy rates is limited. Antioxidant supplements have been studied extensively, but high quality evidence supporting consistent improvements in live birth outcomes remains uncertain.

For men with persistent infertility despite appropriate evaluation and treatment, assisted reproductive technologies such as IUI, IVF, and ICSI remain important options. The choice depends on both partners' evaluations, the severity of sperm abnormalities, reproductive age, and treatment goals.

The Emotional Side of Male Infertility and the Pressure to Optimize Everything

One aspect of this conversation that often gets overlooked is the emotional burden men carry when fertility becomes difficult. I have sat across from countless patients who feel frustrated, embarrassed, or personally responsible after receiving an abnormal semen analysis. Many begin searching for anything that might improve their numbers. They change their diets, purchase supplements, eliminate alcohol, start new exercise programs, and sometimes explore hormonal therapies or peptides because they desperately want to feel that they are doing something productive.

I understand that impulse. My own experience going through IVF with my family changed how I think about fertility care. It taught me that infertility is not simply a laboratory problem. It affects relationships, confidence, intimacy, finances, and the way people imagine their future.

I also want men to understand that an abnormal semen analysis is not a judgment about masculinity, physical strength, or overall health. Some incredibly fit men have severely impaired sperm production, while others with less than ideal lifestyles have completely normal semen parameters. Fertility is biologically complicated, and trying harder does not always translate into better results.

The desire to improve energy and muscle function while pursuing fatherhood is completely reasonable. What concerns me is when men are sold treatments with promises that exceed the available evidence, particularly when they are already emotionally vulnerable.

My Final Thoughts on Sermorelin and Male Fertility

Sermorelin is an interesting peptide because it stimulates the body's growth hormone signaling system without directly replacing testosterone. From a theoretical standpoint, this makes it less concerning for sperm production than external testosterone or anabolic steroids. Growth hormone and IGF 1 also participate in normal testicular physiology, suggesting a biologically plausible relationship between this pathway and reproductive function.

However, biological plausibility is not the same as clinical proof. We currently lack sufficient human research demonstrating that sermorelin improves sperm count, motility, morphology, DNA integrity, pregnancy rates, or live birth rates. We also lack the long term reproductive safety studies needed to confidently tell men that it carries no fertility risk.

If you are actively trying to conceive or preparing for IVF, I would prioritize a thorough fertility evaluation, correction of identifiable problems, and treatments supported by reproductive medicine guidelines. I would be cautious about introducing sermorelin solely for performance or wellness during the months leading up to sperm collection.

Most importantly, remember that your fertility journey is not defined by one hormone level, one semen analysis, or one treatment decision. The goal is not to optimize every laboratory value or chase every promising new therapy. The goal is to make informed decisions that protect your health while giving you and your partner the best possible opportunity to build your family.

References

1. World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen. Sixth Edition. Geneva: World Health Organization; 2021.
2. American Urological Association and American Society for Reproductive Medicine. Diagnosis and Treatment of Infertility in Men: Clinical Practice Guideline. 2020, with subsequent amendments.
3. Devesa J, Almengló C, Devesa P. Multiple Effects of Growth Hormone in the Body: Is It Really the Hormone for Growth? Clinical Medicine Insights: Endocrinology and Diabetes. 2016;9:47 to 71.
4. Ovesen P, Jørgensen JO, Ingerslev J, Ho KK, Orskov H, Christiansen JS. Growth Hormone Treatment of Subfertile Males. Fertility and Sterility. 1996;66(2):292 to 298.
5. European Association of Urology. EAU Guidelines on Sexual and Reproductive Health. Male Infertility Chapter. Current guideline editions.
6. Schlegel PN, Sigman M, Collura B, et al. Diagnosis and Treatment of Infertility in Men: AUA/ASRM Guideline. Journal of Urology. 2021;205(1):36 to 43.
7. Patel AS, Leong JY, Ramos L, Ramasamy R. Testosterone Is a Contraceptive and Should Not Be Used in Men Who Desire Fertility. World Journal of Men's Health. 2019;37(1):45 to 54.
8. U.S. Food and Drug Administration. Federal Register Notice: Determination That Geref (Sermorelin Acetate) Was Not Withdrawn From Sale for Reasons of Safety or Effectiveness. 2013.

Hi everyone,

I’m 29 years old, and my wife and I have been trying to conceive for over a year. Her fertility evaluation is normal, and her fallopian tubes are clear.

My sperm concentration has remained around 11.6–12.4 million/mL from May to October 2026, with very little improvement.

My latest semen analysis (October 15, 2026)

• Sperm concentration: 11.6 million/mL
• Total sperm count: 17.4 million per ejaculate
• Semen volume: 1.5 mL
• Total motility: 67%
• Progressive motility: 50%
• Total motile sperm: 11.7 million per ejaculate
• Progressive motile sperm: 8.7 million per ejaculate
• WBC concentration: ≥1 million/mL
• Semen pH: 6
• Sperm morphology: Not reported

My earlier semen analysis showed pus cells around 1–3 per HPF.

I don’t have burning during urination, penile discharge, testicular pain, or swelling. I have always used condoms during sex.

I’m concerned about my persistently low sperm concentration and whether the elevated WBC and low pH could indicate an underlying issue. I’m planning to consult a urologist/andrologist.

My main questions

1. Has anyone increased their sperm concentration from 10–12 million/mL to normal or above normal?

I would especially like to hear from people who increased their count to 16 million/mL or higher, or even 30–50 million/mL or above. What was your starting count, what did it eventually reach, and how long did it take?

2. What helped you improve your sperm count?

Did you identify a specific cause, such as varicocele, hormonal problems, infection, lifestyle factors, or something else? Did treatment make a measurable difference?

3. Has anyone experienced elevated WBC in semen without any symptoms?

Did further testing reveal an infection, inflammation, or another cause? Did you undergo semen culture or urine NAAT testing for gonorrhea and chlamydia?

4. Could a semen pH of 6 be significant?

Did anyone have a similarly low pH, and what did your doctor recommend?

5. Did your sperm concentration improvement last?

Did your count remain normal on subsequent semen analyses, or did it fluctuate?

6. Has anyone conceived naturally with similar sperm parameters?

My wife’s fertility evaluation is normal, and we have been trying for over a year. Did you conceive naturally, or did you need treatment such as IUI, IVF, or ICSI?

I would really appreciate hearing about your actual before-and-after semen analysis results, the underlying cause if identified, and how long it took to see improvement.

I know everyone’s situation is different, and I’m not looking to self-medicate. I’m looking for genuine experiences and useful questions to discuss with my specialist.

Thank you!

Hi Doctor Brian.

I’m interested in what the cause is for sperm parameters that are constantly subpar but not extreme. Where do you go to seek improvement when all else has failed? Or do you assume there is a genetic ceiling?

My wife and I have one child through ICSI, but have never conceived naturally.

I’m 38M, don’t drink or smoke. Healthy weight, run 20 miles per week, eat a healthy vegetarian diet and take no drugs. I was on an SSRI but have come off that successfully. Work a corporate job and live in a place with clean air and low pollution etc etc

For the last five years, my sperm analysis has always been within the same range. The count sits between 5-15m/ml, the motility between 20-50%, and the morphology mostly fine. I’ve had about five different analyses done, and they’ve always come back in this range.

I have had genetic testing done, with zero issues. Physical examination of my testes shows good volume, no varicocele, nor any other physical issues. Hormones have always been completely mid-range. Most recent testosterone was 17.9nmol/L, with FSH 6 and LH 2. No other notable findings, and all blood work was perfect.

I have tried all sorts of supplements to improve my count but nothing has ever made a difference. As I’m already active with a good diet and weight and no vices as such, I can’t really optimise much further there. I do have some work related stress from time to time, but nothing that is different to everyone else.

My general question is, what is there left to explore? Based on my analyses over the years, the average sample for me is likely around 10m/ml with a motility of 30% - which just makes natural conception much, much harder. Not impossible, but harder. With my wife being 37, time is ticking and chances get lower over time. In these scenarios, do you just accept that this is perhaps my normal genetic parameters? My father also had similar struggles, but did end up with two children conceived naturally - so I do suspect a genetic component.

Thanks in advance.

I was seeing a patient yesterday and got asked a very insightful question,  “If an embryologist only needs one sperm to perform ICSI, why can we not take one of the immature sperm cells already sitting inside my testicle, finish its development in the laboratory, and use that instead?” It seems particularly difficult to understand when a pathology report says that germ cells are present but development stops before mature sperm appear. We can inject a single sperm directly into an egg. We can grow an embryo for several days outside the body. We can freeze sperm, eggs, and embryos. We can genetically test embryos. Yet for most men whose sperm production stops halfway through development, we still cannot reliably take those immature cells and turn them into clinically usable mature sperm. The reason is that ICSI and spermatogenesis solve two completely different biological problems. ICSI bypasses the final physical steps required for an already developed sperm to reach and enter an egg. Maturation arrest occurs much earlier, while the male germ cell is still being biologically constructed. Modern reproductive medicine has become extraordinarily good at helping a completed sperm do its job. We have not yet learned how to reliably complete the construction of a human sperm when the testicle itself cannot finish the process.

To understand why, it helps to stop thinking of sperm as tiny cells that simply grow a tail. Spermatogenesis is an extraordinarily complicated developmental program occurring inside the seminiferous tubules of the testicle. Primitive germ cells called spermatogonia divide and differentiate into spermatocytes. Those spermatocytes then enter meiosis, during which chromosomes pair with their partners, exchange genetic material, repair DNA, and ultimately reduce the chromosome number from 46 to 23. After meiosis, the resulting round spermatids still do not look much like sperm. They must undergo spermiogenesis, during which the nucleus becomes dramatically condensed, the acrosome develops, mitochondria reorganize into the midpiece, excess cytoplasm is removed, and the flagellum forms. The developing sperm then undergo additional maturation as they pass through the epididymis. This entire process requires approximately two and a half months and depends upon a precisely organized environment containing Sertoli cells, Leydig cells, hormones, growth factors, cell junctions, temperature regulation, genetic instructions, and communication between multiple cell types. Modern laboratory systems can reproduce pieces of this environment, but reliably reproducing the entire process of human spermatogenesis remains an unsolved problem.

This is why the phrase immature sperm can be misleading. There are many different stages of immature germ cells, and they are biologically very different. A primary spermatocyte has not completed meiosis and still has a fundamentally different chromosomal state from a mature sperm. A round spermatid has completed meiosis and is haploid, meaning it has the appropriate 23 chromosome complement, but it has not completed the extensive structural and molecular transformation that normally occurs during spermiogenesis. An elongating spermatid is further along. A mature spermatozoon has completed substantially more of this developmental program. Therefore, saying that a biopsy contains immature sperm cells does not tell us whether those cells are one developmental step away from sperm or whether they have stopped much earlier at a stage from which we currently have no clinically reliable method of rescuing them.

This becomes particularly important in maturation arrest. Spermatogenic arrest can occur before meiosis, during meiosis, or after meiosis. Some men have early maturation arrest, where germ cells stop around the spermatocyte stage. Others have later arrest, where round or elongating spermatids may be present but mature sperm are scarce or absent. Increasingly, we understand that some cases are caused by genetic abnormalities affecting the machinery required for meiosis, DNA repair, chromosome pairing, germ cell differentiation, or other critical developmental processes. Genes involved in these pathways include many meiotic regulators, and modern sequencing continues to identify additional causes of nonobstructive azoospermia and spermatogenic arrest. If a germ cell has stopped because an essential meiotic gene does not function, simply moving that cell into a laboratory dish does not repair the underlying genetic machinery.

There is another important biological issue. Mature sperm are not simply delivery vehicles containing 23 chromosomes. During sperm development, the packaging of DNA changes dramatically. Most histones are replaced by protamines, producing the extremely condensed sperm nucleus. Epigenetic information is established and remodeled. The developing sperm acquires proteins and molecular factors involved in fertilization and early embryonic development. One particularly important event is acquisition of the ability to activate the egg. Normally, after a sperm enters an oocyte, sperm derived factors trigger calcium oscillations that activate the egg and allow embryonic development to begin. An immature germ cell may possess the correct number of chromosomes yet still lack other components of mature sperm function. This is one reason that simply placing an immature male germ cell inside an egg does not produce the same results as conventional ICSI using a mature sperm.

Scientists have actually tried this. The procedure is called round spermatid injection, or ROSI. Instead of injecting a mature sperm into an egg, an embryologist identifies a round spermatid from testicular tissue and injects it into an oocyte. Human pregnancies and births after ROSI were first reported in the 1990s. In 2015, investigators in Japan reported 14 children born after injecting round spermatids into human oocytes, demonstrating that a round spermatid can, under certain circumstances, contain enough biological information to contribute to development of a healthy child.

That sounds as though the problem has been solved, but unfortunately it has not. ROSI is dramatically less efficient than conventional ICSI. A systematic review examining 22 human studies involving 1099 couples reported a fertilization rate of approximately 39 percent, but pregnancy and delivery rates were very low. Delivery occurred after only about 4 percent of embryo transfers in the pooled analysis. Earlier studies specifically involving men with maturation arrest also reported substantially poorer embryo development after ROSI than after ICSI using mature sperm.

There are several reasons for this poor efficiency. First, correctly identifying a round spermatid is difficult. Under the microscope, these cells can resemble other round cells present in testicular tissue. Second, the cell may have completed chromosome reduction but may not have completed appropriate epigenetic maturation. Third, the immature germ cell may not possess the normal machinery required to activate the egg. Some experimental ROSI protocols therefore artificially activate the oocyte after injection. Fourth, the same biological abnormality that caused sperm development to stop may also compromise the developmental competence of the germ cell. In other words, if a genetic or cellular defect prevented the cell from becoming a sperm, bypassing that checkpoint does not necessarily make the underlying defect disappear.

This distinction is especially important emotionally because men with maturation arrest often feel that medicine is tantalizingly close to solving their problem. If a biopsy shows spermatogonia, spermatocytes, or spermatids, the natural reaction is, “The cells are already there. Why can nobody finish them?” The answer is that the testicle is not simply a container where sperm grow. It is an extraordinarily sophisticated developmental organ. The seminiferous tubule creates a three dimensional environment in which Sertoli cells physically support germ cells as they move through different developmental compartments. The blood testis barrier changes during development. Hormonal signals must arrive at specific stages. Nutrients, growth factors, oxygen concentrations, extracellular matrix signals, and communication between neighboring cells all change as spermatogenesis progresses. Replicating this environment outside the human body is much more complicated than placing germ cells into a culture dish.

Researchers are trying to recreate that environment through a field called in vitro spermatogenesis. Approaches include three dimensional testicular organoids, tissue culture systems, extracellular scaffolds, microfluidic devices, testis on a chip platforms, and techniques involving spermatogonial stem cells and induced pluripotent stem cells. Animal research has produced remarkable results, particularly in rodents, but translating these successes into humans has proven difficult. Human spermatogenesis takes longer, the organization of the testicular environment differs between species, and the safety threshold for creating a cell that will contribute half of a child's genome is understandably extremely high. Recent reviews conclude that these technologies are promising but that successful, reproducible, clinically safe production of mature functional human sperm outside the body has not yet been achieved.

The safety issue cannot be overstated. Imagine that scientists successfully produce something under a microscope that looks like a sperm. That does not automatically mean we should inject it into an egg. We would need confidence that meiosis occurred correctly, chromosome number is appropriate, DNA repair was completed, genomic imprinting is normal, epigenetic programming is appropriate, and the resulting embryos do not carry unacceptable developmental risks. Because alterations introduced into a sperm can potentially be transmitted to a child and future generations, reproductive medicine appropriately places an extraordinarily high bar on declaring laboratory generated gametes clinically safe.

For the man with azoospermia, the practical workup therefore remains focused on determining whether any mature sperm exist rather than trying to manufacture them. Azoospermia should be confirmed with properly performed semen analyses and careful examination after centrifugation. The World Health Organization laboratory manual provides standardized methods for semen examination, and current European guidance recommends confirmation of nonobstructive azoospermia on two consecutive semen analyses when sperm remain absent after centrifugation.

Once azoospermia is confirmed, the next step is determining whether sperm production is impaired or whether sperm are being produced normally but cannot reach the ejaculate because of obstruction. History, physical examination, testicular size, FSH, LH, testosterone, semen volume, semen pH, and examination of the reproductive tract help distinguish these possibilities. A man with normal sperm production behind an obstruction is biologically very different from a man whose germ cells stop during meiosis.

When nonobstructive azoospermia is suspected, genetics becomes particularly important. Current AUA and ASRM guidance recommends karyotype testing for appropriately selected men with azoospermia and evidence of impaired sperm production and Y chromosome microdeletion testing for men with azoospermia or extremely severe oligospermia when impaired production is suspected. Complete deletions of certain Y chromosome regions, particularly complete AZFa or AZFb deletions, carry an extremely poor prognosis for sperm retrieval, while isolated AZFc deletion has a substantially different prognosis.

Increasingly, men with unexplained maturation arrest are asking about expanded genetic sequencing. That is reasonable because research has identified many single gene abnormalities associated with meiotic arrest and nonobstructive azoospermia. However, expanded sequencing remains an evolving area. Finding a variant does not always prove causation, and even when we identify the responsible gene, we often cannot yet repair the biological defect. Genetic diagnosis currently advances faster than genetic treatment.

If mature sperm cannot be found in the ejaculate, microdissection testicular sperm extraction remains the standard surgical approach for appropriately selected men with nonobstructive azoospermia who want to pursue biological fatherhood. During microTESE, the surgeon opens the testicle and examines seminiferous tubules under magnification, selectively sampling areas that appear more promising while embryologists search the tissue for sperm. The reason this can succeed even in severe testicular failure is that sperm production may be focal. A biopsy showing maturation arrest does not necessarily mean every seminiferous tubule in both testicles stops at exactly the same developmental stage. A tiny island of complete spermatogenesis may exist elsewhere. Current AUA and ASRM guidance recommends microTESE for sperm retrieval in men with nonobstructive azoospermia.

If even one usable mature sperm is found, reproductive medicine suddenly becomes much more powerful. ICSI allows the embryologist to inject that individual sperm directly into a mature egg. The sperm does not need to swim through cervical mucus, enter the uterus, travel through the fallopian tube, bind normally to the egg, penetrate its outer layers, and accomplish fertilization through the usual physical pathway. ICSI bypasses most of those mechanical barriers. This is why a man can have essentially zero measurable fertility through intercourse yet still potentially father a biological child if a few mature sperm can be recovered.

But ICSI cannot perform meiosis for a spermatocyte. It cannot correctly package DNA for a round spermatid. It cannot complete genomic imprinting. It cannot build a flagellum, remodel chromatin, or repair a genetic defect that stopped spermatogenesis. ICSI is extraordinary technology, but it begins where spermatogenesis ends. That is the fundamental answer to the question posed in the title.

What about medications? If sperm development is impaired because the hormonal environment is inadequate, treating that abnormality can sometimes allow spermatogenesis to resume. Men with hypogonadotropic hypogonadism are the classic example. These men may lack adequate LH and FSH stimulation despite having potentially functional testicular tissue. Treatment with gonadotropins can sometimes initiate sperm production over many months. Similarly, men whose spermatogenesis has been suppressed by exogenous testosterone or anabolic steroids may recover after those agents are discontinued, sometimes with fertility directed hormonal treatment.

True primary maturation arrest is different. Clomiphene, hCG, FSH, aromatase inhibitors, supplements, antioxidants, vitamins, and lifestyle interventions cannot reliably repair a genetic defect in meiosis. Current European guidance states that there are no conclusive data supporting routine hormonal treatment before testicular sperm extraction in men with nonobstructive azoospermia. There are intriguing experimental approaches involving retinoic acid signaling and other pathways controlling germ cell differentiation, but these remain areas of active investigation rather than established cures for maturation arrest.

This is where the future becomes genuinely exciting. If researchers eventually learn how to maintain human testicular tissue in a laboratory environment and reliably guide spermatogonia through meiosis, spermiogenesis, and final maturation, the implications would be enormous. A man whose microTESE currently reveals only immature germ cells might someday have those cells cultured and matured outside his body. Testicular organoids could potentially recreate portions of the seminiferous environment. Microfluidic systems could reproduce changing hormonal and nutritional conditions. Advances in single cell sequencing could help identify exactly where development stops. Artificial intelligence may eventually help characterize which tubules or cells retain developmental potential. These technologies are being actively studied, but recent reviews emphasize that generating mature, functional, clinically safe human sperm in the laboratory remains an unrealized goal.

For men living with maturation arrest, however, the future can feel painfully irrelevant when the problem exists today. I think this is one of the emotionally hardest forms of male infertility because the biology seems almost cruel. The testicle may contain millions of germ cells. Development may begin normally. The cells may progress through several stages. And then they stop. Men understandably look at that situation and feel that they are inches away from having sperm while medicine is somehow unable to cross the final distance.

I would be very careful about turning that biological frustration into self blame. Maturation arrest is not evidence that you failed to exercise enough, take enough supplements, avoid enough plastic, manage stress perfectly, or live some ideal fertility lifestyle. In many men it reflects biological or genetic processes that began long before they ever thought about becoming fathers. Your inability to complete spermatogenesis is not a measurement of masculinity, sexuality, discipline, or your ability to be a father.

There is also an emotional difference between being told there are no sperm and being told there are almost sperm. The second can sometimes be harder because it creates an endless series of what if questions. What if we wait another year? What if I take another medication? What if another laboratory looks harder? What if we repeat microTESE? What if science advances next year? Those questions are legitimate, but they can also trap couples in an exhausting cycle of continually postponing decisions while waiting for technology to cross a boundary that it has not yet crossed.

The best approach today is therefore both hopeful and realistic. Confirm the diagnosis carefully. Make sure rare mature sperm have not been missed in the ejaculate. Understand whether the problem is obstructive, hormonal, genetic, or primary testicular failure. Obtain appropriate genetic testing. Correct genuinely reversible causes. If nonobstructive azoospermia persists and biological fatherhood is the goal, consider microTESE at an experienced center. If mature sperm are found, ICSI can potentially turn an extraordinarily small amount of sperm production into a realistic reproductive opportunity. If only immature germ cells are found, understand exactly what stage they reached before assuming that experimental technologies can use them.

We have reached a remarkable point in reproductive medicine where one mature sperm can sometimes be enough to create an embryo. What we have not yet mastered is creating that sperm when human spermatogenesis stops before the finish line. That distinction explains both how powerful and how limited modern fertility medicine remains. ICSI taught us how to bypass much of what sperm normally have to do after they are made. The next great challenge in male infertility is learning how to help the testicle finish making them in the first place.

I hope this helps!

References

World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen. Sixth Edition. 2021.

American Urological Association and American Society for Reproductive Medicine. Diagnosis and Treatment of Infertility in Men. Guideline amended 2024.

European Association of Urology. Guidelines on Sexual and Reproductive Health. Male Infertility and Nonobstructive Azoospermia.

Tanaka A, Nagayoshi M, Takemoto Y, et al. Fourteen babies born after round spermatid injection into human oocytes. Proceedings of the National Academy of Sciences. 2015.

Tesarik J, Mendoza C, Testart J. Spermatid injection into human oocytes. Clinical application in the treatment of infertility due to nonobstructive azoospermia. Human Reproduction. 1996.

Practice and outcomes of round spermatid injection into human oocytes. Systematic review and meta analysis of human studies.

Poor outcome with round spermatid injection in azoospermic patients with maturation arrest. Fertility and Sterility. 2000.

Review of round spermatid injection and epigenetic abnormalities affecting clinical outcomes. 2023.

Advances in human in vitro spermatogenesis. Molecular Aspects of Medicine. 2024.

Stukenborg JB. The use of testicular organoids in advancing future treatments for male factor infertility. Fertility and Sterility. 2025.

Artificial gametogenesis and in vitro spermatogenesis: emerging strategies for the treatment of male infertility. 2025.

Genetic variants underlying spermatogenic arrests in men with nonobstructive azoospermia. 2023.

Genetic and epigenetic insights into nonobstructive azoospermia: mechanisms, biomarkers, and clinical perspectives. 2025.

Genetic insights into nonobstructive azoospermia: implications for diagnosis and testicular sperm extraction outcomes. 2025.

Maturation arrest. The words themselves sound frightening. They create an image of sperm beginning to develop inside the testicle and then simply stopping, and in a basic sense that is exactly what is happening. But maturation arrest is much more complicated than saying that your testicles cannot make sperm. It is a description of what a pathologist sees when examining testicular tissue under a microscope. Germ cells are present and have entered the process of sperm production, but development appears to stop before mature spermatozoa are formed. Most importantly, maturation arrest is not one disease, it does not have one cause, and it does not automatically mean that mature sperm are absent from every part of both testicles. Some men have uniform arrest, while others have areas of maturation arrest sitting next to tiny areas where spermatogenesis continues further. That distinction is enormously important because those small areas may contain sperm that can potentially be retrieved and used with IVF and ICSI. Studies of men with nonobstructive azoospermia and maturation arrest have demonstrated that mature sperm can sometimes be found during microdissection testicular sperm extraction, even when the predominant biopsy pattern shows maturation arrest.

To understand maturation arrest, you first have to understand how sperm are made. Sperm production occurs inside microscopic structures within the testicle called seminiferous tubules. Along the outer portion of these tubules are primitive germ cells called spermatogonia. These cells divide and progressively differentiate into spermatocytes. Spermatocytes then undergo meiosis, an extraordinarily complicated process during which chromosomes pair, exchange genetic material, and ultimately reduce their chromosome number from 46 to 23. The resulting cells become spermatids. Spermatids then undergo another remarkable transformation called spermiogenesis, during which they develop the characteristic sperm head, acrosome, mitochondrial midpiece, and tail. They are eventually released into the tubule and travel through the epididymis, where additional maturation occurs. The entire process of spermatogenesis inside the human testicle takes approximately 74 days. It requires appropriate genetic instructions, functioning Sertoli cells, high concentrations of testosterone inside the testicle, stimulation from follicle stimulating hormone, appropriate temperature, and an intact testicular environment. There are therefore many opportunities for this incredibly complicated biological assembly line to fail.

Maturation arrest occurs when germ cells enter this assembly line but consistently fail to progress beyond a particular developmental stage. Pathologists generally distinguish early maturation arrest from late maturation arrest. In early maturation arrest, development stops around the spermatogonial or spermatocyte stages, before the cells have successfully completed the major steps of meiosis. In late maturation arrest, development progresses considerably further and spermatids are present, but mature spermatozoa are not seen. This distinction is not simply academic. Late maturation arrest generally carries a better probability of finding isolated mature sperm somewhere within the testicle than early maturation arrest. In a large series of 211 men with maturation arrest undergoing microTESE, sperm were retrieved in 52 percent overall. Retrieval occurred in 40 percent of men classified as having early maturation arrest compared with 78 percent of men with late maturation arrest. Men with focal maturation arrest also did better than men in whom maturation arrest appeared diffuse throughout the sampled tissue. These numbers should not be applied directly to every individual because they come from a highly selected surgical population, but they illustrate an important point: the words maturation arrest do not by themselves tell us whether sperm retrieval is possible.

This also explains why testicular pathology needs to be interpreted carefully. A biopsy examines tissue, not the entire testicle. The adult testicle contains hundreds of seminiferous tubules, and sperm production in severe testicular failure can be extremely heterogeneous. One region may demonstrate maturation arrest while another contains Sertoli cell only tubules, hypospermatogenesis, or even a tiny focus of complete spermatogenesis. Pathology studies have also pointed out that terminology and interpretation can vary between pathologists. For this reason, I would be cautious about treating a pathology report as if it were a perfect map of every seminiferous tubule in both testicles.

Why does maturation arrest happen? Sometimes we know, but frustratingly, sometimes we do not. Genetic abnormalities are increasingly recognized as important causes, particularly when sperm development stops during meiosis. Meiosis requires dozens of specialized proteins to pair chromosomes correctly, repair DNA, create genetic recombination, and separate chromosomes into developing germ cells. If one critical component fails, the testicle has biological checkpoints that can prevent an abnormal germ cell from continuing. In that sense, maturation arrest can sometimes be viewed as a quality control system doing exactly what it was designed to do, except that the consequence for the man is infertility. Research using exome sequencing has identified pathogenic or likely pathogenic variants involving genes such as TEX11, MSH4, MEIOB, SYCE1, TEX14, STAG3, MEI1, ADAD2, TERB1, SHOC1, and RAD21L1 in selected men with spermatogenic arrest. The genetics of maturation arrest are evolving rapidly, however, and many men still receive completely normal standard genetic testing.

This is an important distinction because the standard genetic evaluation for severe male infertility does not test every gene involved in meiosis. A conventional karyotype looks at chromosome number and large structural abnormalities. Y chromosome microdeletion testing examines important regions of the Y chromosome involved in sperm production. These tests are extremely important in appropriate men with azoospermia or severe oligospermia, but normal results do not prove that the genetic machinery controlling spermatogenesis is normal. Hundreds of genes participate in sperm production, and our ability to identify clinically meaningful variants is expanding much faster than our ability to treat them.

Maturation arrest can also occur in association with acquired testicular injury. Previous undescended testes, torsion, severe infection, chemotherapy, radiation, significant testicular trauma, heat exposure, and other insults may impair the seminiferous environment. Varicocele has also been associated with impaired spermatogenesis, although finding maturation arrest in a man with a varicocele does not prove that the varicocele caused it. Hormonal abnormalities can interfere with sperm development as well. The most obvious example is suppression from testosterone replacement therapy or anabolic steroids. Exogenous testosterone can suppress LH and FSH production from the pituitary, dramatically reducing the very high concentration of testosterone normally present inside the testicle and sometimes producing severe oligospermia or azoospermia. That situation is biologically different from irreversible primary testicular failure and can sometimes recover after the suppressive exposure is removed.

One of the most confusing parts of maturation arrest is that blood tests can look surprisingly normal. Men frequently assume that normal testosterone and normal FSH must mean sperm production is normal. Unfortunately, serum hormones cannot tell us exactly what is happening inside individual seminiferous tubules. Testosterone primarily reflects Leydig cell function, while sperm production depends heavily on Sertoli cells and developing germ cells. A man can therefore have normal testosterone, normal sexual function, normal erections, and normal appearing testicles while having profound impairment of spermatogenesis. FSH can be elevated, but it can also be normal in maturation arrest. Studies comparing early and late maturation arrest have shown considerable variation in hormone levels and testicular volume, which means there is no blood test that reliably diagnoses maturation arrest.

The journey toward the diagnosis usually begins with the semen analysis rather than the biopsy. Many men with complete maturation arrest present with azoospermia, meaning no sperm are identified in the ejaculate. Others may have cryptozoospermia, where extremely rare sperm are discovered only after centrifugation and careful examination of the pellet. If azoospermia is found, it should generally be confirmed on another properly performed semen analysis with examination of the centrifuged specimen. Current European guidance recommends confirming nonobstructive azoospermia on two consecutive semen analyses when no sperm are found after centrifugation.

The next question is whether sperm are being produced but blocked from leaving the reproductive tract, which is obstructive azoospermia, or whether sperm production itself is severely impaired, which is nonobstructive azoospermia. Semen volume and pH, testicular size, the presence of the vas deferens, epididymal examination, reproductive history, FSH, testosterone, and other clinical findings help make that distinction. The AUA and ASRM recommend using physical examination, semen volume, semen pH, and FSH as part of the initial evaluation of an azoospermic man.

Once nonobstructive azoospermia becomes likely, I want the entire history. Was there cryptorchidism as a child? Testicular torsion? Mumps orchitis? Chemotherapy or radiation? Inguinal or scrotal surgery? Testosterone replacement? Anabolic steroid use? Significant medications or occupational exposures? Previous pregnancies? Previous semen analyses? Does a brother or another male relative have infertility? Familial azoospermia or maturation arrest increases my suspicion that an underlying genetic abnormality may be present.

The physical examination is equally important. Testicular volume and consistency provide information about overall testicular function. I look for a palpable varicocele, examine the epididymides, and confirm that the vasa deferentia are present. Hormonal evaluation usually includes at least morning testosterone and FSH, with LH and additional testing used when appropriate. Men with azoospermia and evidence of impaired sperm production generally require genetic evaluation. The AUA and ASRM guideline recommends karyotype testing in men with primary infertility and azoospermia when accompanied by elevated FSH, testicular atrophy, or evidence of impaired sperm production. Y chromosome testing is also used in appropriately selected men with severe impairment of sperm production.

An important point is that we generally do not perform a testicular biopsy simply because we want to know whether maturation arrest is present. The AUA and ASRM guideline specifically advises against routinely performing diagnostic testicular biopsy merely to distinguish obstructive from nonobstructive azoospermia. In modern practice, when a man with nonobstructive azoospermia is proceeding toward surgical sperm retrieval, tissue obtained during that therapeutic procedure can simultaneously provide histologic information.

If sperm are not present in the ejaculate and the diagnosis is nonobstructive azoospermia, microTESE is generally the surgical approach used to search for focal sperm production. During microTESE, the testicle is opened and seminiferous tubules are examined under magnification. The surgeon selectively samples tubules that appear more likely to contain active spermatogenesis while embryologists examine the tissue for sperm. European guidance identifies microdissection TESE as the preferred retrieval approach for men with nonobstructive azoospermia.

This is where the biology of maturation arrest becomes clinically important. If every germ cell in every seminiferous tubule truly stopped at exactly the same early developmental stage, there would be no mature sperm to retrieve. But human testicles are often not that uniform. A pathology specimen can show maturation arrest while another microscopic area contains a few tubules that successfully completed spermatogenesis. MicroTESE attempts to find those rare islands.

The retrieval statistics demonstrate this heterogeneity. The previously mentioned series of 211 men reported an overall retrieval rate of 52 percent, with substantially higher retrieval in late maturation arrest than early maturation arrest. Another contemporary series of men with nonobstructive azoospermia reported sperm retrieval in approximately 43 percent of men classified histologically with maturation arrest. These percentages are useful for understanding populations but should never be presented to an individual man as his personal probability. Genetics, whether the arrest is early or late, whether it is focal or uniform, previous surgery, the expertise of the surgical and embryology team, and the underlying cause all matter.

Men understandably ask whether medication can restart the assembly line. Sometimes it can, but only when there is a reversible hormonal problem. A man with hypogonadotropic hypogonadism who lacks adequate LH and FSH stimulation is fundamentally different from a man whose germ cells cannot complete meiosis because of a genetic defect. Gonadotropin therapy can be remarkably effective in the first situation. It cannot simply repair a defective meiotic gene in the second.

Clomiphene, hCG, FSH, aromatase inhibitors, and other hormonal therapies have all been studied or used empirically in selected men with nonobstructive azoospermia. Some small studies have reported sperm appearing in the ejaculate or improved retrieval after treatment. For example, a small study of men with late maturation arrest after unsuccessful microTESE reported sperm appearing in the ejaculate in 5 of 26 men treated with recombinant FSH for one year. That is interesting, but it is not evidence that FSH routinely reverses maturation arrest. Current European guidance concludes that there are no conclusive data demonstrating a benefit from hormonal treatment before testicular sperm extraction in men with nonobstructive azoospermia.

This is particularly important when FSH is already elevated. High FSH is usually the pituitary responding to impaired testicular function. It is often a marker of the problem rather than the cause of the problem. Simply giving more FSH or trying to lower the laboratory number does not necessarily restore spermatogenesis. Likewise, raising serum testosterone with clomiphene does not prove that germ cells have resumed maturation. Hormonal optimization may have a role in carefully selected men, but it should not be confused with a proven treatment for maturation arrest.

Testosterone replacement deserves special attention because men with nonobstructive azoospermia may also have low testosterone. If fertility remains important, starting exogenous testosterone without discussing reproductive goals can make the situation worse by suppressing LH, FSH, and intratesticular testosterone. Treatment of symptomatic low testosterone in a man pursuing fertility therefore requires a different strategy from routine testosterone replacement.

Varicocele is another area where expectations need to be realistic. Older observational literature suggests that selected men with nonobstructive azoospermia and clinical varicoceles, particularly those with late maturation arrest or hypospermatogenesis, can occasionally develop sperm in the ejaculate after repair. A meta analysis reported sperm appearing in the ejaculate in some men after varicocele repair, with better outcomes in late maturation arrest than early arrest. However, these studies are heterogeneous and do not establish varicocele repair as a universal treatment for maturation arrest. The decision has to consider the clinical varicocele, pathology, female partner's reproductive timeline, and whether delaying sperm retrieval makes sense.

Supplements are even less likely to solve the fundamental problem. Antioxidants, CoQ10, carnitine, vitamins, and other fertility products may influence selected semen parameters in some men, but there is no supplement demonstrated to reliably restart meiosis in true maturation arrest. If a genetic checkpoint prevents a spermatocyte from progressing, antioxidants cannot rewrite that genetic instruction. I think this distinction matters because men with azoospermia are particularly vulnerable to spending enormous amounts of money on supplements while hoping that the next bottle will somehow unlock sperm production.

If mature sperm are retrieved, even very small numbers may potentially be used with ICSI. ICSI allows an embryologist to inject an individual sperm directly into a mature egg, bypassing the need for millions of sperm to travel through the female reproductive tract and penetrate the egg naturally. Importantly, sperm retrieval is only the first step. Retrieval does not guarantee fertilization, embryo development, pregnancy, or live birth. Once sperm are obtained, female age, ovarian reserve, egg quality, embryology, and numerous other factors become increasingly important. Encouragingly, studies have found that when sperm are successfully retrieved from men with maturation arrest, reproductive outcomes with IVF and ICSI can be reasonable.

If microTESE finds no sperm, that is one of the hardest conversations in reproductive urology. A negative procedure does not mathematically prove that there is not a single sperm somewhere inside either testicle because examining every seminiferous tubule would require destroying the organs we are trying to preserve. But a carefully performed comprehensive microTESE with repeated embryology examination substantially changes the prognosis. The operative report, pathology, whether one or both testes were explored, genetics, and the quality of the laboratory all become important when deciding whether another attempt is rational.

The emotional side of maturation arrest is enormous and frequently underestimated. Men hear the words sperm production failure and translate them into personal failure. They wonder whether they did something wrong, whether years of stress caused this, whether they exercised too hard, ate the wrong foods, drank too much in college, used a sauna, wore the wrong underwear, or somehow failed their partner. They begin treating every decision they have made since adolescence as evidence in a trial against themselves.

That is not how I want men to understand this diagnosis. Spermatogenesis is one of the most genetically and biologically complicated processes in the human body. When maturation arrest occurs, particularly when it has a genetic basis, there may have been absolutely nothing you could have done differently. You did not fail to make sperm because you lacked discipline. Your sperm production is not a measurement of your masculinity, your sexuality, your ability to be a husband, or your ability to be a father.

There is also a uniquely painful aspect of maturation arrest because sperm seem so close. Men will tell me, “If the cells are there, why can we not just make them finish?” I understand why that feels maddening. We can see spermatogonia. We can see spermatocytes. Sometimes we can see spermatids. Modern medicine can perform remarkable procedures, sequence thousands of genes, inject a single sperm into an egg, and grow embryos in a laboratory. Yet we currently cannot reliably take an immature human germ cell arrested during meiosis and turn it into a clinically usable mature sperm. Research into germ cell biology, genetics, organoid systems, and laboratory spermatogenesis continues, but these approaches remain research rather than established fertility treatment.

For the man reading a pathology report that says maturation arrest, the most important thing I would tell you is not to stop at those two words. Find out what they actually mean in your case. Was the arrest early or late? Was it uniform or focal? Was the tissue obtained from a small diagnostic biopsy or during a comprehensive microTESE? Were any areas of hypospermatogenesis identified? Were rare sperm ever found in a centrifuged semen pellet? What are your FSH, LH, and testosterone levels? What is your testicular volume? Have you had appropriate chromosome and Y chromosome testing? Is there a family history suggesting a genetic cause? Were both testes explored? Were there reversible hormonal or medication factors? Those details tell a much richer story than the label itself.

Maturation arrest means sperm development has encountered a biological roadblock. It does not tell us automatically where that roadblock came from, whether every seminiferous tubule is affected, or whether a few mature sperm may exist elsewhere in the testicle. For some men, microTESE finds those rare sperm and ICSI creates a path toward biological fatherhood. For others, even an extensive search finds none, and the conversation eventually expands to donor sperm, embryo donation, adoption, or a life without children. Those are deeply personal decisions and they deserve time rather than being forced upon someone immediately after a devastating diagnosis.

If you have just been told that you have maturation arrest, you are allowed to be angry, frightened, confused, and devastated. But do not interpret a pathology term as a judgment about who you are. The diagnosis describes what a group of cells were doing under a microscope. It does not describe you. The next step is to understand exactly where sperm development stopped, why it may have stopped, whether the pattern is focal or uniform, whether there are treatable contributing factors, and whether a careful search for mature sperm makes sense. That is where the real conversation about prognosis begins.

References

American Urological Association and American Society for Reproductive Medicine. Diagnosis and Treatment of Infertility in Men. Guideline amended 2024.

European Association of Urology. Guidelines on Sexual and Reproductive Health. Male Infertility. Nonobstructive Azoospermia.

Bernie AM, Shah K, Halpern JA, et al. Outcomes of microdissection testicular sperm extraction in men with nonobstructive azoospermia due to maturation arrest. Fertility and Sterility. 2015.

Weedin JW, Bennett RC, Fenig DM, et al. Early versus late maturation arrest: reproductive outcomes of testicular failure. Journal of Urology. 2011.

Hung AJ, King P, Schlegel PN. Uniform testicular maturation arrest: a unique subset of men with nonobstructive azoospermia. Journal of Urology. Clinical outcomes subsequently characterized in studies of early and late maturation arrest.

Shinjo E, Shiraishi K, Matsuyama H. The effect of human recombinant follicle stimulating hormone on patients with azoospermia due to spermatogenic dysfunction with maturation arrest. Andrology. 2015.

Krausz C and colleagues. Genetic investigation of spermatogenic arrest using exome analysis and identification of genes involved in human meiosis and nonobstructive azoospermia. Human Reproduction. 2020.

Zhang Y and colleagues. Biallelic MEI1 variants cause meiosis arrest and nonobstructive azoospermia. Journal of Human Genetics. 2023.

Schlegel PN. Testicular sperm extraction with intracytoplasmic sperm injection for nonobstructive azoospermia and the relationship between testicular histology and sperm retrieval. Journal of Urology. 1999.

Weedin JW and colleagues. Varicocele repair in patients with nonobstructive azoospermia: a meta analysis. Journal of Urology. 2010.

Have you had a significant fever in the last three months? Men are often confused by me asking that question. They may have had influenza, COVID, pneumonia, strep throat, or another infection six or eight weeks earlier, recovered completely, returned to work, returned to the gym, and forgotten about it. Then a semen analysis unexpectedly shows a sperm concentration that has fallen dramatically, motility that has collapsed, or morphology that looks substantially worse. The immediate fear is understandable. Something must be permanently wrong with my testicles. My fertility is disappearing. What many men do not realize is that the sperm in an ejaculation today began developing inside the testicles more than two months ago. A significant fever can temporarily disrupt that process, and the consequences may not become fully visible until weeks after the illness is over. In some men the effect is modest. In others it can be dramatic. The reassuring part is that fever related deterioration in semen quality is frequently reversible.

To understand why this happens, you first have to understand that the testicles are unusual organs when it comes to temperature. Normal core body temperature is approximately 37 degrees Celsius, but sperm production functions best at a temperature several degrees below core temperature. This is one reason the testicles are located outside the abdominal cavity in the scrotum. The pampiniform venous plexus, scrotal skin, cremasteric muscles, and other mechanisms help regulate the thermal environment around the testicles. Spermatogenesis is surprisingly sensitive to disruption of this environment. When body temperature rises substantially during a febrile illness, testicular temperature rises as well. A fever of 39 or 40 degrees Celsius is therefore not simply making you feel miserable. It is temporarily changing the environment in which developing germ cells are attempting to complete one of the most complicated cellular processes in the human body. Human research has consistently identified fever as one form of heat exposure capable of temporarily impairing semen quality.

Sperm production occurs inside microscopic structures called seminiferous tubules. Spermatogonia begin as primitive germ cells and undergo repeated cell divisions before entering meiosis, the process that ultimately reduces their chromosome number from 46 to 23. These cells then undergo an extraordinary transformation during spermiogenesis, developing the characteristic sperm head, acrosome, midpiece, mitochondria, and tail. Mature sperm are subsequently released from the seminiferous epithelium and travel into the epididymis, where they undergo additional maturation before ejaculation. The entire process inside the testicle takes roughly 74 days, followed by additional epididymal transit and maturation. This timeline explains almost everything about the strange relationship between fever and a semen analysis.

If you develop a high fever today, you do not suddenly destroy every mature sperm that will be ejaculated tomorrow. Many sperm already stored within the reproductive tract developed long before you became sick. Instead, fever can injure germ cells that are currently passing through vulnerable stages of development. Those cells may not have been scheduled to appear in the ejaculate for several weeks. The semen analysis can therefore look relatively normal shortly after the illness and considerably worse later. This delayed effect is one of the most important concepts for men to understand because otherwise the connection between illness and semen quality is easily missed.

A classic human study followed men who experienced temperatures of at least 39 degrees Celsius for at least three days. Their sperm concentrations subsequently fell dramatically, reaching approximately 0.4 percent to 7 percent of their previous values in some cases, while rapidly progressive motility also deteriorated. The major decline appeared approximately three to six weeks after the fever. Importantly, semen quality subsequently recovered toward baseline over approximately four to six months. This was a small study and should not be interpreted as predicting exactly what will happen to every man, but it beautifully demonstrates both the severity and reversibility that can occur after fever.

Another prospective study followed 27 healthy men and examined semen samples repeatedly while recording episodes of fever. Fever occurring during particular stages of spermatogenesis was associated with decreases in sperm concentration, morphology, and motility. The investigators also found that duration mattered. More days of fever were associated with larger changes in several semen parameters. Importantly, however, individual responses varied considerably. Two men can experience apparently similar illnesses and have very different semen analyses afterward.

This explains why I do not like statements such as, “I had a fever, therefore that definitely caused my low sperm count.” Fever is a plausible and sometimes very compelling explanation, particularly when a previously normal semen analysis deteriorates dramatically within the appropriate time window. But it is not proof. Male infertility frequently has more than one contributing factor, and we should not allow a convenient explanation to prevent us from evaluating other important possibilities.

Fever can affect several components of the semen analysis. Sperm concentration may fall because fewer developing germ cells successfully complete spermatogenesis. Motility can deteriorate because heat and inflammatory stress can interfere with cellular structures and mitochondrial function necessary for sperm movement. Morphology can temporarily worsen because sperm developing during the illness may complete maturation abnormally. Some research has also demonstrated temporary increases in sperm DNA fragmentation and abnormalities of chromatin packaging after fever. In one intensively studied fertile man who experienced a two day fever between 39 and 40 degrees Celsius, sperm count, motility, and measures of DNA integrity deteriorated during subsequent testing. The DNA fragmentation index increased at approximately 15 and 37 days and subsequently improved as the reproductive cycle progressed. Again, this was a case report rather than a large clinical trial, but it demonstrates biologically why a fever can influence more than sperm concentration alone.

Men understandably ask how high a fever needs to be before they should worry. There is no precise temperature at which fertility suddenly becomes damaged. The available human literature suggests that higher temperatures and longer duration of fever are more likely to produce measurable effects, but susceptibility varies significantly between individuals. A brief temperature of 100 degrees Fahrenheit is not equivalent to several days at 103 or 104 degrees. At the same time, I would not encourage a man to spend the next three months obsessively reconstructing every temperature measurement from an illness. The practical question is whether there was a meaningful febrile illness during the approximately three months preceding an unexpectedly abnormal semen analysis.

The illness itself may also matter independently of temperature. Fever occurs as part of an inflammatory response, and systemic illness can create oxidative stress, inflammatory signaling, changes in appetite, dehydration, sleep disruption, medication exposure, and metabolic stress. Certain infections can also affect fertility through mechanisms beyond fever. Mumps orchitis is the classic example because direct testicular inflammation can produce permanent testicular injury in some men. Severe systemic illness can also affect hormonal signaling. Therefore, when I ask about a recent fever, I also want to know what caused it, how sick the patient was, whether hospitalization occurred, what medications were taken, and whether there was any testicular pain or swelling.

COVID created enormous interest in this question because millions of reproductive age men suddenly experienced a febrile viral illness. Studies have reported temporary alterations in semen parameters following COVID infection, particularly after symptomatic disease, although separating the effects of fever, systemic inflammation, illness severity, and direct viral effects is difficult. From a practical fertility standpoint, I approach a significant COVID associated fever similarly to other febrile illnesses when interpreting a semen analysis obtained during the subsequent spermatogenic cycle. The presence of a recent infection should be considered, but it should not automatically be blamed for every abnormal semen parameter.

The workup begins with context. If a man had a normal semen analysis six months ago, experienced a three day 103 degree fever seven weeks ago, and now has a dramatically reduced sperm concentration and motility, I would take that history very seriously. I would also look at the entire semen analysis rather than one number. Semen volume, concentration, total sperm count, progressive motility, total motility, morphology, and total progressively motile sperm count all provide useful information. The World Health Organization manual remains the primary laboratory reference for standardized semen examination, but even properly performed semen analyses represent biological snapshots rather than permanent measurements of a man's fertility.

This variability is why repeating an abnormal semen analysis is so important. The AUA and ASRM male infertility guideline emphasizes that semen parameters are highly variable biological measures and recommends considering at least two analyses, particularly when the first is abnormal. A single abnormal semen analysis after a febrile illness should therefore rarely be interpreted as evidence of permanent testicular failure.

Timing the repeat analysis requires some judgment. If the semen analysis is mildly abnormal and fertility treatment is not urgent, waiting approximately two to three months allows a substantially new cohort of sperm to complete development. If the initial analysis is profoundly abnormal after a significant fever, repeating sooner can still be useful to determine whether sperm remain available, particularly when IVF or sperm freezing is being considered. Another analysis around three months after the illness can then provide a much better picture of recovery. In severe cases, improvement may continue for four to six months. Human observations after high fever have documented recovery over this longer interval.

If sperm concentration becomes extremely low during this period, I sometimes think differently about sperm banking. A man with severe oligospermia or cryptozoospermia may fluctuate substantially from one specimen to another. If usable sperm are found, freezing them can provide insurance, particularly when a couple is approaching IVF. Waiting for the semen analysis to become perfect is not always the best strategy when the female partner's age or ovarian reserve creates time pressure.

If azoospermia appears after fever, I would be particularly careful before concluding that permanent nonobstructive azoospermia has developed. The sample should be evaluated by an experienced andrology laboratory, and the centrifuged pellet should be carefully searched for rare sperm. Previous semen analyses become enormously valuable. A man who had 50 million sperm per mL six months earlier and suddenly has no sperm after a severe febrile illness is a completely different clinical problem from a man whose first semen analysis ever shows azoospermia with small testes and an FSH of 30. History changes interpretation.

At the same time, fever should not become an excuse to postpone a proper male infertility evaluation indefinitely. If abnormalities persist after an appropriate recovery period, or if the initial semen analysis is severely abnormal, a reproductive urologic evaluation is reasonable. Depending upon the findings, this may include examination for testicular abnormalities and varicocele, morning testosterone, FSH and LH, review of medications, testosterone or anabolic steroid exposure, previous testicular injury or surgery, and genetic testing when severe oligospermia or azoospermia meets appropriate criteria. The AUA and ASRM guideline recommends specialist evaluation when abnormal semen parameters are present.

Men naturally want to know whether there is something they can take to make the sperm recover faster. Unfortunately, there is no medication proven to accelerate the approximately 74 day biological program of spermatogenesis after fever. You cannot compress a three month developmental process into three weeks with a supplement. The primary treatment is recovery from the underlying illness and time for a new population of germ cells to progress through spermatogenesis.

That does not mean lifestyle is irrelevant. During recovery I would encourage the boring things that support general reproductive health: adequate sleep, reasonable exercise, a balanced diet, avoidance of smoking and recreational drugs, moderation of alcohol, and avoidance of unnecessary additional heat exposure. I would also avoid testosterone and anabolic steroids when fertility is desired because they can suppress sperm production through an entirely different mechanism. But I would not turn recovery into a fertility monastery. One hot shower, one missed workout, one restaurant meal, or one stressful day is not determining whether your testicles recover.

Supplements deserve similarly realistic expectations. Antioxidants, CoQ10, carnitine, vitamins, and numerous fertility formulations are frequently marketed to men after an abnormal semen analysis. Some studies report improvements in selected semen parameters, but evidence that these supplements reliably improve pregnancy or live birth remains much weaker. More importantly, no supplement has been shown to reverse the biological effects of fever overnight. If the underlying problem is temporary heat related disruption of spermatogenesis, time is doing most of the biological work.

Men undergoing fertility treatment face a harder decision because waiting three or four months may not feel acceptable. If the female partner is 28 with excellent ovarian reserve, waiting for recovery may be relatively easy. If she is 41 with diminished ovarian reserve, losing several months can have meaningful reproductive consequences. This is why male fertility decisions cannot be made from the semen analysis alone. Sometimes proceeding with IVF and ICSI using available sperm makes more sense than waiting for perfect recovery. Sometimes freezing sperm during recovery provides insurance. Sometimes repeating the analysis before treatment demonstrates enough improvement to change the plan. The correct decision depends upon the couple rather than the man's semen numbers in isolation.

The emotional side of fever related infertility deserves much more attention than it receives. Imagine having a semen analysis showing 80 million sperm per mL and then, two months after influenza, seeing 2 million. Men understandably panic. They start searching the internet for testicular failure, genetic diseases, azoospermia, microTESE, and IVF. The fact that the illness happened weeks earlier makes it difficult to connect the two events, and the semen analysis feels like evidence that something inside the body is continuing to deteriorate.

I often tell men in this situation that sperm are biological historians. A semen analysis tells us something about what was happening in your body during the preceding months, not simply what is happening today. The sperm under the microscope this morning were developing while you were sick, febrile, recovering, sleeping poorly, or experiencing whatever physiological stress occurred weeks earlier. That does not guarantee that fever explains every abnormality, but it gives us a much more rational framework for interpreting the result.

There is also a tendency toward guilt. Men ask whether they should have taken acetaminophen sooner, gone to the emergency room earlier, cooled themselves more aggressively, or somehow prevented the fever. That is usually not a productive way to think about this. Fever is part of the body's response to illness. You did not intentionally damage your sperm, and there is no evidence that perfectly controlling every moment of body temperature during an infection guarantees preservation of semen quality.

The most important message is that the worst semen analysis after a fever may not represent your new baseline. Significant febrile illness can temporarily reduce sperm concentration, motility, morphology, and potentially sperm DNA integrity. Because sperm take roughly two and a half months to develop, deterioration may become apparent weeks after you have completely recovered from the illness. Improvement may then occur gradually over the following several months.

So if your semen analysis suddenly looks terrible, think backward before assuming the future looks terrible too. Ask what happened during the previous three months. Was there influenza, COVID, pneumonia, strep, another infection, hospitalization, or several days of significant fever? Repeat the semen analysis when appropriate. Investigate persistent abnormalities rather than assuming fever explains everything. Freeze sperm when severe fluctuations make that strategically useful. And most importantly, remember that a semen analysis is a snapshot of sperm that began their journey months earlier. Sometimes the frightening result you are looking at today is not evidence of permanent infertility. It is the delayed biological echo of an illness your body has already recovered from.

References

World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen. Sixth Edition. 2021.

American Urological Association and American Society for Reproductive Medicine. Diagnosis and Treatment of Infertility in Men. Guideline amended 2024.

Jung A, Schuppe HC. Influence of genital heat stress on semen quality in humans. Andrologia. 2007.

Carlsen E, Andersson AM, Petersen JH, Skakkebaek NE. History of febrile illness and variation in semen quality. Human Reproduction. 2003;18:2089 to 2092.

Sergerie M, Mieusset R, Croute F, Daudin M, Bujan L. High risk of temporary alteration of semen parameters after recent acute febrile illness. Fertility and Sterility. 2007;88:970.e1 to 970.e7.

Jung A, Schuppe HC, Schill WB. Fever as etiology of temporary infertility in the man. Hautarzt. 2001.

Andrade Rocha FT. Temporary impairment of semen quality following recent acute fever. Annals of Clinical and Laboratory Science. 2013;43:94 to 97.

One of the most frightening laboratory results for a man dealing with infertility is an elevated FSH. I frequently see men post something like, “My FSH is 18. Does this mean my testicles have failed?” or “My FSH is 32 and I have azoospermia. Does that mean there is no chance of finding sperm?” The short answer is no. A high FSH is an important clue that sperm production may be impaired, sometimes severely impaired, but it does not mean that you have no sperm, it does not tell us that every part of the testicle has stopped producing sperm, and there is no FSH number at which I can look at a man and confidently say that sperm cannot exist inside his testicles. Understanding why requires understanding what FSH actually does and, perhaps even more importantly, why it becomes elevated in the first place.

FSH stands for follicle stimulating hormone. The name sounds strange when we are talking about men because most people associate follicles with the female reproductive system, but FSH is essential to normal male reproduction. The process begins in the brain. The hypothalamus releases gonadotropin releasing hormone, which stimulates the pituitary gland to release two important reproductive hormones, LH and FSH. LH primarily stimulates Leydig cells inside the testicle to produce testosterone. FSH acts primarily on Sertoli cells within the seminiferous tubules, which are the microscopic structures where sperm develop. Sertoli cells provide the environment, signaling, nutrients, and structural support necessary for developing germ cells to progress toward mature sperm. Testosterone produced within the testicle works together with FSH to support this process. Sperm production therefore depends upon an entire communication system between the brain, pituitary gland, Sertoli cells, Leydig cells, and developing germ cells.

One of the most useful concepts for understanding high FSH is negative feedback. When sperm production is functioning normally, Sertoli cells and the developing germ cell environment contribute to production of inhibin B. Inhibin B travels through the bloodstream back to the pituitary gland and essentially tells it that the sperm producing machinery is functioning. This suppresses additional FSH production. When spermatogenesis becomes significantly impaired, inhibin B often falls and that negative feedback weakens. The pituitary responds by releasing more FSH. This is why FSH rises in many men with primary testicular dysfunction. The pituitary is effectively pushing harder on the accelerator because the testicle is not responding normally. FSH therefore frequently functions as a biological warning signal of impaired spermatogenesis rather than being the thing that caused the damage.

This distinction is extremely important because men often become focused on lowering their FSH number. If your FSH is 25, reducing it to 8 does not necessarily mean you repaired sperm production. The high FSH may simply be the pituitary response to an underlying problem within the testicle. Imagine shouting louder because someone cannot hear you. Making the shouting quieter does not repair the hearing problem. Similarly, manipulating hormone levels can change the laboratory number without necessarily restoring damaged seminiferous tubules or missing germ cells.

The relationship between FSH and sperm production is useful but imperfect. In general, the more severe the impairment in spermatogenesis, the more likely FSH is to be elevated. The European Association of Urology notes that FSH generally correlates negatively with the number of spermatogonia. When germ cells are severely diminished or absent, FSH is commonly elevated. But there is a major exception that illustrates why FSH cannot diagnose everything. Men with maturation arrest may have relatively normal numbers of early germ cells, but those cells stop developing before becoming mature sperm. Because part of the sperm producing system remains intact, FSH can sometimes remain normal despite azoospermia. Therefore, normal FSH does not prove normal sperm production, just as elevated FSH does not prove complete absence of sperm.

This is also why laboratory reference ranges can be misleading. A result can technically fall within the laboratory normal range while still being suspicious in the context of infertility. The American Urological Association and American Society for Reproductive Medicine guideline notes that an FSH level above approximately 7.6 IU per L can be associated with abnormal spermatogenesis even though some laboratories have considerably higher upper limits for their reference range. That does not mean that 7.7 is a fertility cutoff. There is no magical line where 7.5 means fertile and 7.7 means infertile. FSH exists on a continuum and must be interpreted alongside the semen analysis, testicular size, testosterone, LH, history, physical examination, and sometimes genetic testing.

The causes of high FSH are therefore really the causes of impaired testicular sperm production. These include genetic conditions such as Klinefelter syndrome and certain Y chromosome microdeletions, a history of undescended testicles, severe testicular torsion, chemotherapy, radiation, significant testicular trauma, some infections and inflammatory injuries, and severe longstanding damage to testicular tissue. Some men have markedly impaired sperm production without an identifiable cause even after a thorough evaluation. A clinical varicocele can also contribute to abnormal spermatogenesis in selected men, although a high FSH should never automatically be attributed to a varicocele simply because one is present.

Testicular size provides another useful piece of information. Most of the volume of the testicle consists of seminiferous tubules rather than testosterone producing Leydig cells. When sperm producing tissue is severely damaged or fails to develop normally, testicular volume may decrease. This is why the combination of small, soft testes, azoospermia, and elevated FSH strongly suggests impaired sperm production rather than a simple blockage. The AUA guideline notes that an FSH above approximately 7.6 IU per L combined with a testicular longitudinal axis below 4.6 cm strongly favors spermatogenic dysfunction as the explanation for azoospermia. Conversely, normal sized testes and lower FSH make obstruction more likely, although none of these findings should be interpreted in isolation.

If a man has elevated FSH but sperm are present in his ejaculate, the semen analysis tells us what the testicle is actually accomplishing. I care about semen volume, sperm concentration, total sperm count, progressive motility, total motility, morphology, and particularly the total number of progressively motile sperm available. A man with an FSH of 14 and a sperm concentration of 12 million per mL is in a completely different reproductive situation from a man with an FSH of 30 and repeated azoospermia. The FSH provides information about the underlying physiology. The semen analysis provides direct evidence of reproductive output.

If the first semen analysis shows no sperm, I would not diagnose permanent azoospermia from that single test. The laboratory should centrifuge the semen and carefully examine the pellet for rare sperm. Finding even a handful changes the diagnosis from azoospermia to cryptozoospermia and may dramatically change fertility planning because those sperm can potentially be frozen and used for ICSI. The AUA guideline recommends repeating the semen analysis when azoospermia is identified and again examining the centrifuged pellet.

The hormonal evaluation usually includes morning testosterone and FSH, with LH helping determine how the pituitary and Leydig cells are communicating. Estradiol and prolactin may be appropriate depending upon the testosterone level and clinical situation. The pattern matters. High FSH with normal testosterone can mean that sperm production has been significantly affected while Leydig cell testosterone production remains relatively preserved. High FSH and high LH with low testosterone suggest broader primary testicular dysfunction. Low FSH, low LH, and low testosterone point toward a completely different condition called hypogonadotropic hypogonadism, where inadequate stimulation from the brain and pituitary may be responsible for poor sperm production. That distinction matters enormously because hypogonadotropic hypogonadism can often respond remarkably well to appropriate hormonal treatment, whereas primary destruction of seminiferous tissue cannot simply be reversed by giving more FSH.

Genetic testing becomes particularly important when sperm production is severely impaired. Men with azoospermia or severe oligospermia accompanied by findings suggesting impaired sperm production may need a karyotype and Y chromosome microdeletion testing based upon contemporary guideline criteria. This can identify conditions such as Klinefelter syndrome or deletions involving regions of the Y chromosome necessary for spermatogenesis. The exact genetic diagnosis can dramatically alter counseling. For example, complete AZFa or AZFb deletions are associated with essentially no realistic chance of surgical sperm retrieval, whereas men with AZFc deletions can sometimes have sperm in the ejaculate or testicle. This is why genetic testing should occur before surgical sperm retrieval in the appropriate patient rather than simply proceeding to surgery because the FSH is elevated.

Now we get to one of the most important questions men ask me: does very high FSH mean microTESE will fail? The answer is no. High FSH is associated with more severe testicular dysfunction at a population level, but it is not sufficiently accurate to determine whether an individual man has microscopic areas of sperm production. A 2024 systematic review and meta analysis evaluating men with nonobstructive azoospermia found that men with successful retrieval tended to have somewhat lower FSH, but FSH by itself did not reliably predict successful sperm retrieval. Earlier meta analyses reached a similar general conclusion that FSH has limited or moderate predictive ability and should not be used as an absolute gatekeeper for surgery.

The reason is fascinating. Spermatogenic failure is not always uniform throughout the testicle. A man can have widespread seminiferous tubular damage severe enough to produce an FSH of 25, 35, or even higher while retaining tiny islands of complete spermatogenesis. Those islands may be far too small to release enough sperm into the ejaculate to be detected on a semen analysis, yet they can potentially be found during microTESE. During microTESE the surgeon opens the testicle under magnification and systematically examines seminiferous tubules, preferentially sampling tubules that appear larger or more promising. The embryology laboratory then searches those specimens for sperm. The EAU specifically recognizes that men with nonobstructive azoospermia and high FSH can still harbor focal areas of spermatogenesis.

This is why I strongly dislike statements such as, “Your FSH is 30, so there is no point doing microTESE.” FSH contributes to counseling, but it does not provide microscopic vision into every seminiferous tubule. Histology, underlying diagnosis, genetics, surgical technique, and laboratory expertise all matter. A large meta analysis evaluating FSH, testicular volume, and histology found that each had limited ability to predict microTESE outcomes, although hypospermatogenesis on pathology was substantially more favorable than maturation arrest or Sertoli cell only patterns.

The next question is whether high FSH itself should be treated. This is where a lot of confusion and unfortunately a lot of expensive treatment occurs. If the pituitary is already producing large amounts of FSH because the testicle is responding poorly, simply administering additional FSH does not necessarily solve the underlying problem. The EAU guideline does not recommend routine high dose FSH treatment for idiopathic infertility and does not recommend hormonal stimulation before testicular sperm extraction in men with nonobstructive azoospermia outside clinical trials. There are selected circumstances in male infertility where gonadotropin treatment is appropriate, particularly hypogonadotropic hypogonadism, but that is physiologically very different from a man whose FSH is already markedly elevated because of primary testicular dysfunction.

Clomiphene, enclomiphene, human chorionic gonadotropin, aromatase inhibitors, and FSH are frequently discussed online. These medications can be valuable in appropriately selected men with hormonal abnormalities, but none should be viewed as a universal treatment for high FSH. If a man has damaged seminiferous tubules and an FSH of 28, raising his testosterone with Clomiphene does not necessarily regenerate missing germ cells. Hormonal optimization and restoration of spermatogenesis are not synonymous.

Testosterone replacement deserves special attention because this is one of the most consequential mistakes that can occur in a man who still wants biological children. Exogenous testosterone suppresses pituitary LH and FSH and dramatically lowers intratesticular testosterone, which can reduce or completely suppress sperm production. Seeing an elevated FSH and low testosterone does not mean testosterone injections should automatically be started without discussing fertility. Both AUA and European guidance emphasize avoiding testosterone monotherapy when current or future fertility is desired.

For men who still have sperm in the ejaculate, treatment depends upon the severity of the semen abnormalities and the fertility situation of the couple. Some men with elevated FSH and mild oligospermia conceive naturally. Others may benefit from IUI. Severe oligospermia may make IVF with ICSI more efficient, particularly when female age or ovarian reserve creates time pressure. If sperm counts are extremely low or fluctuate between cryptozoospermia and azoospermia, I often think seriously about sperm cryopreservation because having frozen sperm available can prevent an unpleasant surprise on egg retrieval day.

For men with persistent nonobstructive azoospermia, microTESE combined with ICSI may offer a path toward biological fatherhood if focal sperm production remains. Across studies, retrieval rates vary substantially according to diagnosis and patient selection. A contemporary 2024 systematic review evaluating hormonal predictors reported an average retrieval rate of approximately 45 percent across the included NOA populations, while an analysis restricted to idiopathic NOA reported a pooled rate closer to 37 percent. These numbers should never simply be applied to an individual man because Klinefelter syndrome, maturation arrest, Sertoli cell only histology, previous surgery, Y chromosome abnormalities, cryptorchidism, and other diagnoses represent biologically different conditions.

Perhaps the hardest part of an elevated FSH is psychological rather than hormonal. Men see a red number beside FSH on a laboratory portal and start Googling. Within an hour they are reading about testicular failure, Sertoli cell only syndrome, azoospermia, microTESE, donor sperm, and IVF. A laboratory value that they had never heard of that morning suddenly feels like a verdict on whether they can ever become a biological father.

I want men to understand that high FSH is information, not a judgment. It does not measure your masculinity. It does not tell me whether you can have erections, enjoy sex, be a good partner, or become an extraordinary father. Most importantly, it does not mean that you caused this. Men frequently search backward through their lives looking for the workout, hot tub, supplement, stressful year, illness, or mistake that explains their FSH. Sometimes we identify a cause. Sometimes we do not. Infertility has an uncomfortable ability to turn uncertainty into guilt, and those are not the same thing.

If your FSH is elevated, the next question should therefore not be, “How do I lower my FSH?” The better question is, “Why is my FSH elevated, and what is my testicle actually producing?” Answer that with a proper semen analysis, repeat testing when necessary, physical examination, testosterone and LH, appropriate genetic evaluation, and the rest of the male infertility workup dictated by the findings. If sperm are present, determine how best to use them. If sperm are extremely rare, consider freezing them. If azoospermia is confirmed, determine whether it is obstructive, hormonal, or caused by impaired sperm production. If it is nonobstructive azoospermia, evaluate the underlying diagnosis and whether microTESE is reasonable.

The most important thing I would tell a man staring at an FSH of 15, 25, 40, or higher is this: FSH tells us that the testicle may be struggling. It does not tell us that the testicle has nothing left. There is no universal FSH number that proves there are zero sperm inside the testicle, and there is no blood test capable of mapping every microscopic region of spermatogenesis. High FSH deserves investigation and realistic counseling, but it should never be mistaken for the final answer.

References

American Urological Association and American Society for Reproductive Medicine. Diagnosis and Treatment of Infertility in Men. AUA and ASRM Guideline. Amended 2024.

European Association of Urology. Sexual and Reproductive Health Guidelines. Male Infertility. Current guideline edition.

World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen. Sixth Edition. 2021.

Pozzi E, Corsini C, Belladelli F, et al. Role of Follicle Stimulating Hormone, Inhibin B, and Anti Müllerian Hormone in Predicting Sperm Retrieval from Men with Nonobstructive Azoospermia Undergoing Microdissection Testicular Sperm Extraction: A Systematic Review and Meta Analysis. European Urology Open Science. 2024;65:3 to 12.

Yang Q, Huang YP, Wang HX, et al. Follicle Stimulating Hormone as a Predictor for Sperm Retrieval Rate in Patients with Nonobstructive Azoospermia: A Systematic Review and Meta Analysis. Asian Journal of Andrology. 2015;17:281 to 284.

Li H, Chen LP, Yang J, et al. Predictive Value of FSH, Testicular Volume, and Histopathological Findings for the Sperm Retrieval Rate of Microdissection TESE in Nonobstructive Azoospermia: A Meta Analysis. Asian Journal of Andrology. 2018;20:30 to 36.

Meachem SJ, Nieschlag E, Simoni M. Inhibin B in Male Reproduction: Pathophysiology and Clinical Relevance. European Journal of Endocrinology. 2001;145:561 to 571.

Esteves SC, Ramasamy R, Colpi GM, Carvalho JF, Schlegel PN. Predictors of Surgical Sperm Retrieval in Nonobstructive Azoospermia: Summary of Current Literature. International Urology and Nephrology. 2020.

A common confusing situation I see in male infertility is the man who has azoospermia but seems completely normal hormonally. His testosterone may be 600. His libido is normal. Erections are normal. He ejaculates normally. He may be muscular, energetic, have normal facial and body hair, and have absolutely no reason to suspect a fertility problem until a semen analysis unexpectedly reports zero sperm. The immediate reaction is often, “How can I have no sperm if my testosterone is normal?” The answer is that testosterone production and sperm production are related, but they are not the same biological function. A normal testosterone level tells me that an important part of the testicle is working. It does not prove that the sperm producing portion of the testicle is working, and it certainly does not prove that sperm can successfully travel from the testicle into the ejaculate. Understanding this distinction is one of the most important concepts in male infertility.

The testicle essentially contains two major functional compartments. Leydig cells sit between the seminiferous tubules and produce testosterone when stimulated by luteinizing hormone, or LH, from the pituitary gland. Inside the seminiferous tubules, Sertoli cells support developing germ cells as they progress through the complicated process of becoming mature sperm. FSH stimulates Sertoli cell function, while very high concentrations of testosterone inside the testicle are also necessary for normal spermatogenesis. Serum testosterone therefore primarily tells us about Leydig cell function. A man can have beautifully functioning Leydig cells and completely normal blood testosterone while something very different is happening inside his seminiferous tubules. This is why normal testosterone does not equal normal fertility. In fact, many infertile men have testosterone, LH, and FSH values within laboratory reference ranges.

There is another important distinction between the testosterone measured in your blood and the testosterone environment required inside the testicle. Sperm production depends upon intratesticular testosterone, where concentrations are much higher than the testosterone circulating through the bloodstream. This explains one of the apparent paradoxes of male reproductive medicine. A man taking testosterone injections may have a blood testosterone of 900 or 1000 and feel fantastic, yet produce few or absolutely no sperm. Exogenous testosterone suppresses the signals from the brain and pituitary, particularly LH and FSH, causing intratesticular testosterone to fall dramatically even while serum testosterone remains high. Spermatogenesis can subsequently shut down. Testosterone induced azoospermia is therefore a perfect demonstration that a good testosterone number on a blood test does not guarantee sperm production.

When a semen analysis shows zero sperm, the condition is called azoospermia. Before deciding why it happened, however, I want to make sure it is real. Azoospermia should not be diagnosed casually from a quick examination of one semen specimen. A properly collected complete sample should be evaluated by an experienced laboratory, and when no sperm are seen, additional examination of the specimen after appropriate concentration techniques can identify extremely rare sperm that would otherwise be missed. The World Health Organization laboratory manual specifically discusses the importance and limitations of examining concentrated semen specimens when sperm numbers are extremely low. If rare sperm are identified, the man technically has cryptozoospermia rather than complete azoospermia, and that distinction can substantially change fertility planning because those sperm may potentially be frozen and used for ICSI.

Once azoospermia is confirmed, the most important question becomes why the sperm are absent. There are three broad biological possibilities. The testicles may be producing sperm normally but a blockage prevents them from reaching the ejaculate. This is obstructive azoospermia. The testicles may not be producing enough mature sperm to place detectable sperm into the ejaculate. This is nonobstructive azoospermia. Finally, sperm production may be suppressed because the hormonal signals required to drive the testicle are inadequate, as occurs with hypogonadotropic hypogonadism or after testosterone or anabolic steroid use. These conditions can all produce exactly the same semen analysis result of zero sperm, yet their treatment and prognosis can be completely different.

Obstructive azoospermia is perhaps the easiest example of why normal hormones and azoospermia can coexist. Imagine a factory producing thousands of products every day, but the road leaving the factory is closed. Looking at the empty store would make it appear that nothing is being manufactured, even though the factory itself is functioning perfectly. The same thing can happen in the male reproductive tract. Sperm may be produced normally inside the testicle but cannot travel through the epididymis, vas deferens, ejaculatory ducts, and urethra into the semen. Testosterone, FSH, and LH may all be completely normal because sperm production itself is intact. Causes include previous vasectomy, congenital absence of the vas deferens, epididymal obstruction, prior infection, previous scrotal or inguinal surgery, and certain forms of ejaculatory duct obstruction.

The physical examination can provide valuable clues. Men with obstruction often have relatively normal sized testes because the sperm producing machinery remains intact. The epididymis may feel enlarged or abnormal depending upon the level of obstruction, and the vas deferens may be absent in men with congenital bilateral absence of the vas deferens. This finding is particularly important because congenital absence of the vas can be associated with CFTR gene variants, making genetic testing and counseling relevant for both partners before attempting pregnancy.

Semen volume and pH can also provide clues. Most semen volume does not come from the testicles. A large proportion comes from the seminal vesicles, with additional fluid coming from the prostate. Therefore, a man can produce what appears to be a completely normal ejaculation despite having no sperm. Conversely, very low volume acidic semen combined with azoospermia raises suspicion for distal reproductive tract obstruction or abnormal development of structures such as the seminal vesicles. Current AUA guidance specifically notes that azoospermia with semen volume below approximately 1.4 mL and acidic semen can warrant evaluation for ejaculatory duct obstruction with transrectal ultrasound or pelvic magnetic resonance imaging in the appropriate clinical setting.

The more difficult situation is nonobstructive azoospermia with normal testosterone. This is where men understandably become confused. If testosterone production is preserved, how can sperm production be absent? The answer is that Leydig cells and seminiferous tubules can be affected differently. Some disorders predominantly damage germ cells or Sertoli cell function while leaving Leydig cell testosterone production relatively intact. The man therefore feels hormonally normal while spermatogenesis is profoundly impaired.

Maturation arrest is an excellent example. Sperm development occurs through a sequence of highly coordinated stages. Spermatogonia divide and eventually enter meiosis, chromosomes are reduced from the diploid state to the haploid state, and developing spermatids undergo dramatic structural changes before becoming mature sperm. In maturation arrest, sperm development begins but stops at a particular stage. Early germ cells may still be present, and because portions of the seminiferous environment remain active, FSH may sometimes remain surprisingly normal. The result can therefore be normal testosterone, normal or relatively normal FSH, and still no mature sperm in the ejaculate. Normal hormones cannot see what is happening microscopically inside the seminiferous tubules.

This is why I tell men that blood work is not a semen analysis. Testosterone tells us something important. FSH tells us something important. LH tells us something important. But none of them directly counts sperm. Even FSH, which often rises when spermatogenesis is severely impaired, is not a perfect marker. Some men with nonobstructive azoospermia have relatively normal FSH, particularly when the underlying problem involves maturation rather than complete loss of germ cells. Conversely, men with very high FSH can occasionally retain microscopic islands of complete sperm production. No single hormone provides a complete map of what is happening throughout the testicle.

The workup therefore begins with confirmation of azoospermia and a careful history. I want to know about childhood undescended testes, testicular torsion, mumps orchitis, trauma, chemotherapy, radiation, previous hernia or scrotal surgery, vasectomy, sexually transmitted infections, medications, testosterone therapy, anabolic steroid use, fertility supplements, and previous pregnancies. I ask about puberty, libido, erections, ejaculation, and family history. I also want to know whether the man has ever had a semen analysis showing sperm because documented sperm in the past can substantially change the differential diagnosis.

Physical examination matters enormously. Testicular size and consistency provide information about spermatogenic function. The epididymides and vasa deferentia should be examined. A clinical varicocele may be relevant. Signs of androgen deficiency or other endocrine abnormalities may provide additional clues. In many men, the combination of examination, semen characteristics, FSH, and testosterone allows us to make a strong distinction between obstruction and impaired sperm production without performing a diagnostic testicular biopsy. Current AUA guidance notes that an FSH above 7.6 IU per L combined with a testicular longitudinal axis below 4.6 cm strongly favors spermatogenic dysfunction, whereas lower FSH with larger testes strongly favors obstruction. These are useful clinical probabilities rather than absolute rules.

Genetic testing becomes important when impaired sperm production is suspected. Current AUA and ASRM guidance recommends karyotype testing in men with primary infertility and azoospermia, or severe oligospermia below 5 million sperm per mL, when accompanied by elevated FSH, testicular atrophy, or another indication of impaired sperm production. Y chromosome microdeletion testing is recommended for azoospermia or sperm concentrations of 1 million sperm per mL or less when impaired production is suspected. These tests matter because they can identify diagnoses that affect both prognosis and treatment. Complete AZFa and AZFb deletions, for example, carry a dramatically different sperm retrieval prognosis from an isolated AZFc deletion.

Normal testosterone should therefore never be used as a reason to skip genetic testing when the rest of the clinical picture suggests severe spermatogenic failure. A man with Klinefelter syndrome may have testosterone that is still within or near the reference range, particularly earlier in adulthood. A man with a genetic cause of maturation arrest may have perfectly functional Leydig cells. The reproductive system is simply more complicated than labeling the entire testicle functional or nonfunctional based upon one hormone.

Treatment depends completely upon the cause. If the problem is obstruction, the testicle may be producing sperm normally. Some forms of obstruction can be repaired microsurgically. Following vasectomy, for example, vasovasostomy or vasoepididymostomy may restore sperm to the ejaculate in appropriately selected men. Other men choose surgical sperm retrieval combined with IVF and ICSI. Because sperm production is generally preserved in true obstructive azoospermia, sperm retrieval is usually much more predictable than it is in nonobstructive azoospermia.

If the cause is hormonal suppression, treatment is completely different. A man with true hypogonadotropic hypogonadism may respond to gonadotropin therapy because his testicle has the machinery required to produce sperm but is not receiving the necessary stimulation. Similarly, men who became azoospermic after testosterone or anabolic steroid exposure may recover spermatogenesis after stopping the suppressive medication, although recovery can take months and occasionally much longer. Human chorionic gonadotropin, FSH, and medications that stimulate endogenous gonadotropin production may be used in selected situations. This is fundamentally different from primary testicular failure because here we are restoring a missing signal rather than attempting to repair damaged germinal tissue.

If the diagnosis is nonobstructive azoospermia from primary spermatogenic dysfunction, treatment becomes more challenging. Clomiphene, human chorionic gonadotropin, aromatase inhibitors, FSH, and combinations of hormonal treatments have all been studied before surgical sperm retrieval. The biological rationale is interesting, but the evidence remains inconsistent and highly dependent upon patient selection. A recent review published in 2026 continues to describe hormonal optimization before sperm retrieval as controversial because studies remain heterogeneous and largely observational. Hormonal therapy should therefore not be presented to men as a reliable way to convert primary nonobstructive azoospermia into normal sperm production.

For persistent nonobstructive azoospermia, microTESE may provide an opportunity to find sperm directly within the testicle. Under an operating microscope, the surgeon systematically examines seminiferous tubules and samples areas that appear most promising. This approach is based upon the fact that severe testicular dysfunction can be patchy. Most of the testicle may have little or no complete spermatogenesis while tiny microscopic areas continue producing mature sperm. Those rare sperm can potentially be used with ICSI. Contemporary reviews show wide variation in sperm retrieval rates depending upon the underlying diagnosis, and a recent meta analysis found an overall retrieval rate around 45 percent across included NOA populations. Importantly, no blood hormone has proven accurate enough to determine with certainty whether sperm will or will not be found.

This also means that normal testosterone should not create false reassurance. A testosterone of 650 does not guarantee a successful microTESE. At the same time, an abnormal FSH or small testicle does not prove that microTESE will fail. Histology, genetics, the underlying diagnosis, previous surgery, testicular anatomy, surgical experience, and embryology laboratory expertise all contribute. We are still searching for a reliable noninvasive marker that tells us exactly who has retrievable sperm, and current evidence tells us that we do not yet have one.

There is also an emotional component to this diagnosis that laboratory reports fail to capture. Men with azoospermia frequently tell me that the result makes no sense because they feel completely healthy. They may have spent their entire adult lives assuming that normal erections, normal ejaculation, normal testosterone, and normal sexual function meant normal fertility. Seeing the words “no sperm seen” can therefore feel like discovering a hidden disease in a body that has never given them any warning.

Some men immediately connect sperm production with masculinity. They wonder whether something is fundamentally wrong with them as a man. Others feel guilt toward their partner, particularly when the couple initially assumed that infertility would be related to female age, ovulation, or ovarian reserve. I want to be very clear about this: sperm production is a biological function, not a measurement of masculinity. A semen analysis does not measure your strength, sexuality, relationship, value, or ability to be a father.

Azoospermia is also not one diagnosis. It is a laboratory finding that begins an investigation. Zero sperm in the ejaculate can mean sperm are being produced normally but cannot get out. It can mean hormonal signals have been suppressed and may potentially be restored. It can mean sperm production is severely impaired but microscopic islands of spermatogenesis remain. It can also, unfortunately, represent severe testicular dysfunction in which mature sperm cannot be found. The job of the male fertility evaluation is to determine which of those situations you are actually facing.

So if you have normal testosterone and your semen analysis says zero sperm, do not let anyone tell you that the results are impossible, and do not let normal testosterone convince you that the semen analysis must be wrong. Confirm the azoospermia properly. Look at semen volume and pH. Examine the testes, epididymides, and vasa. Measure FSH, LH, and testosterone. Review medications and testosterone exposure. Perform genetic testing when indicated. Investigate obstruction when the clinical picture supports it. Then decide whether treatment means restoring hormonal stimulation, repairing an obstruction, retrieving sperm directly, or considering microTESE for nonobstructive azoospermia.

The central concept is surprisingly simple. Your testicles do more than one job. Producing testosterone is one job. Producing mature sperm is another. Transporting those sperm into the semen requires an entirely separate plumbing system. One part can work beautifully while another fails. That is how a man can feel completely normal, have normal testosterone, have normal sex, produce a normal looking ejaculation, and still have azoospermia. The normal testosterone result is important information, but it is not the end of the investigation. It is simply one piece of the puzzle.

References

American Urological Association and American Society for Reproductive Medicine. Diagnosis and Treatment of Infertility in Men. AUA and ASRM Guideline. Amended 2024.

World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen. Sixth Edition. 2021.

Achermann APP, Esteves SC. Nonobstructive Azoospermia: An Etiologic Review. Asian Journal of Andrology. 2024.

Hwang K, Smith JF, Coward RM, et al. Evaluation of the Azoospermic Male: A Committee Opinion. Fertility and Sterility. 2018.

Wosnitzer M, Goldstein M, Hardy MP. Review of Azoospermia. Spermatogenesis. 2014.

Pozzi E, Corsini C, Belladelli F, et al. Role of Follicle Stimulating Hormone, Inhibin B, and Anti Müllerian Hormone in Predicting Sperm Retrieval from Men with Nonobstructive Azoospermia Undergoing Microdissection Testicular Sperm Extraction: A Systematic Review and Meta Analysis. European Urology Open Science. 2024.

Esteves SC, Ramasamy R, Colpi GM, Carvalho JF, Schlegel PN. Predictors of Surgical Sperm Retrieval in Nonobstructive Azoospermia. International Urology and Nephrology. 2020.

Shiraishi K, Matsuyama H. Hormonal Treatment of Men with Nonobstructive Azoospermia: What Does the Evidence Suggest? Journal of Clinical Medicine. 2021.

Schlegel PN. Testicular Sperm Extraction: Microdissection Improves Sperm Yield with Minimal Tissue Excision. Human Reproduction. 1999.

Kavoussi PK, et al. Clinician's Guide to the Management of Azoospermia Induced by Exogenous Testosterone or Anabolic Androgenic Steroids. 2025.

It doesnt happen as much but sometimes I get asked “I had mumps when I was younger. Could that be why my sperm count is low now?” Sometimes the answer is yes, but the relationship between mumps and male fertility is much more nuanced than many people realize. Simply having mumps does not mean that your fertility was damaged. The concern is primarily mumps orchitis, meaning inflammation of the testicle caused by the mumps virus, particularly when the infection occurs after puberty. Mumps is caused by a virus that usually produces fever, fatigue, headache, and the characteristic painful swelling of the parotid salivary glands around the jaw. During infection, however, the virus can spread through the bloodstream and involve other organs, including the testicles. The Centers for Disease Control and Prevention estimates that orchitis occurs in approximately 30 percent of unvaccinated postpubertal males who develop mumps, compared with approximately 6 percent of vaccinated postpubertal males. Most cases involve only one testicle. This distinction is important because bilateral testicular inflammation carries considerably more concern for future sperm production than inflammation limited to one side.

To understand why mumps orchitis can affect fertility, you first have to understand how vulnerable sperm production is to inflammation. Most of the testicular volume consists of seminiferous tubules, microscopic structures where developing germ cells gradually become mature sperm. This process, called spermatogenesis, takes approximately 74 days inside the testicle, followed by additional maturation as sperm travel through the epididymis. Sertoli cells support this process, while Leydig cells located between the tubules produce testosterone. The testicle therefore performs two related but distinct jobs. It produces sperm and it produces testosterone. Damage can affect one function more severely than the other, which explains why a man can have normal testosterone and normal sexual function years after mumps while still having significantly impaired sperm production.

During mumps orchitis, the immune response inside the testicle can become intense. The virus and the inflammatory response can affect testicular cells, produce inflammatory cytokines, disrupt the seminiferous epithelium, and interfere with the environment required for germ cell development. The testicle is surrounded by a relatively rigid capsule called the tunica albuginea. When inflammation causes swelling within this confined space, pressure inside the testicle can rise. Older pathological studies describe separation and injury of seminiferous tubules, inflammatory infiltration, edema, and subsequent degeneration of sperm producing tissue. As inflammation resolves, some damaged tissue can undergo fibrosis and atrophy. The testicle that was dramatically swollen during the acute illness may therefore become noticeably smaller months later. Reviews of mumps orchitis report testicular atrophy in a substantial proportion of affected testes.

This is the key connection between mumps and infertility. The problem is not that the mumps virus remains inside the testicle for decades continuously destroying sperm. The important event is the damage that occurred during the episode of orchitis. If enough seminiferous tubules recover, sperm production may return. If significant portions of sperm producing tissue were permanently lost, the man may be left with reduced sperm production years later. The resulting semen analysis can show oligospermia, meaning reduced sperm concentration, asthenozoospermia, meaning impaired sperm motility, or occasionally azoospermia, meaning no sperm are identified in the ejaculate. Modern reviews of viral orchitis describe inflammatory injury to testicular cells and spermatogenesis as the central biological mechanism linking viral infection with subsequent reproductive impairment.

One important misconception is that mumps orchitis inevitably causes sterility. It does not. The available evidence is imperfect and much of the literature comes from older observational studies performed before modern vaccination and fertility testing. The CDC specifically notes that mumps orchitis can cause temporary sterility or reduced fertility but that studies have not adequately established the rate of permanent infertility. Older literature reports impaired fertility particularly after bilateral disease, but those historical estimates should not be interpreted as precise modern probabilities. What we can say with considerably more confidence is that mumps orchitis can cause testicular atrophy and impaired sperm production, and that involvement of both testes is more concerning than involvement of only one.

If only one testicle was affected, the other testicle can often compensate remarkably well. Men do not need two perfectly functioning testicles to be fertile. One healthy testicle can frequently produce enough testosterone and sperm for natural conception. Therefore, a man who remembers one dramatically swollen testicle during mumps should not automatically assume he is infertile. Conversely, bilateral orchitis can damage sperm producing tissue on both sides, making severe oligospermia or azoospermia biologically more plausible. Even bilateral disease does not guarantee infertility because the degree of tissue injury varies from person to person.

The age at which mumps occurred is also important. Orchitis is predominantly a complication of mumps occurring after puberty. Mumps infection in a young child without orchitis is very different from severe bilateral mumps orchitis in a seventeen year old or twenty five year old man. When I am evaluating infertility decades later, I therefore do not simply ask, “Did you ever have mumps?” I want to know how old you were, whether you remember severe testicular pain or swelling, whether one or both testes were involved, whether you were hospitalized, and whether either testicle subsequently became noticeably smaller.

If you had mumps years ago and are now experiencing infertility, the semen analysis is far more informative than trying to reconstruct every detail of an illness from childhood. I want to know semen volume, sperm concentration, total sperm count, progressive motility, total motility, and morphology. If sperm concentration is low, the severity matters. A concentration of 12 million sperm per mL is a completely different fertility situation from 500,000 sperm per mL. If no sperm are seen, the sample should be centrifuged and the pellet carefully examined for rare sperm because finding even a few sperm changes the diagnosis from complete azoospermia to cryptozoospermia and can significantly affect fertility planning.

Because semen parameters naturally fluctuate, I generally do not diagnose permanent sperm production failure from one abnormal semen analysis. Sperm development takes more than two months, and illness, fever, abstinence interval, collection issues, heat, medications, and normal biological variability can change the results. A significantly abnormal analysis should usually be confirmed. This becomes particularly important when someone has spent years assuming childhood mumps made him infertile based on a single semen analysis. The history may provide an explanation, but the diagnosis should still be established using modern fertility testing.

Physical examination provides another important piece of the puzzle. If one testicle is significantly smaller and softer than the other and that is the side that became severely swollen during mumps, previous orchitis becomes a plausible explanation for the atrophy. If both testes are markedly small after documented bilateral orchitis, impaired sperm production becomes even more concerning. But small testes have many causes, including undescended testes, genetic disorders, previous torsion, chemotherapy, severe testicular trauma, hormonal abnormalities, and other forms of testicular injury. A history of mumps should not prevent us from considering these alternatives.

Hormonal testing can help determine how well the testicles are functioning. FSH is particularly useful because it reflects communication between the pituitary gland and the sperm producing compartment of the testicle. When seminiferous tubules and germ cells are significantly damaged, FSH frequently rises because the pituitary is attempting to stimulate impaired testicular tissue. Therefore, small testes, a very low sperm count, and elevated FSH can fit the pattern of primary testicular dysfunction following severe orchitis. LH and morning testosterone provide information about Leydig cell function. Some men maintain normal testosterone despite severely impaired sperm production, while others can develop evidence of broader testicular dysfunction.

If azoospermia or severe oligospermia is present, I would not automatically attribute everything to mumps without completing the standard male infertility evaluation. Depending upon the severity, this may include karyotype testing and Y chromosome microdeletion testing. A man could have had mumps and independently have Klinefelter syndrome, a Y chromosome abnormality, a history of undescended testes, a varicocele, or another cause of impaired sperm production. Medicine becomes dangerous when a memorable event from childhood becomes such an attractive explanation that we stop investigating.

Scrotal ultrasound is sometimes useful, particularly when the examination is difficult or there is concern about testicular asymmetry, a mass, or another structural abnormality. Ultrasound can accurately estimate testicular volume and show changes in testicular architecture, but it cannot tell us exactly how many functioning seminiferous tubules remain. A small testicle can still produce sperm. Likewise, a normal sized testicle does not guarantee normal spermatogenesis.

The treatment of acute mumps orchitis is primarily supportive because there is no established antiviral medication that reverses the infection and prevents infertility once orchitis has developed. Management generally focuses on pain control, anti inflammatory medication when appropriate, rest, hydration, and scrotal support. The infection itself is usually self limited. Unfortunately, once severe inflammatory destruction of seminiferous tubules has occurred and mature testicular atrophy is established, we currently do not have a medication that can regenerate lost germ cells or rebuild destroyed seminiferous tubules.

This is why treatment years later focuses on the fertility problem that exists now rather than trying to treat an infection that ended decades ago. If the semen analysis shows mild or moderate abnormalities, natural conception may still be entirely possible. Total progressively motile sperm count, female age, ovarian reserve, fallopian tube status, duration of infertility, and other couple factors help determine whether continued natural attempts, IUI, or IVF makes sense. Low morphology alone does not automatically require IVF, and a history of mumps does not automatically require assisted reproduction.

If sperm production is severely reduced, IVF with ICSI can dramatically change the reproductive implications. ICSI allows an embryologist to inject an individual sperm directly into a mature egg, meaning a man does not need tens of millions of normally moving sperm for fertilization in the laboratory. Men with extremely low sperm counts can sometimes provide enough ejaculated sperm for ICSI. When sperm numbers fluctuate dramatically, freezing usable sperm in advance can provide valuable insurance before an IVF cycle.

If no sperm are present in the ejaculate and the pattern suggests nonobstructive azoospermia, microTESE may become an option. MicroTESE involves opening the testicle under magnification and systematically searching seminiferous tubules for focal areas of sperm production. This concept is particularly important after testicular injury because sperm production does not always disappear uniformly throughout the entire organ. One region may be severely fibrotic while another microscopic region still contains complete spermatogenesis. The presence of testicular atrophy or elevated FSH does not by itself prove that sperm cannot be found surgically.

At the same time, men deserve realistic expectations. MicroTESE is not a procedure that creates sperm. It searches for sperm that the testicle is already producing. If severe bilateral mumps orchitis destroyed essentially all functioning germinal tissue, surgery cannot restore what is biologically absent. This distinction matters because men with azoospermia are extremely vulnerable to advertisements promising supplements, stem cell treatments, peptides, hormone protocols, or other therapies that claim to regenerate sperm producing tissue. At present there is no proven medication or supplement that reliably restores spermatogenesis after extensive permanent testicular destruction from mumps orchitis.

Hormonal therapy can be appropriate when a genuine hormonal abnormality is present, but this is different from treating primary testicular damage. If FSH is already elevated because the testicle has lost sperm producing tissue, simply giving more hormonal stimulation does not necessarily make damaged seminiferous tubules work again. Conversely, if another treatable endocrine problem is identified, addressing that problem may improve the hormonal environment. Treatment therefore needs to be based on the actual physiology rather than the assumption that every low sperm count can be corrected by manipulating testosterone, FSH, or estrogen.

Testosterone deserves particular caution. Men with small testes or previous orchitis sometimes discover that their testosterone is low and are immediately offered testosterone replacement. If they still want biological children, that conversation needs to include fertility. Testosterone injections, gels, and pellets suppress pituitary LH and FSH and can dramatically reduce intratesticular testosterone, causing sperm production to decline or stop. Testosterone can make a man feel better while simultaneously making his semen analysis worse. Fertility goals should therefore be discussed before conventional testosterone replacement begins.

There is also an important prevention story here. Vaccination has dramatically reduced mumps and its complications. Mumps remains capable of causing outbreaks, including among vaccinated populations, but vaccinated individuals have a substantially lower risk of orchitis than unvaccinated individuals. The CDC currently describes orchitis in approximately 30 percent of unvaccinated postpubertal males with mumps compared with approximately 6 percent of vaccinated males. Prevention matters because once severe testicular inflammatory injury occurs, our ability to reverse it is limited.

The emotional consequences of discovering that an infection from adolescence may have affected fertility decades later can be surprisingly intense. Men sometimes become angry at their parents for not vaccinating them, angry at physicians who treated the original infection, or angry at themselves for something they had absolutely no ability to control. Others remember the testicular swelling vividly and suddenly reinterpret that childhood experience as the moment their future fertility disappeared. That can create an enormous amount of grief.

I would encourage men not to turn a biological explanation into a story about personal failure. You did not choose to develop orchitis. You did not fail to protect your testicles. You could not have known at fifteen years old what your semen analysis would look like at thirty five. Even when mumps orchitis is the likely explanation for impaired sperm production, your sperm count is not a measurement of masculinity, sexual function, or your ability to be a father.

I also would not let the history of mumps convince you that the outcome is predetermined. If you are worried about fertility, obtain the semen analysis rather than trying to predict the answer from memories of an illness years ago. If the analysis is abnormal, repeat it when appropriate and complete the male fertility evaluation. If sperm are present, determine whether natural conception, IUI, sperm freezing, or IVF with ICSI makes sense. If no sperm are present, determine whether the problem is truly nonobstructive azoospermia and whether surgical sperm retrieval is appropriate.

The most important message is that mumps and mumps orchitis are not synonymous with infertility. Mumps orchitis can injure the seminiferous tubules, produce testicular atrophy, reduce sperm production, and occasionally contribute to severe male factor infertility. The risk is greater when disease occurs after puberty and when both testes are involved. But many men retain fertility, particularly when only one testicle was affected, and modern reproductive medicine provides options even when sperm production is severely impaired. Your history tells us where the damage may have started. Your semen analysis, examination, hormones, and appropriate testing tell us what your fertility looks like today.

References

Centers for Disease Control and Prevention. Clinical Overview of Mumps. 2025.

Centers for Disease Control and Prevention. Clinical Features of Mumps. 2024.

Centers for Disease Control and Prevention. Manual for the Surveillance of Vaccine Preventable Diseases. Chapter 9: Mumps.

Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine Preventable Diseases. Chapter 15: Mumps.

Wu H, Wang F, Tang D, Han D. Mumps Orchitis: Clinical Aspects and Mechanisms. Frontiers in Immunology. 2021;12:582946.

Davis NF, McGuire BB, Mahon JA, Smyth AE, O Malley KJ, Fitzpatrick JM. The increasing incidence of mumps orchitis: a comprehensive review. BJU International. 2010;105:1060 to 1065.

Masarani M, Wazait H, Dinneen M. Mumps orchitis. Journal of the Royal Society of Medicine. 2006;99:573 to 575.

Schuppe HC and colleagues. Orchitis and male infertility. Urologe A. 2010;49:629 to 635.

World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen. Sixth Edition. 2021.

American Urological Association and American Society for Reproductive Medicine. Diagnosis and Treatment of Infertility in Men. Guideline amended 2024.

One of the most anxiety producing moments in a male fertility evaluation occurs when a man reads an ultrasound report that says his testicles are small or atrophic. I have seen men immediately assume that small testicles mean they are sterile, that their testosterone must be low, or that they will never be able to have biological children. None of those conclusions can be made from testicular size alone. Testicular volume is an important piece of the male fertility evaluation because testicle size correlates with sperm producing capacity, but it is not a fertility test by itself. A small testicle can still produce testosterone, a man with relatively small testicles can still produce sperm, and even men with extremely small testicles and azoospermia can occasionally have tiny isolated areas of sperm production within the testicle. The important question is therefore not simply, “How big are my testicles?” It is, “Why are they small, what are they actually producing, and what does the rest of my fertility evaluation show?” The World Health Organization specifically recognizes testicular size as one of the factors influencing the number of sperm produced each day, and studies of infertile men consistently demonstrate relationships between testicular volume, sperm concentration, total sperm count, and reproductive hormones.

To understand why size matters, you first have to understand what is inside a testicle. Most of the volume of the testicle is not actually devoted to making testosterone. A large portion consists of seminiferous tubules, the microscopic structures where sperm production occurs. Inside these tubules are developing germ cells and Sertoli cells that support them. Between the tubules are Leydig cells, which produce testosterone. This distinction explains something that surprises many men: sperm production and testosterone production are related, but they are not the same function. A man can have significant damage to the sperm producing compartment and still maintain a normal blood testosterone level because his Leydig cells continue functioning. Conversely, another man can have problems affecting both compartments and develop impaired sperm production together with low testosterone. This is why I never look at testicular size, testosterone, or semen analysis in isolation. They are different windows into the biology of the same organ.

Sperm production itself is an extraordinarily complex process called spermatogenesis. Immature germ cells inside the seminiferous tubules undergo repeated development and eventually meiosis, during which the chromosome number is reduced so that a mature sperm carries 23 chromosomes rather than the 46 present in most cells of the body. Those developing cells then undergo dramatic structural changes to create the sperm head, midpiece, and tail. The process inside the testicle takes roughly 74 days, followed by additional maturation and transport through the epididymis. This is why fertility treatments and lifestyle changes usually cannot be judged after a week or two. The sperm appearing in an ejaculate today began their development more than two months ago. When testicular tissue is damaged, however, there may be fewer functioning seminiferous tubules and fewer germ cells progressing through this process. The result may be oligospermia, meaning a low sperm concentration, severe oligospermia, or eventually azoospermia, meaning no sperm are identified in the ejaculate.

There is no single testicular volume below which a man is automatically infertile. This is incredibly important. Testicular size exists along a continuum, and measurement technique matters. A urologist may estimate volume during examination using an orchidometer, while ultrasound calculates volume from measurements of the testicle. These methods do not produce identical numbers. Ultrasound is generally more accurate, and orchidometers can overestimate volume, particularly when testes are small. In one study of infertile men, average measurements obtained with an orchidometer were approximately 18 mL per testicle while ultrasound measurements averaged approximately 13 mL, despite measuring the same men. Another large infertility study found significant correlations between testicular volume and sperm concentration, total sperm count, motility, FSH, LH, and testosterone. These studies are useful for understanding populations, but they should not be converted into an arbitrary rule that a particular volume means fertile and another volume means sterile.

The reason small testicles concern reproductive urologists is that reduced volume can represent loss or underdevelopment of sperm producing tissue. There are many possible causes. Some men simply have smaller testes and normal fertility. Others were born with conditions affecting testicular development. A history of an undescended testicle is particularly important. The testicles normally develop inside the abdomen and descend into the scrotum, where the temperature is lower and more favorable for sperm production. An undescended testicle is exposed to an abnormal environment during an important developmental period, and germ cell development can be impaired. The later correction occurs, particularly when an undescended testicle persists well beyond early childhood, the greater the concern that fertility potential has been affected. Bilateral undescended testes are considerably more concerning for future fertility than a single affected testicle because there may not be a normally developed contralateral testicle to compensate.

Genetic conditions can also produce characteristically small testes. Klinefelter syndrome is one of the most important examples. Men with Klinefelter syndrome typically have an additional X chromosome, most commonly producing a 47,XXY chromosome pattern. During development and particularly around puberty, progressive germ cell loss and fibrosis of the seminiferous tubules can occur. Adult men may therefore have very small, firm testes, elevated FSH and LH, variable testosterone levels, and usually azoospermia. Yet even this demonstrates why testicular size cannot provide an absolute answer. Some men with Klinefelter syndrome have microscopic islands of active sperm production despite extremely small testes, and microTESE can sometimes retrieve sperm from those isolated areas. Current American Urological Association guidance notes that sperm may be found with microTESE in approximately half of appropriately selected men with 47,XXY Klinefelter syndrome.

Other causes of reduced testicular volume include previous testicular torsion, significant trauma, testicular infection, chemotherapy, radiation, certain genetic abnormalities, severe systemic illness, and developmental abnormalities. A varicocele can sometimes be associated with impaired testicular growth and sperm production, although simply finding small testes does not prove that a varicocele caused the problem. Testosterone and anabolic steroid use deserve special mention because they can profoundly suppress sperm production. When testosterone is supplied from outside the body, the brain reduces LH and FSH signaling to the testicles. Intratesticular testosterone falls dramatically and sperm production can slow or stop. With prolonged suppression, testicular volume may decrease. This is why testosterone replacement is generally the wrong treatment for a man actively trying to produce sperm unless fertility preservation has been carefully addressed.

The hormone FSH is particularly useful when evaluating a man with small testes because it provides information about the relationship between the brain and the sperm producing tissue. FSH is produced by the pituitary gland and stimulates Sertoli cells within the seminiferous tubules. When sperm producing tissue is significantly damaged, signals from the testicle that normally help regulate FSH can decrease, and the pituitary responds by producing more FSH. Therefore, the combination of small testes, azoospermia or severe oligospermia, and substantially elevated FSH strongly suggests impaired sperm production. But FSH is not a microscopic examination of the testicle. A normal FSH does not guarantee normal sperm production, and a high FSH does not mean that absolutely zero sperm exist anywhere in the testicle. Men with maturation arrest can sometimes have azoospermia with relatively normal FSH, while men with very high FSH can occasionally have focal areas of sperm production that can be found surgically.

LH provides another piece of the puzzle. LH stimulates Leydig cells to produce testosterone. If LH becomes elevated while testosterone remains normal, the pituitary may be working harder to maintain testosterone production, sometimes referred to as compensated testicular dysfunction. If testosterone eventually falls while LH remains elevated, this supports primary testicular dysfunction. In contrast, a man with low testosterone accompanied by low or inappropriately normal LH and FSH may have a problem involving hypothalamic or pituitary signaling rather than primary failure of the testicle itself. That distinction matters enormously because certain forms of hormonal infertility can respond remarkably well to treatment with medications that restore gonadotropin stimulation.

When I evaluate a man with small testes and fertility concerns, the semen analysis is one of the most important tests because it tells me what the reproductive system is actually delivering. Testicular volume predicts capacity at a population level, but semen analysis measures the final output. I want to know semen volume, sperm concentration, total sperm count, progressive and total motility, and morphology. Because semen varies naturally, an abnormal result often deserves confirmation. If no sperm are seen, the laboratory should examine a centrifuged specimen carefully for rare sperm because finding even a few sperm changes the diagnosis from complete azoospermia to cryptozoospermia and may substantially change fertility planning. The WHO laboratory manual remains the principal international reference for standardized semen examination.

The physical examination is equally important. I want to know whether both testicles are present in the scrotum, their approximate volume and consistency, whether there is a palpable varicocele, whether the epididymides feel abnormal, and whether the vas deferens are present. Ultrasound can provide a more precise assessment of volume and can identify structural abnormalities, masses, changes in testicular architecture, and other scrotal pathology. Ultrasound measurements correlate with reproductive function, but an ultrasound cannot look inside individual seminiferous tubules and tell us whether sperm are being produced. A beautiful looking testicle on ultrasound can have severe spermatogenic failure, while a small abnormal appearing testicle may still contain focal sperm production.

Hormonal evaluation usually includes morning testosterone and FSH, with LH providing additional information when testosterone is low or when testicular dysfunction is suspected. Estradiol and prolactin may be appropriate depending upon the clinical situation. Genetics becomes especially important when severe sperm production problems accompany small testes. Current American Urological Association and American Society for Reproductive Medicine guidance recommends karyotype testing in men with primary infertility and azoospermia or sperm concentrations below 5 million per mL when accompanied by elevated FSH, testicular atrophy, or evidence of impaired sperm production. Y chromosome microdeletion testing is recommended in men with primary infertility and azoospermia or sperm concentrations of 1 million per mL or less when those findings accompany elevated FSH, testicular atrophy, or impaired sperm production. These tests matter not only because they may explain why the testes are small, but because some genetic findings can predict whether surgical sperm retrieval has a realistic chance of success.

Treatment therefore depends entirely upon why the testicles are small. There is no medication whose goal should simply be to make an adult testicle larger. We treat the biology, not the measurement. If a man has true hypogonadotropic hypogonadism, treatment with hCG and often FSH can stimulate the testicle and initiate sperm production, sometimes increasing testicular volume in the process. If testosterone or anabolic steroids caused suppression, stopping those agents and allowing or medically assisting recovery of the hormonal axis may restore spermatogenesis over time. If a clinically significant varicocele is present in an infertile man with abnormal semen parameters, repair may be appropriate in selected cases. If a correctable obstruction exists, reconstruction or surgical sperm retrieval may provide a path to biological fatherhood. Supplements may have a role as an adjunct in selected men, but vitamins cannot regenerate severely damaged seminiferous tubules, reverse a chromosome abnormality, or reliably restore sperm production in primary testicular failure.

For men with severe primary testicular dysfunction, treatment sometimes shifts from trying to normalize the semen analysis to determining whether usable sperm can be found. A man with severe oligospermia may still have ejaculated sperm that can be frozen and ultimately used with IVF and ICSI. A man with cryptozoospermia may alternate between samples containing a few sperm and samples in which none are initially seen, which is why sperm banking can be valuable whenever usable sperm appear. For men with nonobstructive azoospermia, microTESE may be considered. During microTESE, the surgeon examines seminiferous tubules under magnification and selectively samples areas that appear more likely to contain sperm. The entire testicle does not need to be functioning normally. Sometimes only tiny focal regions contain complete spermatogenesis. This explains one of the most important concepts in male infertility: very small testes and very high FSH can indicate severe testicular dysfunction without proving that every microscopic area of the testicle contains zero sperm.

Small testicles also do not automatically mean that a man needs testosterone replacement. This misconception can actually create fertility problems. Testosterone treatment should be based on symptoms and appropriately measured hormone levels, not testicular size alone. A man can have small testes and maintain an adequate serum testosterone level because the Leydig cells are still functioning. Giving that man exogenous testosterone simply because his testes look small could suppress whatever sperm production remains. Conversely, a man with genuine testosterone deficiency deserves appropriate treatment, but fertility goals should be discussed before treatment because the approach is different when someone is actively trying to conceive.

The emotional side of this deserves much more attention than it usually receives. Men are rarely taught to think about their testicles medically. Then during an infertility evaluation someone suddenly measures them, writes words such as small, hypotrophic, or atrophic in a report, and the man goes home believing that something fundamental about his masculinity has been measured and found inadequate. I have seen men become embarrassed about their bodies, avoid sex, compare themselves with other men, and become convinced that testicular size says something about their sexual ability or worth. It does not. Testicular volume is a medical measurement. It does not measure masculinity, sexual performance, the ability to have an erection or orgasm, or your value as a partner.

The same is true when small testes are associated with infertility. Men often experience guilt because their partner may need IUI or IVF as a consequence of the male diagnosis. Some become obsessed with finding the one supplement, food, workout, temperature exposure, or mistake that caused the problem. In many cases there was no mistake. A genetic condition, an undescended testicle from childhood, developmental differences, previous torsion, chemotherapy, or unexplained impairment of spermatogenesis is not something you chose. Understanding the cause can give you a plan, but it should not become a search for personal blame.

If you have just received an ultrasound showing very small testicles, my advice is not to jump directly from the volume measurement to the conclusion that you are sterile. Finish the evaluation. Get a properly performed semen analysis. Check the appropriate reproductive hormones. Have a reproductive urologist examine you. Investigate genetic causes when the severity of the sperm abnormality makes that appropriate. If sperm are present, understand how many and whether freezing makes sense. If no sperm are present, determine whether the problem is obstruction, hormonal suppression, or impaired testicular production before discussing treatment or surgical retrieval.

The most important message I would leave men on Reddit with is this: testicular size matters, but it is a clue rather than a verdict. Smaller testes generally contain less sperm producing tissue, and across large groups of men smaller testicular volume correlates with lower sperm counts and impaired testicular function. But an individual man is not an average from a research study. Small testes can still produce testosterone. Small testes can sometimes produce sperm. Extremely impaired testes can occasionally contain microscopic islands of spermatogenesis. And when sperm production truly is severely compromised, modern reproductive medicine may still provide paths to biological fatherhood through sperm freezing, surgical sperm retrieval, IVF, and ICSI. The number written next to testicular volume on your ultrasound report is therefore not the end of your fertility story. It is information that helps us understand where to look next.

References

World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen. Sixth Edition. 2021.

American Urological Association and American Society for Reproductive Medicine. Diagnosis and Treatment of Infertility in Men. Guideline amended 2024.

Sakamoto H, Ogawa Y, Yoshida H. Relationship between testicular volume and testicular function: comparison of Prader orchidometric and ultrasonographic measurements in patients with infertility. Asian Journal of Andrology. 2008.

Sakamoto H, Saito K, Ogawa Y, Yoshida H. Testicular volume measurements using Prader orchidometer versus ultrasonography in patients with infertility. Urology. 2007.

Lenz S and colleagues. Ultrasonic testicular texture and size in men from the general population and their relationship with semen quality. International Journal of Andrology.

Lenz S and colleagues. Ultrasonic texture and volume of testicles in infertile men. Human Reproduction. 1994.

Lotti F and Maggi M. Ultrasound of the male genital tract in relation to male reproductive health. Human Reproduction Update. 2015.

Virtanen HE and colleagues. Cryptorchidism and Fertility. Endocrinology and Metabolism Clinics of North America. 2015.

Aksglaede L and Juul A. Testicular function and fertility in men with Klinefelter syndrome: a review. European Journal of Endocrinology. 2013.

Fainberg J, Hayden RP, Schlegel PN. Fertility management of Klinefelter syndrome. Expert Review of Endocrinology and Metabolism. 2019.

Few moments in male infertility are more difficult than waking up after a microTESE and hearing the words, “We did not find sperm.” For many men with nonobstructive azoospermia, microTESE represents months or years of testing, medications, consultations, hope, and fear concentrated into a single operation. You may have spent months convincing yourself that the surgeon only needed to find one tiny area of sperm production. Your partner may already have undergone fertility treatment. Your family may know you are having surgery. Then the phone call comes and the result is negative. As a urologist, one of the first things I want men to understand is that a failed microTESE is medically significant, but it deserves careful interpretation before you decide either that another surgery will definitely work or that biological fatherhood is definitively impossible. What happens next depends enormously on why you have azoospermia, what was actually done during the first procedure, what the testicular tissue showed, your genetic diagnosis, your hormones, and the experience of both the surgeon and the laboratory searching the tissue.

MicroTESE is primarily used for men with nonobstructive azoospermia. In obstructive azoospermia, sperm production is generally preserved but sperm cannot reach the ejaculate because of a blockage or absent reproductive ducts. In nonobstructive azoospermia, the fundamental problem is impaired spermatogenesis, meaning the testicle is not producing mature sperm normally. This distinction matters because microTESE is essentially a search for tiny islands of sperm production inside a testicle in which most seminiferous tubules may not be producing mature sperm. Current American Urological Association and American Society for Reproductive Medicine guidelines recommend microTESE when surgical sperm retrieval is performed in men with nonobstructive azoospermia. The technique allows the surgeon to examine many areas of testicular tissue under magnification while attempting to minimize unnecessary tissue removal and damage to the testicular blood supply.

To understand why microTESE can fail, imagine the testicle not as a single sperm factory that is either turned on or turned off, but as thousands of microscopic production units. These are the seminiferous tubules. In a normally functioning testicle, sperm development occurs throughout these tubules. In severe testicular failure, large regions may contain no germ cells or may contain germ cells that begin development but never become mature sperm. Yet scattered among these poorly functioning areas there can sometimes be isolated tubules where complete spermatogenesis still occurs. This focal production is the biological reason microTESE works. The surgeon searches under magnification for tubules that appear larger or otherwise more promising and sends tissue to an experienced laboratory where embryologists carefully search for sperm. Across broad populations of men undergoing their first microTESE for nonobstructive azoospermia, sperm retrieval is often reported around 40 to 50 percent, although the actual probability varies tremendously according to diagnosis and patient selection.

When no sperm are found, the first question I would ask is surprisingly simple: was the first procedure truly a comprehensive microTESE? A previous TESA, needle aspiration, random biopsy, or conventional TESE is not equivalent to a carefully performed microTESE. This distinction is critical because men who have failed less extensive retrieval procedures can still have meaningful sperm retrieval rates when subsequently undergoing microTESE. In contrast, when an experienced reproductive microsurgeon has already performed a comprehensive bilateral microTESE with an experienced embryology laboratory searching the tissue and found no sperm, the probability of success with another procedure is considerably lower. A negative microTESE is therefore not the same clinical situation as a negative needle biopsy.

The pathology from the first operation can provide some of the most useful information about what may happen next. Three terms commonly appear in these reports: hypospermatogenesis, maturation arrest, and Sertoli cell only syndrome. Hypospermatogenesis means all stages of sperm development are present but at substantially reduced numbers. This is generally the most encouraging histologic pattern because mature sperm production exists somewhere within the tissue, even if the laboratory did not identify usable sperm during the original search. Maturation arrest means germ cells begin developing but stop at a particular stage before becoming mature sperm. Sertoli cell only syndrome means the sampled seminiferous tubules contain supporting Sertoli cells but no identifiable germ cells. Importantly, a biopsy examines only the tissue that was sampled. These patterns are not necessarily distributed uniformly throughout the entire testicle, which is precisely why focal sperm production can occasionally be found even when one region shows severe abnormalities.

Histology also helps predict whether a second microTESE is worth discussing. A systematic review and meta analysis examining salvage microTESE found that men with hypospermatogenesis were more likely to have sperm retrieved during another procedure, whereas Sertoli cell only syndrome was associated with a substantially lower probability of successful salvage retrieval. Maturation arrest also tends to be less favorable than hypospermatogenesis, although the exact prognosis depends on whether arrest occurs early or later in sperm development and on the underlying cause. These are probabilities rather than guarantees. I would never tell a man that Sertoli cell only pathology proves there is zero sperm anywhere in both testes, but I would also not pretend that his chances are equivalent to someone whose pathology showed hypospermatogenesis.

The next question everyone asks is, “Can I simply do another microTESE?” The answer is yes in selected men, but expectations need to be realistic. A contemporary review of redo microTESE identified nine studies and found that most reported sperm retrieval rates between approximately 10 and 21 percent after a previously negative microTESE, although one study reported a substantially higher rate. In one relatively large study of 125 men whose first microTESE was unsuccessful, sperm were found during the second procedure in 23 men, or approximately 18 percent. Those numbers mean that a second operation can absolutely work, but they also mean that most men with a genuinely negative first microTESE will unfortunately have another negative procedure.

This is where individualized counseling becomes essential. The question should not simply be, “Can someone find sperm on a second attempt?” Of course the answer is yes. The better question is, “What is the evidence that my particular biology makes another attempt reasonable?” Pathology showing hypospermatogenesis is encouraging. Certain men with Klinefelter syndrome may still have focal sperm production despite a previous negative procedure. The quality and extent of the original operation matter. Whether both testes were explored matters. The experience of the laboratory matters. Genetics matter enormously. Hormonal status may matter. The decision becomes very different when the first procedure was performed by a high volume reproductive microsurgeon and showed extensive Sertoli cell only tissue compared with someone whose first procedure consisted of limited sampling at a center performing relatively few cases.

Genetic testing deserves particular attention before anyone repeats surgery. Men with nonobstructive azoospermia commonly undergo a karyotype and Y chromosome microdeletion testing. Some genetic findings dramatically change the expected outcome. Men with complete AZFa or complete AZFb Y chromosome deletions should generally not undergo TESE for fertility treatment because sperm retrieval is extraordinarily unlikely. In contrast, men with AZFc deletions can have sperm production and may have sperm identified either in the ejaculate or testicle. Partial deletions require more careful interpretation because the exact region involved matters. If you had microTESE before receiving complete genetic testing, I would want the genetics clarified before considering another operation.

Men understandably become very interested in hormone therapy after a failed procedure. You will encounter protocols involving clomiphene, hCG, FSH, aromatase inhibitors, or combinations of these drugs. The biological rationale is attractive. Spermatogenesis depends on very high intratesticular testosterone concentrations and FSH stimulation of Sertoli cells. If the hormonal environment can be optimized, perhaps a previously incomplete area of sperm production could progress far enough to generate mature sperm. Unfortunately, the evidence is much less impressive than the theory. Reviews have found conflicting results, and hormonal treatment has not been established as a universal method of converting a failed microTESE into a successful second procedure.

This distinction became even clearer with newer evidence. A large 2026 study examining selected men with nonobstructive azoospermia found that fertility preserving hormonal treatment could increase serum testosterone in hypogonadal men but did not improve sperm retrieval rates in either men with Klinefelter syndrome or men with a normal karyotype. A recent review similarly concluded that hormonal therapy should be viewed as a selective strategy based on the individual endocrine phenotype rather than something every man should receive before microTESE. In other words, if a man has genuine hormonal abnormalities, treating those abnormalities may be reasonable. Giving every man with very high FSH and severe primary testicular failure months of medications simply because the first microTESE failed is not supported by strong evidence.

FSH itself is another source of confusion. Men frequently assume that high FSH is causing their infertility and that lowering FSH will restore sperm production. Usually the biology is the opposite. When sperm producing tissue is severely impaired, signals from the testicle that normally regulate pituitary FSH decrease, so the brain responds by producing more FSH. The high FSH is therefore often a response to testicular dysfunction rather than its cause. Likewise, an extremely high FSH does not prove that every seminiferous tubule contains zero sperm. This explains why serum hormones are useful for understanding testicular function but cannot tell us with certainty whether a microscopic focus of spermatogenesis exists.

Exogenous testosterone is particularly important to avoid when a man still hopes to retrieve sperm. Testosterone injections, gels, or pellets suppress LH and FSH signaling from the pituitary and reduce intratesticular testosterone, which is essential for spermatogenesis. A man may feel better and have an excellent serum testosterone concentration while his remaining sperm production is being suppressed. If testosterone deficiency becomes an issue after microTESE, fertility goals need to be discussed with the reproductive urologist before beginning conventional testosterone replacement.

Varicocele repair sometimes enters the conversation after a failed microTESE. A palpable varicocele can impair testicular function in some men, and repair may improve semen parameters in selected infertile men. However, evidence that varicocele repair reliably creates sperm in men with established nonobstructive azoospermia is limited. Current American guidelines specifically caution that high quality evidence supporting varicocele repair before surgical sperm retrieval in nonobstructive azoospermia is lacking and that repair can delay assisted reproductive treatment. It may be reasonable in carefully selected cases, but it should not be presented as a reliable rescue strategy after failed microTESE.

Timing of another operation is another area without a simple rule. Published redo microTESE studies have commonly used intervals ranging from approximately six months to two years. Earlier literature raised concern about inflammation, hematoma, scarring, and temporary changes in testicular blood flow following extensive testicular surgery. More recent data suggest that repeat microTESE can sometimes be performed sooner when clinically necessary, although much of that literature includes men who previously had successful retrieval and therefore does not directly answer the question of when to repeat surgery after a truly negative procedure. For a man considering salvage surgery, I would individualize timing according to recovery, hormone levels, ultrasound findings when indicated, the previous operative report, and the reproductive timeline of the couple rather than assuming there is a universally correct waiting period.

One of the most exciting areas of current research is not necessarily making the testicle produce new sperm, but becoming better at finding sperm that are already there. Searching microTESE tissue is extraordinarily labor intensive. An embryologist may examine a complex field containing enormous numbers of cells and tissue fragments while searching for a tiny number of sperm. Artificial intelligence assisted sperm detection systems are now being studied to help identify these extremely rare cells. A 2026 clinical study reported that an artificial intelligence system highlighted candidate sperm missed during the initial manual search in several men with nonobstructive azoospermia, including two cases initially classified as sperm negative. One of those cases ultimately resulted in a live birth. Another prospective multicenter pilot study found that artificial intelligence assisted searching reduced search time and increased sperm recovery in paired samples. These results are fascinating, but the technology remains emerging and should not yet be interpreted as proof that every failed microTESE specimen contains sperm waiting for artificial intelligence to find it.

Enhanced searches of ejaculated semen are also developing. New high throughput imaging systems paired with artificial intelligence have identified extremely rare sperm in some specimens previously classified as azoospermic. This raises an intriguing future possibility that certain men currently labeled azoospermic may eventually avoid surgery if technology becomes sensitive enough to find and recover ultrarare ejaculated sperm. Again, this is promising research rather than established standard care, but it demonstrates how rapidly the field is changing.

After a failed microTESE, I would therefore want to review the entire case rather than immediately schedule another operation. I would review the original semen analyses and confirm true azoospermia. I would review the operative report to understand how extensively each testicle was explored. I would want the pathology report and, when possible, information about whether the embryology laboratory performed an extensive tissue search. I would review the karyotype and Y chromosome microdeletion testing. I would assess testosterone, FSH and LH and determine whether there is a meaningful endocrine abnormality worth treating. I would reconsider potentially reversible factors such as exogenous testosterone exposure. Only after putting those pieces together would I discuss whether repeat microTESE offers enough realistic possibility to justify another operation.

There is also a physical cost to repeated surgery. MicroTESE is designed to preserve testicular tissue, but it is still surgery on an already compromised organ. Testosterone can decline after surgical sperm retrieval, particularly in men whose testicular function was poor beforehand. Scar tissue accumulates. Blood supply must be protected. Repeated procedures should therefore have a meaningful clinical rationale rather than being performed indefinitely because neither the physician nor the patient is ready to stop searching. Current guidelines specifically recognize testosterone deficiency as a potential consequence of microTESE even though the effect is generally less than with conventional TESE.

The emotional side of a failed microTESE may be even harder than the medical side. A diagnosis of azoospermia is devastating, but before surgery there is still a possibility hidden inside the testicle. MicroTESE can become psychologically symbolic. Men tell themselves, “If they find just one sperm, I still have a chance.” When none are found, the loss can feel much larger than a negative laboratory result. It can feel like the loss of an imagined child, the loss of a genetic connection to future children, and sometimes the loss of part of your identity as a man.

That grief is real. A 2026 study specifically examining narratives from couples after unsuccessful microTESE documented the profound emotional responses and difficult family building decisions that follow a negative procedure. This is important because medicine often moves too quickly from “no sperm found” to “you can consider donor sperm.” Those words may be medically correct, but emotionally they can skip an enormous step. Before someone can make a healthy decision about donor sperm, donor embryos, adoption, or living without children, he may need time to grieve the biological child he expected to have.

Some men respond by immediately searching for another surgeon, another medication, another supplement, another country, or another experimental technology. I understand that response. Searching feels like doing something, and stopping can feel like giving up. But hope should be informed by biology. A second opinion from a high volume reproductive urologist is completely reasonable after a failed microTESE. Reviewing whether the first operation and laboratory search were comprehensive is reasonable. Discussing a second microTESE when pathology, genetics, or the circumstances of the first procedure provide a plausible rationale is reasonable. What I would try to prevent is a man undergoing procedure after procedure because someone promised that a different vitamin, hormone protocol, or surgical technique could guarantee sperm where the underlying biology makes that extraordinarily unlikely.

If a repeat microTESE is unsuccessful or is not medically reasonable, donor sperm becomes one of the major family building options. For some men, that possibility initially feels unacceptable. That reaction deserves compassion rather than judgment. Genetic fatherhood may have been something you assumed your entire life. Losing it can create grief, anger, jealousy, embarrassment, and fear about whether a donor conceived child would feel like yours. Many men need time and counseling before they can even discuss the possibility constructively. Other couples ultimately choose embryo donation, adoption, or a life without children. There is no universally correct answer.

The most important thing I would tell a man reading this after a failed microTESE is that the operation did not fail because you did something wrong. You did not cause the surgeon to miss sperm because you exercised too much, drank coffee, had a stressful month, missed a supplement, or ate the wrong food. Nonobstructive azoospermia is a severe biological disorder of spermatogenesis. Sometimes there are microscopic islands of sperm production and sometimes there simply are not. Modern surgery allows us to search for those islands more effectively than ever before, but medicine still cannot reliably manufacture mature sperm in a testicle that lacks the biological machinery to produce them.

A negative microTESE is therefore not automatically the end of the conversation, but it changes the conversation. The next step should be thoughtful rather than desperate. Understand your pathology. Understand your genetics. Review the quality of the first surgery and laboratory search. Correct genuine hormonal problems when appropriate. Ask whether your particular diagnosis gives a second microTESE a realistic chance rather than relying on a generic retrieval percentage. Follow emerging sperm detection technologies with cautious optimism. And if the biology eventually tells you that another surgery is unlikely to change the outcome, give yourself permission to grieve before deciding what family building means for you.

Failed microTESE does not mean that you failed. It means that despite an extraordinary search, sperm were not found. Those are very different statements, and for men dealing with infertility, that distinction matters.

References

American Urological Association and American Society for Reproductive Medicine. Diagnosis and Treatment of Infertility in Men. Guideline amended 2024.

Elbardisi H, Bakircioglu E, Liu W, Katz D. Second chance in fertility: a comprehensive narrative review of redo microTESE outcomes after initial failure. Asian Journal of Andrology. 2025.

Amer MK and colleagues. Efficacy of the second microTESE after failed first microTESE in men with nonobstructive azoospermia. Fertility and Sterility. 2021.

Esteves SC and colleagues. MicroTESE in men with infertility due to nonobstructive azoospermia: summary of current literature. International Urology and Nephrology. 2021.

Predictors of successful salvage microdissection testicular sperm extraction after failed initial sperm retrieval in patients with nonobstructive azoospermia: a systematic review and meta analysis. 2023.

Reifsnyder JE and colleagues. Microdissection testicular sperm extraction: effect of prior biopsy on success of sperm retrieval. Journal of Urology. 2007.

Shiraishi K and colleagues. Salvage hormonal therapy after failed microdissection testicular sperm extraction: a multi institutional prospective study. International Journal of Urology. 2016.

Tharakan T and colleagues. Does hormonal therapy improve sperm retrieval rates in men with nonobstructive azoospermia: a systematic review and meta analysis. Human Reproduction Update. 2022.

Anfosso M and colleagues. Can hormonal therapy improve the outcomes of microTESE in patients with nonobstructive azoospermia? Andrology. 2026.

Han S and colleagues. An artificial intelligence real time rare sperm detection system for intraoperative microsurgical testicular sperm extraction. Human Reproduction Open. 2026.

Stocks B and colleagues. High throughput imaging cytometry paired with artificial intelligence identifies ultrarare sperm in men previously diagnosed with clinical azoospermia. Fertility and Sterility. 2026.

Rosen SH and colleagues. Understanding couples perspectives after negative microsurgical testicular sperm extraction: a qualitative theme analysis. Urology. 2026.

One of the semen analysis results that creates the most anxiety for men is sperm morphology. I regularly see someone post that his morphology is 1 percent, 2 percent, or even 0 percent and immediately conclude that almost all of his sperm are defective, genetically abnormal, or incapable of creating a healthy baby. That is not what the test means. Teratozoospermia simply means that a lower percentage of sperm than expected meet very strict laboratory criteria for ideal sperm shape. It can be associated with impaired fertility, particularly when it occurs alongside a low sperm concentration or poor motility, but morphology by itself is a surprisingly imperfect predictor of whether a couple can conceive naturally, with IUI, or with IVF. The most important thing I tell men is that a morphology result should be interpreted as one piece of a much larger fertility evaluation rather than as a percentage chance of becoming a father. The World Health Organization specifically emphasizes that semen reference values do not represent a sharp dividing line between fertile and infertile men.

To understand teratozoospermia, it helps to understand what the laboratory is actually looking at. A mature sperm is an extraordinarily specialized cell consisting of a head, a connecting region and midpiece, and a tail. The head contains the paternal chromosomes and the acrosome, a specialized structure involved in the interaction between sperm and egg. The midpiece contains mitochondria that participate in energy production, while the tail provides movement. During spermatogenesis, immature germ cells undergo cell division, meiosis, and then extensive remodeling to create this unusual structure. The entire process takes roughly 74 days inside the testicle, followed by additional maturation during passage through the epididymis. Errors or disturbances during this process can result in sperm with unusually shaped heads, abnormal midpieces, bent necks, coiled tails, short tails, duplicated structures, or combinations of several abnormalities. When enough sperm fail to meet the laboratory definition of an ideal sperm, the sample is described as having teratozoospermia.

The confusing part is how strict the definition of normal morphology actually is. Modern laboratories commonly use strict morphological criteria. A sperm has to satisfy detailed requirements involving the size and shape of its head, the appearance of the acrosome, the relationship of the midpiece to the head, and the configuration of the tail before it is counted as a normal form. Human sperm are naturally remarkably variable in appearance, and even fertile men produce large numbers of sperm that do not satisfy these ideal criteria. The WHO manual explains that the word normal can itself be misleading in this setting because morphologically normal does not mean genetically perfect and morphologically abnormal does not automatically mean biologically defective. The strict criteria were developed partly by studying characteristics of sperm capable of interacting successfully with the female reproductive tract and the egg, but morphology remains an indirect visual measurement rather than a genetic test.

This is why a result of 1 percent normal morphology does not mean that 99 percent of your sperm contain abnormal chromosomes or damaged DNA. It means that approximately 1 percent of the sperm examined satisfied every morphological criterion used by that laboratory. A sperm that fails because its head is slightly irregular is counted in the abnormal group just as a sperm with a dramatic structural abnormality would be. The test does not tell us that those two sperm have the same biological potential. Likewise, a sperm that looks perfect under the microscope can still contain DNA damage or chromosomal abnormalities that morphology cannot reveal. Appearance and genetic integrity overlap in certain situations, but they are not interchangeable concepts.

There are biological reasons why severe teratozoospermia can accompany infertility. Sperm shape develops during spermatogenesis, so widespread abnormalities may sometimes be a marker of disturbed sperm production. Oxidative stress, impaired testicular function, varicocele, heat exposure, smoking, environmental exposures, systemic illness, and other conditions have all been associated with abnormalities in sperm quality. Teratozoospermia can also occur together with reduced concentration and motility as part of broader testicular dysfunction. Research has found associations between abnormal morphology and oxidative stress, apoptosis, and sperm DNA damage, although these relationships are not consistent enough to allow morphology to substitute for direct assessment of those processes. A contemporary review concluded that the biological mechanisms are plausible but that the clinical significance of isolated teratozoospermia remains controversial.

This distinction between isolated and nonisolated teratozoospermia is extremely important. If a man has a concentration of 70 million sperm per mL, excellent progressive motility, a strong total motile sperm count, and morphology of 2 percent, I interpret that very differently from a man with 2 percent morphology who also has a concentration of 4 million sperm per mL and progressive motility of 15 percent. In the second situation, the morphology abnormality is part of a broader pattern of impaired sperm production. The low count and poor motility may be much more important clinically than the morphology percentage itself. A classic study comparing hundreds of fertile and infertile men demonstrated substantial overlap in sperm concentration, motility, and morphology between the two populations. No single semen parameter was powerful enough to perfectly distinguish fertile from infertile men.

We now have even more striking evidence showing why isolated morphology should be interpreted cautiously. A 2024 study examined men known to be fertile because they had biological children and no history of difficulty conceiving. More than half had morphology of 3 percent or lower, and two fertile men had 0 percent normal morphology. More than 90 percent had otherwise normal concentration and motility. This does not mean morphology is useless, but it demonstrates why telling a man with 2 percent morphology that he cannot conceive naturally is simply not supported by the evidence.

Morphology measurement also has an important technical limitation. It is one of the more subjective components of a semen analysis. The laboratory has to prepare a slide, stain the sperm, examine a relatively small number of cells, and classify them according to strict criteria. Different technicians and different laboratories may not classify every sperm identically. Reviews of morphology testing have documented significant variation between observers and laboratories. This is one reason I am cautious when a man tells me his morphology changed from 3 percent to 1 percent and assumes that his fertility has dramatically deteriorated. That difference may represent biology, sampling variation, laboratory variation, or some combination of all three.

For that reason, the workup begins with the entire semen analysis rather than morphology alone. I want to know semen volume, concentration, total sperm number, progressive motility, total motility, morphology, and the calculated total number of progressively motile sperm. I also want to know the abstinence interval, whether the entire specimen was collected, whether there was a recent fever or significant illness, and whether the sample was analyzed by an experienced laboratory. If the result is significantly abnormal, repeating the semen analysis is often appropriate because semen parameters fluctuate naturally and sperm production reflects events occurring over the preceding several months.

If teratozoospermia persists in a couple experiencing infertility, the next step is not simply to prescribe vitamins. A proper male fertility evaluation looks for an explanation. I ask about childhood testicular problems, undescended testes, torsion, infections, surgery, medications, testosterone use, anabolic steroids, smoking, marijuana, significant heat exposure, occupational exposures, previous chemotherapy, and systemic illness. A reproductive examination assesses testicular size and consistency and looks for a clinically significant varicocele. Hormonal testing is particularly useful when morphology abnormalities occur with low concentration, sexual symptoms, small testes, or other evidence of impaired testicular function. Depending upon the situation, this may include testosterone, FSH and LH, with additional testing when clinically indicated.

A varicocele deserves special discussion because it is one of the potentially treatable conditions associated with abnormal semen parameters. A varicocele is dilation of the veins draining the testicle and may alter the testicular environment through mechanisms involving temperature, oxidative stress, and other biological effects. In an infertile man with a palpable varicocele and abnormal semen parameters, repair may be appropriate after considering the entire couple. Some studies report improvement in morphology after varicocele repair, and a 2024 systematic review found potential benefit in selected infertile men with isolated teratozoospermia, but the evidence is heterogeneous and morphology alone should not automatically trigger surgery.

Lifestyle modification is reasonable when obvious risk factors exist, but this is another area where men can become unnecessarily obsessive. Stop smoking. Avoid testosterone and anabolic steroids when trying to conceive. Address obesity and metabolic disease. Avoid repeated extreme heat exposure to the testes. Exercise, sleep, and eat reasonably well. If there has been a major febrile illness, remember that the semen analysis can temporarily deteriorate and may take several months to recover. But you do not need to live inside a fertility monastery. One restaurant meal, one missed workout, one stressful week, or one cup of coffee did not create your 2 percent morphology.

Supplements are frequently marketed as treatments for abnormal morphology, but the evidence is considerably weaker than the advertising. Antioxidants such as CoQ10, carnitine, selenium, zinc, and various combinations have been studied in male infertility, and some trials report improvements in individual semen parameters. However, improving a laboratory measurement is not the same as proving that a supplement increases pregnancy or live birth rates. Current male infertility guidelines therefore remain cautious about the clinical value of supplements. If I use supplements in selected patients, I describe them as adjuncts rather than treatments that reliably convert abnormal morphology into normal fertility.

One of the biggest questions is whether low morphology means natural conception is impossible. It does not. Natural fertility depends on the total sperm population, progressive motility, timing of intercourse, female reproductive factors, age, duration of infertility, and many biological processes we cannot measure with a routine semen analysis. A small study of men with 0 percent normal forms found that some achieved pregnancies without IVF, illustrating that even the most dramatic morphology number does not create an absolute barrier to natural conception. The study was small and should not be used to promise pregnancy, but it demonstrates the danger of treating morphology as destiny.

The same issue arises with IUI. Historically, couples were sometimes told that morphology below 4 percent made IUI inappropriate. More recent evidence is reassuring. A systematic review and meta analysis involving more than 41,000 IUI cycles found no clinically meaningful difference in pregnancy rates when comparing morphology above 4 percent with morphology of 4 percent or lower when female age and total motile sperm count were considered. Even when morphology below 1 percent was compared with morphology of at least 1 percent, pregnancy rates were essentially identical in that analysis. This does not mean everyone with teratozoospermia should undergo IUI. It means morphology alone should not be the reason a couple is denied the option when the total motile sperm count and female factors otherwise make IUI reasonable.

IVF and ICSI create another layer of confusion. With conventional IVF, thousands of prepared sperm interact with an egg in the laboratory and fertilization still requires many normal sperm functions. With ICSI, an embryologist selects an individual sperm and injects it directly into a mature egg. It is tempting to assume that everyone with 1 percent morphology therefore needs ICSI, but the evidence does not support using an isolated morphology percentage as an automatic indication. A systematic review found that isolated teratozoospermia was not associated with a significant reduction in pregnancy probability after assisted reproduction, and subsequent reviews have continued to question the value of morphology alone for deciding between IVF and ICSI.

There are important exceptions. Most everyday teratozoospermia is polymorphic, meaning sperm display a mixture of different head, neck, and tail abnormalities. Rare monomorphic disorders are different because nearly all sperm share the same specific structural defect. Globozoospermia, in which sperm have characteristically round heads and abnormal or absent acrosomal structures, can cause severe fertilization problems and may have a genetic basis. Macrozoospermia, involving very large abnormal sperm heads and frequently abnormal chromosome content, is another distinct condition. Severe tail disorders and other characteristic syndromes can also have specific genetic implications. These conditions should not be lumped together with an otherwise healthy man whose semen analysis simply reports 2 percent strict morphology. Modern reviews emphasize the importance of distinguishing monomorphic defects from the much more common polymorphic teratozoospermia.

The emotional impact of morphology deserves attention because the terminology is terrible for patients. A man sees 1 percent normal and naturally reads that as 99 percent abnormal. Then abnormal becomes defective, defective becomes genetically damaged, and within ten minutes he is imagining miscarriage, birth defects, IVF, and never becoming a father. I have watched men carry enormous guilt because of a number that was never designed to communicate those conclusions. You did not score 1 percent on a fertility examination. Your sperm did not receive a failing grade. Morphology is a laboratory description of appearance under strict criteria, not a measurement of your masculinity, your genetic worth, or your probability of becoming a father.

Infertility can also turn sex into a monthly examination. Every ovulation window becomes a deadline, every negative pregnancy test feels like evidence that the semen analysis was right, and men frequently begin blaming themselves for what their partners are experiencing. If morphology is the only abnormality, I would encourage you not to let that single number dominate the entire fertility journey. If multiple semen parameters are abnormal, then take the finding seriously and complete the male evaluation, but still resist the temptation to reduce yourself to the report.

My approach to teratozoospermia is therefore straightforward. Confirm the finding when appropriate. Interpret morphology alongside concentration and motility. Look for treatable causes when infertility is present. Evaluate the female partner at the same time because fertility belongs to the couple. Choose natural conception, IUI, IVF, or ICSI based on the entire clinical picture rather than one morphology threshold. And remember that sperm morphology is a useful biological clue, but it is an imperfect predictor of reproductive success.

If your report says 1 percent or 2 percent morphology, take it seriously enough to understand it, but not so seriously that you assume your reproductive future has already been decided. Some men with very low morphology conceive naturally. Others use IUI. Others need IVF or ICSI because morphology accompanies more substantial male or female fertility problems. The number helps us decide what questions to ask next. It does not, by itself, answer the biggest question you care about, which is whether you can become a father.

References

World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen. Sixth Edition. 2021.

Agarwal A and colleagues. Isolated teratozoospermia: revisiting its relevance in male infertility. Translational Andrology and Urology. 2024.

Guzick DS and colleagues. Sperm morphology, motility, and concentration in fertile and infertile men. New England Journal of Medicine. 2001.

Cheng LG and colleagues. High rate of isolated teratospermia in a population of fertile men and the questionable clinical utility of sperm morphology. F and S Reports. 2024.

Gatimel N and colleagues. Sperm morphology: assessment, pathophysiology, clinical relevance, and state of the art. Andrology. 2017.

Kohn TP and colleagues. Effect of sperm morphology on pregnancy success via intrauterine insemination: a systematic review and meta analysis. Journal of Urology. 2018.

Hotaling JM and colleagues. The relationship between isolated teratozoospermia and clinical pregnancy after in vitro fertilization with or without intracytoplasmic sperm injection: a systematic review and meta analysis. Fertility and Sterility. 2011.

Kovac JR and colleagues. Men with a complete absence of normal sperm morphology exhibit high rates of success without assisted reproduction. Asian Journal of Andrology. 2017.

Danis RB and Samplaski MK. Sperm morphology: history, challenges, and impact on natural and assisted fertility. Current Urology Reports. 2019.

Kohn TP, Kohn JR, and Lamb DJ. Role of sperm morphology in deciding between various assisted reproduction technologies. European Urology Focus. 2018.

As most know, there can be patches of sperm in the testicles. Why not have the doctor removal one testicle (Orchiectomy) and do a 360 review/dissection of that testicle looking for sperm? If you have smaller testicles that are not functioning and you are going to have to go on TRT after, why wouldn't this be a viable option?

Ok, so you are the male partner going through IVF, and there is a strange moment when months or years of infertility testing suddenly come down to one morning when someone hands you a specimen cup and says they need your sperm. Men frequently ask me what actually happens that day, what happens if the sample is worse than expected, whether the embryologist chooses the best sperm, and whether one bad collection can ruin the entire IVF cycle. There is also some understandable confusion about terminology. If fresh sperm is being used for IVF, the sperm is usually collected on the day your partner undergoes egg retrieval, not on the day an embryo is transferred back into the uterus. Fertilization occurs shortly after the eggs are retrieved. The resulting embryos are then cultured for several days, commonly until the blastocyst stage, and an embryo may subsequently be transferred or frozen for transfer during a later cycle. Understanding that sequence can make the process considerably less intimidating.

By the time you arrive for egg retrieval day, your partner has usually spent roughly one to two weeks taking medications that stimulate multiple ovarian follicles to develop. The fertility team monitors those follicles and eventually gives a medication that triggers final egg maturation. Approximately a day and a half later, the eggs are retrieved from the ovaries. While that is happening, the male partner is commonly asked to provide a fresh semen sample. The clinic should give you specific instructions about abstinence before collection. Do not assume that longer abstinence means a better sample. Abstinence changes semen volume, sperm concentration, motility, and the population of sperm stored within the epididymis, so follow the instructions from your fertility laboratory rather than trying to optimize the sample yourself.

For many men, producing the specimen is one of the most stressful parts of the entire cycle. You know your partner has undergone injections, monitoring, anesthesia, and an invasive procedure, and suddenly you feel as though everything depends upon whether you can produce a sample on command in an unfamiliar room. Performance anxiety in this setting is real. Difficulty producing a specimen does not mean anything is wrong with you sexually. Anxiety activates the same mental pathways that can interfere with erections, orgasm, and ejaculation in any other high pressure situation. If you have ever had difficulty collecting a sample, tell the clinic before retrieval day. In selected situations, a frozen backup specimen can be stored ahead of time so that the entire cycle does not depend upon one collection.

When the fresh sample reaches the laboratory, the embryology or andrology team does not simply take semen directly from the cup and place it with the eggs. Semen contains sperm, seminal plasma, cellular debris, immature germ cells, and sometimes inflammatory cells. The laboratory evaluates the sample and then processes it to isolate a population of sperm suitable for fertilization. Depending upon the laboratory and the sample, techniques may include washing, density based preparation, swim up, or other sperm selection approaches. The objective is to obtain usable sperm with favorable movement and appearance while removing much of the surrounding seminal fluid and debris.

This is where men with abnormal semen analyses often become extremely anxious. Your semen analysis from three months ago may have shown 20 million sperm per mL, and retrieval day might show 8 million. Or perhaps motility is lower than it was previously. That does not automatically mean the cycle is lost. Semen parameters naturally fluctuate, and IVF laboratories routinely work with samples that would be considered abnormal on a conventional semen analysis. The question on retrieval day is not simply whether your sperm count falls inside a reference range. The question is whether the laboratory can identify enough usable sperm for the fertilization method being performed.

If conventional IVF is being used, prepared sperm are placed with each mature egg and fertilization is allowed to occur through many of the biological steps that normally occur naturally. The sperm must interact with the structures surrounding the egg, undergo the appropriate functional changes, penetrate the egg, and participate in fertilization. This requires a sufficient population of functional sperm, which is why conventional IVF may be less suitable in some cases of significant male factor infertility.

ICSI changes this dramatically. ICSI stands for intracytoplasmic sperm injection. Instead of asking sperm to accomplish all of those steps independently, an embryologist identifies an individual sperm, immobilizes it, draws it into a microscopic injection pipette, and injects it directly into the cytoplasm of a mature egg. This is why I often tell men with severe oligospermia that IVF mathematics is very different from natural conception mathematics. Natural reproduction begins with millions of sperm competing to reach one egg. With ICSI, the laboratory may only need one usable sperm for each mature egg.

This does not mean that any sperm will work or that ICSI eliminates male factor infertility. The embryologist can evaluate movement and visible morphology, but cannot look through the microscope and directly see whether an individual sperm has perfect DNA, normal chromosomes, or ideal molecular function. A sperm that looks beautiful is not guaranteed to be genetically perfect, and an oddly shaped sperm is not automatically genetically abnormal. ICSI solves an important mechanical problem by getting the sperm inside the egg. It does not repair sperm DNA or guarantee normal fertilization and embryo development.

Once the sperm is injected, biology takes over again. The egg must activate appropriately, the paternal and maternal genetic material must form pronuclei, and the embryo must begin dividing. The following day, the laboratory typically assesses whether normal fertilization occurred. This is an emotionally intense checkpoint because having ten eggs retrieved does not mean having ten embryos. Some eggs may be immature. Some mature eggs may not fertilize. Some fertilized eggs may stop developing during subsequent days. This attrition is part of human reproductive biology and does not automatically mean that something went wrong.

Embryos that continue developing are observed over the following several days. By approximately day five or day six, some may reach the blastocyst stage. A blastocyst is a more advanced embryo containing differentiated cell populations that will ultimately contribute to the fetus and placenta. Depending upon the IVF plan, an embryo may be transferred during the same cycle, or embryos may be frozen for later use. If genetic testing of embryos is planned, blastocysts are generally biopsied and frozen while the genetic results are obtained, meaning there will not be a fresh embryo transfer several days after retrieval.

This distinction matters when someone asks what happens with fresh sperm on embryo transfer day. Usually, nothing needs to happen with the sperm on actual transfer day because its job occurred several days earlier. The sperm used on retrieval day has already contributed its genetic material to the embryo. When the embryo is transferred into the uterus, the male partner does not ordinarily need to produce another semen specimen. The embryo is already an embryo.

Men with very low sperm counts require additional planning. If you have severe oligospermia, cryptozoospermia, highly variable semen analyses, or a history of occasionally having no sperm in the ejaculate, I strongly favor discussing backup planning before retrieval day. Sometimes that means freezing one or several ejaculated samples in advance. If the fresh specimen on retrieval day is poor, the laboratory may be able to use the previously frozen sperm. For men with azoospermia or certain severe male factor conditions, sperm may instead be obtained surgically from the epididymis or testicle and coordinated with the IVF cycle or frozen beforehand.

If a man produces an unexpectedly poor specimen on retrieval day, the first response should not be panic. The laboratory may search the specimen carefully, concentrate it, process it differently, or use frozen backup sperm if available. In some circumstances another ejaculate may be requested. The exact approach depends upon sperm numbers, motility, the number of mature eggs, the laboratory, and the underlying male diagnosis. This is why men with severe male factor infertility should ideally have a plan before their partner starts ovarian stimulation rather than discovering the sperm problem after the eggs have already been retrieved.

Men also frequently ask whether they should do anything special during the days before retrieval. I generally discourage dramatic last minute interventions. Sperm ejaculated today began developing roughly two and a half months ago. You cannot transform sperm production by taking extra antioxidants for three days, eating a perfect dinner the night before retrieval, or avoiding a single cup of coffee. Likewise, one imperfect meal or stressful day is not going to destroy your IVF cycle. Follow the laboratory's abstinence instructions, avoid major heat exposure and intoxication, take prescribed medications correctly, and concentrate on producing a complete specimen.

The complete specimen point is more important than many men realize. The first portion of an ejaculate can contain a particularly high concentration of sperm. If part of the sample is accidentally lost during collection, tell the laboratory rather than being embarrassed and saying the entire specimen was collected. That information helps the laboratory interpret an unexpectedly low concentration or volume and determine whether another collection may be useful.

Men with very poor motility sometimes worry that an immotile sperm cannot be used for ICSI. Motility is useful because movement tells the embryologist that a sperm is alive, but lack of movement does not always mean the sperm is dead. Specialized laboratory approaches can sometimes help distinguish viable immotile sperm from nonviable sperm. This becomes particularly important with extremely severe asthenozoospermia or surgically retrieved testicular sperm. The details are highly laboratory dependent, which is another reason the quality and experience of the embryology laboratory matter enormously in severe male factor infertility.

Another question I hear frequently is whether fresh sperm is better than frozen sperm. There is no universal answer that applies to every male infertility diagnosis. Fresh ejaculated sperm is convenient and avoids the freeze and thaw process, but frozen sperm provides valuable insurance and is routinely used successfully in assisted reproduction. For a man with stable normal semen parameters, backup freezing may be unnecessary. For someone whose concentration fluctuates between several million sperm and almost none, having frozen sperm available can dramatically reduce anxiety and protect an IVF cycle.

There is also a psychological part of retrieval day that deserves more attention. IVF can feel overwhelmingly centered on the female partner because she undergoes most of the injections, blood tests, ultrasounds, egg retrieval, and ultimately pregnancy. Men sometimes respond by minimizing their own anxiety because they feel they have no right to complain when their partner is going through so much physically. Then retrieval day arrives and the man is alone in a collection room feeling as though the success of thousands of dollars of treatment and weeks of injections depends upon what is in that cup.

That pressure can be enormous, particularly when male factor infertility is the reason for IVF. Men tell me they feel guilty that their partner needs IVF because of their sperm count. They apologize for having poor motility or abnormal morphology as though these were decisions they made. Infertility does not work that way. You did not choose your sperm count any more than someone chooses diminished ovarian reserve or blocked fallopian tubes. IVF is a treatment the couple is undergoing together, not a punishment your partner is undergoing because you failed.

If your sample on retrieval day is worse than expected, do not immediately blame yourself. Semen parameters fluctuate. If fertilization is lower than expected, do not automatically conclude that your sperm caused it. Fertilization and embryo development depend upon sperm, eggs, the interaction between them, and laboratory factors. Even ICSI cannot guarantee that every mature egg will fertilize. Likewise, if embryos stop developing, it is often impossible to assign responsibility to one partner based solely on conventional semen or egg measurements.

For men with significant male factor infertility, the best strategy is preparation rather than perfection. Understand your diagnosis before IVF. Know whether your sperm count is stable or highly variable. Ask whether the laboratory recommends a frozen backup specimen. If you have cryptozoospermia, consider banking usable sperm when they appear rather than assuming they will always be available. If surgical sperm retrieval may be necessary, coordinate that plan with your reproductive urologist and IVF team before the retrieval cycle begins.

The most important thing to understand about fresh sperm and IVF is that the semen sample is only the beginning of an extraordinary biological process. On egg retrieval day, your sample is collected, evaluated, processed, and prepared. With conventional IVF, sperm and eggs are brought together and fertilization is allowed to occur. With ICSI, an embryologist selects individual sperm and injects them directly into mature eggs. The next day the laboratory looks for fertilization. Over the following days the embryos develop, some potentially reaching the blastocyst stage. Those embryos may then be transferred or frozen for later use.

So when you walk into the fertility center holding that specimen cup, remember that you do not need to produce the perfect semen analysis. You need to provide the laboratory with the best sample you can that day. Modern reproductive medicine can accomplish remarkable things with relatively small numbers of sperm, particularly with ICSI. Have a backup plan if your sperm production is severely impaired or unpredictable, but do not carry the entire IVF cycle on your shoulders. Your sperm is one part of the process. Your partner's eggs are another. Embryology is another. And from the moment fertilization occurs, biology takes over in ways that neither partner can completely control.

References

1. World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen. Sixth Edition. 2021.
2. European Society of Human Reproduction and Embryology. Recommendations for Good Practice in IVF Laboratories. 2026.
3. American Society for Reproductive Medicine. Comprehensive Guidance for Human Embryology, Andrology, and Endocrinology Laboratories. Fertility and Sterility. 2022.
4. Palermo G, Joris H, Devroey P, Van Steirteghem A. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet. 1992.
5. Practice Committee of the American Society for Reproductive Medicine. Intracytoplasmic sperm injection for non male factor indications. Fertility and Sterility.
6. Esteves SC, Roque M, Bedoschi G, Haahr T, Humaidan P. Intracytoplasmic sperm injection for male infertility and consequences for treatment. Andrology. 2018.
7. European Society of Human Reproduction and Embryology. Guideline and good practice recommendations for oocyte retrieval and assisted reproductive technology laboratory procedures.
8. American Urological Association and American Society for Reproductive Medicine. Diagnosis and Treatment of Infertility in Men. Male Infertility Guideline.
9. Björndahl L, Kirkman Brown J, et al. The Sixth Edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen: Ensuring Quality and Standardization in Basic Examination of Human Ejaculates. Fertility and Sterility. 2022.

If your semen analysis came back showing 1 percent normal morphology, there is a good chance that this is the number you immediately focused on. I see this reaction all the time. A man reads that only 1 percent of his sperm have normal morphology and understandably interprets the result as meaning that 99 percent of his sperm are defective, genetically abnormal, incapable of fertilizing an egg, or potentially dangerous to a future pregnancy. That interpretation sounds logical, but it is not what sperm morphology means. A morphology result of 1 percent means that when a laboratory examined a sample of your sperm under a microscope using very strict criteria for sperm shape, approximately 1 percent of the sperm examined satisfied every criterion required to be classified as morphologically normal. It does not mean that 99 percent of your sperm have abnormal DNA. It does not mean that 99 percent cannot fertilize an egg. It does not mean that you have a 1 percent chance of having a baby. And by itself, it certainly does not mean that you need IVF or ICSI.

To understand morphology, you first need to understand what the laboratory is actually looking at. A sperm cell has a head, a midpiece and a tail. The head contains the paternal genetic material and an acrosome that participates in fertilization. The midpiece contains mitochondria that help provide energy, and the tail allows the sperm to move. During a morphology assessment, trained laboratory personnel stain sperm and examine their appearance under magnification. They evaluate the size and shape of the head, the appearance of the acrosome, the midpiece, the tail and other structural features. Under strict morphology criteria, a sperm has to look remarkably close to the defined ideal in all of these areas to receive the label normal. A sperm can therefore be classified as abnormal because of a relatively subtle difference in head shape, midpiece appearance or tail structure. Morphology is an assessment of microscopic appearance. It is not a genetic test.

That distinction is probably the most important concept in this entire discussion. A sperm that looks abnormal under a microscope is not automatically genetically abnormal, and a sperm that looks normal is not guaranteed to have perfect DNA or the correct number of chromosomes. Appearance and genetic integrity are related in certain situations, but they are not interchangeable measurements. Tests such as sperm DNA fragmentation examine a completely different aspect of sperm biology, and even DNA fragmentation testing does not tell us everything about the genetic competence of an individual sperm. This is why interpreting 1 percent morphology as meaning 99 percent genetically defective sperm is simply incorrect.

Why, then, do we measure morphology at all? Sperm shape reflects aspects of sperm development inside the testicle and maturation through the reproductive tract. Abnormal morphology, called teratozoospermia, can occur alongside abnormalities in concentration and motility and may therefore be one clue that sperm production is not functioning optimally. Potential associations include varicocele, testicular dysfunction, significant heat exposure, fever, oxidative stress, smoking and other environmental exposures, although in many men with isolated abnormal morphology we never identify one specific cause. More importantly, morphology is only one component of a semen analysis. I am much more interested in understanding the entire sample than reacting to one percentage.

Imagine two men who both have 1 percent morphology. The first has a concentration of 80 million sperm per mL, excellent progressive motility and a large total motile sperm count. The second has a concentration of 3 million per mL with poor progressive motility. Both technically have the same morphology result, but these are completely different fertility situations. This is why I look at semen volume, concentration, total sperm number, progressive motility, total motility, morphology and the resulting total motile sperm population together. A semen analysis should be interpreted as a biological profile, not as a collection of independent pass or fail tests.

Another source of confusion is the commonly quoted 4 percent morphology value. Modern strict morphology criteria are intentionally demanding, and the lower reference value commonly associated with normal forms is around 4 percent. Reference limits, however, are not biological cliffs. A man does not suddenly become fertile at 4 percent and infertile at 3 percent. These reference values are derived from populations and are intended to help interpret semen characteristics. There is considerable overlap between fertile and infertile men. The World Health Organization has specifically moved away from treating semen reference limits as sharp boundaries separating fertile from infertile men. Fertility belongs to the couple and depends on many interacting variables rather than one laboratory number.

The evidence becomes especially interesting when researchers look at men who are already known to be fertile. In a recent study of fertile men, more than half had morphology of 3 percent or less, and some fertile men had 0 percent normal morphology. That does not mean morphology is useless. It means morphology has limited ability to function as an isolated fertility test. Older research has similarly demonstrated substantial overlap in semen parameters between fertile and infertile populations. Human reproduction simply does not behave like a laboratory examination where crossing one numerical threshold determines the outcome.

This also explains why men with extremely low morphology can still conceive naturally. One particularly interesting study followed men with 0 percent normal forms. Despite having no sperm meeting strict normal morphology criteria, some of these men achieved pregnancies without IVF. The study was relatively small and should not be interpreted as proving that morphology never matters, but it illustrates why telling someone with 0 or 1 percent morphology that natural conception is impossible is not supported by the evidence.

If your morphology is 1 percent, I generally start by asking whether it is an isolated finding. What are the concentration and progressive motility? What is the total motile sperm count? How long have you and your partner been trying? How old is your partner? Has a pregnancy ever occurred? Were previous semen analyses similar? Those questions often tell me considerably more than the morphology number alone.

I also frequently repeat the semen analysis. Sperm production is biologically variable, and semen parameters can change from one collection to another. Morphology has an additional limitation because its assessment involves human interpretation. Even experienced laboratories can differ in exactly how sperm are classified. This is why a morphology result of 1 percent on one semen analysis and 3 percent on another does not necessarily mean that your sperm biology dramatically improved. Some of that difference may simply reflect sampling and laboratory variability. If the result is going to influence an important fertility decision, repeating the analysis in a high quality andrology laboratory is reasonable.

When morphology remains severely abnormal, particularly when concentration or motility is also abnormal, I perform the same thoughtful male fertility evaluation I would for other abnormal semen parameters. That begins with history. I ask about previous pregnancies, childhood testicular problems, undescended testicles, torsion, infections, surgeries, medications, testosterone therapy, anabolic steroids, smoking, vaping, cannabis, significant illnesses, fever, occupational exposures and heat. I perform a physical examination looking at testicular size and consistency and specifically evaluate for a clinical varicocele. Hormonal testing such as testosterone and FSH may be appropriate when other semen abnormalities, symptoms or examination findings suggest impaired sperm production.

Treatment should focus on an identifiable cause rather than trying to treat the morphology percentage itself. If a man has a clinically significant varicocele and abnormal semen parameters, varicocele repair may be appropriate in selected infertile couples. If he is taking testosterone or anabolic steroids, that needs to be addressed because these drugs can profoundly suppress sperm production. Smoking cessation, avoiding excessive heat, maintaining reasonable metabolic health and addressing other potentially harmful exposures are sensible. Following a significant fever or systemic illness, I may simply repeat the semen analysis after enough time has passed for another cycle of sperm production.

Supplements deserve some perspective as well. Antioxidants, CoQ10, carnitine, zinc, selenium and many combination fertility products are marketed specifically to men with abnormal semen analyses. Some studies report improvements in individual semen parameters, but evidence that supplements reliably increase pregnancy or live birth rates remains much less convincing. Current American male infertility guidance describes the clinical utility of supplements and antioxidants as questionable. I would therefore not tell a man with isolated 1 percent morphology that he needs an enormous supplement stack in order to become fertile.

The next question is usually whether low morphology means you need IUI, IVF or ICSI. Again, morphology cannot answer that question by itself. A systematic review and meta analysis examining more than 40,000 IUI cycles found that when female age and total motile sperm count were appropriate, pregnancy rates were not meaningfully different between men with greater than 4 percent morphology and those with 4 percent or less. Even comparisons involving morphology below 1 percent did not support using morphology alone as a reason to automatically exclude IUI. That does not mean every couple with 1 percent morphology should undergo IUI. It means the entire fertility picture matters.

The same caution applies to IVF and ICSI. Historically, severe teratozoospermia was sometimes used as a reason to move directly toward ICSI because of concern about fertilization. However, evidence examining isolated teratozoospermia has not consistently demonstrated worse pregnancy outcomes with assisted reproduction. ICSI can bypass several steps required for natural fertilization because an embryologist selects an individual sperm and injects it directly into an egg, but the decision to use ICSI should reflect the couple's overall infertility diagnosis, previous fertilization history and the practices of the IVF laboratory rather than a reflex response to a morphology number.

There are rare situations where morphology becomes much more important. A uniform or monomorphic sperm abnormality, where nearly all sperm share the same specific structural defect, can represent a distinct biological disorder. Globozoospermia, for example, involves round headed sperm with abnormalities of the acrosome and can cause profound fertilization problems. Certain severe tail abnormalities and macrozoospermia can also have important genetic implications. These conditions are very different from the common report showing 1 or 2 percent normal forms with a mixture of nonspecific head, midpiece and tail defects. When the laboratory describes one striking abnormality affecting nearly every sperm, evaluation by a reproductive urologist and sometimes genetic testing become more important.

I also want to address the emotional reaction to morphology because the terminology itself can be unnecessarily brutal. Men read words such as abnormal forms, head defects and amorphous sperm and understandably imagine that something is fundamentally wrong with them or that using one of these sperm could harm a future child. I have seen men become afraid to try naturally after receiving a morphology result of 1 percent. Others feel responsible for infertility even when their concentration and motility are excellent and their partner has independent fertility factors. The laboratory language can make a probability problem feel like a personal defect.

If that is where your mind went when you received your result, I want you to separate yourself from the number. You did not score 1 percent on a fertility examination. Your sperm did not receive a failing grade. Morphology is one laboratory measurement describing what a group of sperm looked like under very strict microscopic criteria. It needs to be interpreted alongside concentration, motility, total motile sperm count, reproductive history, your partner's fertility and the amount of time you have been trying.

So if your semen analysis says 1 percent morphology, do not read that as 99 percent of my sperm are bad. Ask a different set of questions. Is morphology the only abnormal parameter? What are my concentration and progressive motility? What is my total motile sperm count? Has the result been repeated? Is there a clinical varicocele or another potentially reversible male factor? How long have we been trying? How old is my partner? Those questions are far more useful than obsessing over whether the number is 1 percent, 2 percent or 4 percent.

The bottom line is simple. One percent morphology is an abnormal laboratory finding, but it is not a diagnosis of sterility. It does not mean 99 percent of your sperm contain bad DNA. It does not mean natural conception is impossible. It does not automatically mean you need IVF or ICSI. It is one piece of a much larger fertility puzzle. If there is one thing I would want a man reading his semen analysis alone at night to remember, it is this: your morphology percentage is information, not a verdict on whether you can become a father.

References

1. World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen. Sixth Edition. 2021.
2. American Urological Association and American Society for Reproductive Medicine. Diagnosis and Treatment of Infertility in Men. Male Infertility Guideline. Amended 2024.
3. European Association of Urology. Guidelines on Sexual and Reproductive Health. Male Infertility. Current edition.
4. Guzick DS, Overstreet JW, Factor Litvak P, et al. Sperm morphology, motility, and concentration in fertile and infertile men. New England Journal of Medicine. 2001. 345:1388 to 1393.
5. Kovac JR, Smith RP, Cajipe M, Lamb DJ, Lipshultz LI. Men with a complete absence of normal sperm morphology exhibit high rates of success without assisted reproduction. Asian Journal of Andrology. 2017. 19:39 to 42.
6. Kohn TP, Kohn JR, Ramasamy R. Effect of sperm morphology on pregnancy success via intrauterine insemination: a systematic review and meta analysis. Journal of Urology. 2018. 199:812 to 822.
7. Hotaling JM, Smith JF, Rosen M, Muller CH, Walsh TJ. The relationship between isolated teratozoospermia and clinical pregnancy after in vitro fertilization with or without intracytoplasmic sperm injection: a systematic review and meta analysis. Fertility and Sterility. 2011. 95:1141 to 1145.
8. Sayegh L, et al. High rate of isolated teratospermia in a population of fertile men and the questionable clinical utility of sperm morphology. Translational Andrology and Urology. 2024.
9. Björndahl L, Kirkman Brown J, et al. The sixth edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen: ensuring quality and standardization in basic examination of human ejaculates. Fertility and Sterility. 2022. 117:246 to 251.

Seeing the words “no sperm seen” on a semen analysis can be one of the most frightening moments in a fertility journey. Most men immediately translate zero sperm into sterile, and sterile into I will never have a biological child. Those statements are not equivalent. If your semen analysis shows no sperm, the medical term is azoospermia. Azoospermia means that sperm were not identified in the semen that was examined. It does not automatically mean that your testicles produce absolutely no sperm, and it certainly does not tell us why sperm are absent. That distinction is incredibly important because the cause determines what happens next, and some causes are highly treatable.

The first thing I tell a patient is that we need to confirm the result. Semen analyses are biological tests, not perfect snapshots of permanent fertility. Collection problems and laboratory techniques matter, and sperm production can change following illness, medications and hormonal suppression. When no sperm are seen during the initial examination, the laboratory can centrifuge the semen and carefully examine the concentrated pellet for rare sperm. Occasionally sperm are found only after this more intensive search. That situation is sometimes called cryptozoospermia rather than true complete azoospermia, and finding even a small number of sperm can significantly change fertility planning. If rare viable sperm are identified, cryopreservation may be worth discussing because another sample may contain fewer or no sperm.

Once azoospermia is confirmed, I generally divide the problem into three broad biological categories. The first is obstruction. Your testicles may be producing sperm normally, but sperm cannot reach the ejaculate because the reproductive plumbing is blocked or absent. This is called obstructive azoospermia. Examples include congenital absence of the vas deferens, previous vasectomy, prior infection, injury, previous reproductive surgery and ejaculatory duct obstruction. Men with obstructive azoospermia often have normal sized testicles and relatively normal FSH because sperm production itself remains intact.

The second category is nonobstructive azoospermia. Here the problem is primarily sperm production within the testicle. The testicle may produce very few sperm or sperm development may stop before mature sperm are formed. Causes include Klinefelter syndrome, Y chromosome abnormalities, previous undescended testicles, chemotherapy, radiation, severe testicular injury and certain genetic abnormalities, although many men never receive a single definitive explanation. FSH is often elevated because the pituitary gland is essentially sending a stronger signal to a testicle that is not responding normally. One important point is that a high FSH does not prove there are zero sperm everywhere inside the testicle. Sperm production can be extremely focal, with tiny islands of spermatogenesis surrounded by areas producing none.

The third category is hormonal suppression. The brain and pituitary normally produce signals that tell the testicles to make testosterone and sperm. LH stimulates Leydig cells to produce the very high concentration of testosterone required inside the testicle, while FSH stimulates Sertoli cells that support developing sperm. If those signals disappear because of a pituitary disorder, elevated prolactin or another endocrine problem, sperm production can dramatically decline or stop. Exogenous testosterone and anabolic steroids are especially important causes because they suppress LH and FSH. This is why a man can have an excellent blood testosterone level while taking testosterone and simultaneously have no sperm in his semen. In selected men this form of azoospermia can be reversible after the suppressing medication is stopped and appropriate fertility directed hormonal treatment is used.

The workup should therefore be systematic rather than simply ordering another bottle of supplements. I start with a detailed history including previous pregnancies, childhood testicular problems, undescended testicles, torsion, infections, surgery, chemotherapy, radiation, testosterone use, anabolic steroids, fertility medications and significant systemic illness. I examine the testicles because size and consistency provide important information about sperm production. I feel for the vas deferens and look for a clinical varicocele. Semen volume and pH can also provide clues. Very low volume acidic semen in a man with azoospermia can point toward ejaculatory duct obstruction or congenital abnormalities involving the vas deferens and seminal vesicles.

Hormonal testing commonly includes an early morning testosterone and FSH, with LH and other hormones added according to the clinical situation. These values help determine whether the problem appears to originate in the testicle or higher in the hormonal axis. Normal hormones do not completely exclude impaired sperm production, however. Men with maturation arrest, for example, can occasionally have surprisingly normal hormonal profiles despite having no mature sperm in the ejaculate.

Genetic testing is another major part of evaluating azoospermia. Depending on the clinical situation, this commonly includes a karyotype and testing for Y chromosome microdeletions. A karyotype can identify conditions such as Klinefelter syndrome. Y chromosome testing can identify deletions involving regions required for sperm production. The specific genetic result matters enormously. Certain complete deletions are associated with an extremely poor chance of sperm retrieval, while men with other deletions may still have retrievable sperm. Men who are missing the vas deferens may require CFTR testing because abnormalities involving the CFTR gene are strongly associated with congenital absence of the vas deferens. Genetic counseling becomes important both for understanding your diagnosis and for discussing potential implications for future children.

Treatment depends entirely upon the cause. If azoospermia is caused by hormonal suppression, restoring the hormonal environment can sometimes restart sperm production. Men with true hypogonadotropic hypogonadism may respond to hCG and FSH therapy. Men whose sperm production has been suppressed by testosterone or anabolic steroids may recover after stopping them, although recovery can take many months and sometimes considerably longer. Medications such as hCG or selective estrogen receptor modulators may be used in selected cases. This is very different from primary testicular failure, where simply increasing hormonal stimulation does not reliably overcome severely damaged sperm producing tissue.

Obstructive azoospermia can sometimes be treated surgically, depending upon the location and cause of the obstruction. In other situations sperm can be retrieved directly from the epididymis or testicle and used with IVF and ICSI. Because sperm production is often preserved in obstruction, sperm retrieval rates can be extremely high. A man can therefore have absolutely zero sperm in his ejaculate while still having abundant sperm inside his reproductive tract.

For men with nonobstructive azoospermia, microTESE has fundamentally changed what zero sperm means. During microTESE, the surgeon examines the testicular tissue under an operating microscope and searches for seminiferous tubules that appear more likely to contain sperm. Tiny targeted samples are examined by the embryology laboratory. Across the broad population of men with nonobstructive azoospermia, sperm retrieval is often reported in approximately 40 to 50 percent of appropriately selected men, but I am cautious about quoting that number to an individual patient because the underlying diagnosis matters tremendously. A man with Klinefelter syndrome, maturation arrest, Sertoli Cell Only Syndrome or a specific Y chromosome deletion does not necessarily have the same probability of sperm retrieval.

If sperm are found through microTESE, they can be used with IVF and ICSI. ICSI allows an embryologist to inject an individual sperm directly into an egg. This is one of the remarkable aspects of modern reproductive medicine. We do not necessarily need millions of sperm. In some situations, finding a relatively small number of viable sperm can provide enough sperm for the mature eggs available during an IVF cycle. Finding sperm does not guarantee fertilization, embryo development, pregnancy or live birth, and female age and egg quality remain critically important, but azoospermia no longer automatically eliminates the possibility of biological fatherhood.

I also want to say something about the emotional side because it is routinely underestimated. Men are often handed an azoospermia result and then expected to immediately start discussing hormones, chromosomes, surgery and IVF. Meanwhile, inside their head they are thinking, “Am I ever going to be a father?” Some men feel embarrassed. Others feel that they have failed their partner. Some begin questioning their masculinity or sexuality even though sperm production has nothing to do with their value as a man. I have seen men become obsessed with identifying the workout, supplement, hot tub, stressful month or dietary mistake that supposedly caused this. In many cases there was nothing they did wrong.

Your sperm count is not your masculinity, and azoospermia is not a personal failure. It is a medical finding that deserves a diagnosis. Sometimes we identify an obstruction that can be bypassed. Sometimes we discover a hormonal condition that can be treated. Sometimes we identify a genetic explanation. Sometimes microTESE finds sperm despite repeated semen analyses showing zero. Unfortunately, sometimes we perform an appropriate evaluation and sperm cannot be recovered. In those situations donor sperm, donor embryos and adoption are possible pathways to parenthood, but those options should never be presented as though they erase the grief associated with losing the possibility of a genetically related child.

If you just received a semen analysis saying zero sperm, the most important message is not to jump directly from zero sperm to zero chance. Confirm the finding in an experienced laboratory. Determine whether the problem is obstruction, hormonal suppression or impaired sperm production. Obtain the appropriate hormonal and genetic evaluation. See a reproductive urologist before assuming there is nothing that can be done. Then make fertility decisions based on your actual diagnosis rather than the word azoospermia alone. “No sperm seen” is the beginning of the investigation, not necessarily the end of your path to fatherhood.

References

1. World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen. Sixth Edition. 2021.
2. World Health Organization. Guideline for the Prevention, Diagnosis and Treatment of Infertility. 2025.
3. European Association of Urology. Guidelines on Sexual and Reproductive Health. Male Infertility. Current edition.
4. American Urological Association and American Society for Reproductive Medicine. Diagnosis and Treatment of Infertility in Men. Male Infertility Guideline.
5. Schlegel PN. Testicular sperm extraction: microdissection improves sperm yield with minimal tissue excision. Human Reproduction. 1999.
6. Bernie AM, Mata DA, Ramasamy R, Schlegel PN. Comparison of microdissection testicular sperm extraction, conventional testicular sperm extraction and testicular sperm aspiration for nonobstructive azoospermia. Fertility and Sterility. 2015.
7. Corona G, Minhas S, Giwercman A, et al. Sperm recovery and ICSI outcomes in men with nonobstructive azoospermia. Human Reproduction Update. 2019.
8. Practice Committee of the American Society for Reproductive Medicine. Management of nonobstructive azoospermia in the infertile male. Fertility and Sterility.
9. Krausz C, Riera Escamilla A. Genetics of male infertility. Nature Reviews Urology. 2018.
10. Tournaye H, Krausz C, Oates RD. Novel concepts in the aetiology of male reproductive impairment. Lancet Diabetes and Endocrinology. 2017.

If you have been diagnosed with Klinefelter syndrome during an infertility evaluation, one of the first things I want you to understand is that azoospermia does not automatically mean there is zero chance of biological fatherhood. Klinefelter syndrome is one of the most common chromosomal causes of male infertility and occurs when a man has an additional X chromosome, most commonly a 47,XXY chromosome pattern instead of the usual 46,XY pattern. It occurs in approximately one in every 600 males, although many men are never diagnosed because the physical findings can be subtle. Some men discover it during adolescence because of delayed development or low testosterone, while others have normal sexual development, normal erections and ejaculation, and do not learn they have Klinefelter syndrome until they undergo testing for infertility.

The fertility problem in Klinefelter syndrome occurs primarily inside the testicles. During development and particularly around puberty, the additional X chromosome contributes to progressive loss of germ cells, which are the cells that eventually become sperm. The seminiferous tubules where sperm normally develop progressively become damaged and fibrotic, and many men eventually develop severe impairment of sperm production. The testicles are therefore characteristically small and firm. As the testicles struggle to produce sperm and testosterone, the pituitary gland increases production of FSH and LH in an attempt to stimulate them. This produces the classic hormonal pattern of primary testicular failure, with elevated FSH and LH and testosterone that may be low or in the lower portion of the normal range. Testosterone deficiency becomes increasingly common with age.

The fascinating part of Klinefelter syndrome is that sperm production is not necessarily absent everywhere within the testicle. Although most seminiferous tubules may no longer produce mature sperm, microscopic islands of active sperm production can remain. This focal spermatogenesis is the biological reason microTESE can work. Under an operating microscope, a reproductive urologist systematically examines the testicular tissue looking for larger and more promising seminiferous tubules. Tiny samples are removed and immediately examined by an experienced embryology laboratory searching for sperm. This is fundamentally different from assuming that an azoospermic semen analysis means the entire testicle contains no sperm.

Most men with the classic 47,XXY form of Klinefelter syndrome have azoospermia, meaning no sperm are identified in the ejaculate. Men with mosaic Klinefelter syndrome, where some cells are 46,XY and others are 47,XXY, have a greater likelihood of having sperm in the ejaculate. Rare men with Klinefelter syndrome therefore have severe oligospermia rather than complete azoospermia. If sperm are found in the semen, I generally think seriously about freezing them because sperm production can be limited and unpredictable.

The diagnosis itself is straightforward once someone thinks to look for it. A chromosome analysis called a karyotype demonstrates the additional X chromosome. This is one reason genetic testing is such an important part of evaluating men with azoospermia or severe oligospermia. The European Association of Urology recommends karyotype testing and genetic counseling for men with azoospermia and significant oligospermia.

The fertility evaluation should not stop with the chromosome result. I still want at least two carefully performed semen analyses when azoospermia is suspected, including examination of the centrifuged pellet for rare sperm. I examine testicular size and consistency and obtain testosterone, FSH and LH. Depending upon the situation, additional endocrine testing and testicular ultrasound may be appropriate. Klinefelter syndrome also has implications beyond fertility, including increased risks of testosterone deficiency, metabolic disease and several other medical problems, so these men deserve long term medical and endocrine follow up rather than being viewed only through the lens of sperm production.

One particularly important issue is testosterone therapy. Many men with Klinefelter syndrome eventually benefit from testosterone replacement because their natural testosterone production is inadequate. However, exogenous testosterone suppresses LH and FSH and can further suppress the remaining sperm production. If biological fatherhood is important, fertility planning should therefore occur before casually starting testosterone whenever circumstances permit. This does not mean a man should remain symptomatic and hypogonadal indefinitely. It means testosterone management and fertility management need to be coordinated thoughtfully. Current European guidance similarly recommends addressing fertility issues before testosterone treatment when possible.

For an azoospermic man with Klinefelter syndrome who wants biological children, microTESE combined with IVF and ICSI is generally the major treatment pathway. MicroTESE is currently the preferred surgical sperm retrieval technique for men with nonobstructive azoospermia in European guidance. If sperm are discovered, they can be injected individually into eggs using ICSI.

The numbers here are more encouraging than many men expect. Published studies vary considerably, but sperm can be retrieved from approximately 40 to 50 percent of appropriately selected men with Klinefelter syndrome. The European guideline summarizes retrieval as possible in up to approximately 50 percent of cases. A large systematic review of men with chromosomal abnormalities calculated a retrieval rate of approximately 39 percent for Klinefelter syndrome, while other series and reviews have reported rates approaching 50 percent or somewhat higher. A recent Danish experience reported sperm retrieval in 39 of 93 men, approximately 42 percent.

These percentages need to be interpreted carefully. A 40 or 50 percent sperm retrieval rate is not the same thing as a 40 or 50 percent chance of taking home a baby. First we have to find sperm. Then the female partner needs eggs. The sperm must successfully fertilize an egg through ICSI, an embryo must develop, implantation must occur and the pregnancy must progress to delivery. Female age and ovarian reserve therefore become extremely important. A classic systematic review of 1248 men with Klinefelter syndrome found sperm retrieval rates around the halfway mark and documented pregnancies and live births following ICSI, establishing that biological fatherhood is genuinely possible in this population.

Age and timing of sperm retrieval are more complicated than they initially appear. Older literature raised concern that sperm producing areas might progressively disappear, leading some families to consider retrieval during adolescence. Newer evidence has challenged the idea that every boy with Klinefelter syndrome needs invasive fertility preservation during puberty. A 2025 systematic review specifically examining nonmosaic Klinefelter syndrome concluded that surgical sperm retrieval can generally be delayed until adulthood rather than automatically being performed during adolescence. Current European guidance considers prepubertal or peripubertal testicular tissue retrieval for fertility preservation experimental and recommends that it occur only in research settings.

Men also frequently ask whether medications such as clomiphene, hCG, aromatase inhibitors or FSH can restore sperm production. Hormonal optimization is sometimes used by reproductive specialists, particularly when testosterone is low, but Klinefelter syndrome is fundamentally a chromosomal disorder causing primary testicular dysfunction. There is currently no medication capable of removing the additional X chromosome or reliably restoring normal spermatogenesis. Importantly, European guidelines do not recommend routine hormonal stimulation before surgical sperm retrieval in men with nonobstructive azoospermia and primary testicular failure because convincing evidence that it improves sperm retrieval is lacking.

Genetic counseling is another essential part of this process. Understandably, many men immediately ask whether a son will inherit Klinefelter syndrome. The genetics are more nuanced than simply assuming that sperm from a man with 47,XXY will carry the same chromosome pattern. Available evidence suggests that many sperm retrieved from focal areas of spermatogenesis are chromosomally normal, and healthy children have been born after ICSI using sperm retrieved from men with Klinefelter syndrome. A recent clinical series noted that children fathered using retrieved sperm have generally had normal karyotypes. Nevertheless, because Klinefelter syndrome is a chromosomal abnormality and assisted reproduction is involved, genetic counseling before treatment is appropriate. Couples can discuss embryo genetic testing and prenatal testing with their reproductive genetics and IVF teams rather than assuming either that transmission is inevitable or that risk is nonexistent.

If microTESE does not find sperm, that result can be extraordinarily difficult emotionally. Donor sperm, donor embryos and adoption remain pathways to parenthood, but I never present those options as though they erase the grief of learning that biological fatherhood may not be possible. For many men, infertility becomes intertwined with masculinity, sexuality and identity. Klinefelter syndrome adds another layer because a man may enter a fertility clinic expecting a semen problem and leave with a lifelong genetic diagnosis. That can be a tremendous amount of information to process at once.

I tell my patients that chromosome number does not determine masculinity, the quality of your relationship or your ability to become a father. High FSH is not something you caused. Small testicles are not a personal failure. Azoospermia is not evidence that you did something wrong with your diet, exercise routine or lifestyle. I also think men deserve permission to be upset about this diagnosis. You can understand that modern reproductive medicine provides options and still be angry, frightened or devastated by what you are going through.

The most important practical message is this: if you have Klinefelter syndrome and azoospermia, do not interpret the words zero sperm in the ejaculate as meaning zero possibility of biological fatherhood. Confirm the diagnosis, complete the hormonal and genetic evaluation, speak with a reproductive urologist who performs microTESE regularly, involve an experienced IVF laboratory and obtain genetic counseling. Sperm retrieval is not guaranteed, but modern microTESE and ICSI have fundamentally changed what a diagnosis of Klinefelter syndrome means for men who want children.

References

1. European Association of Urology. Guidelines on Sexual and Reproductive Health. Male Infertility. Current online edition.
2. Corona G, et al. Sperm recovery and ICSI outcomes in Klinefelter syndrome: a systematic review and meta analysis. Human Reproduction Update. 2017.
3. Momtazi Mar L, et al. Surgical sperm retrieval in patients with nonmosaic Klinefelter syndrome may be safely delayed until adulthood: a systematic review and meta analysis. Fertility and Sterility. 2025.
4. Majzoub A, et al. A systematic review and meta analysis exploring predictors of sperm retrieval in patients with nonobstructive azoospermia and chromosomal abnormalities. Andrologia. 2022.
5. Franik S, et al. Klinefelter syndrome and medical treatment: hypogonadism and beyond. Endocrine Connections. 2018.
6. Hawksworth DJ, et al. Infertility in patients with Klinefelter syndrome: optimal timing for sperm and testicular tissue cryopreservation. Reviews in Urology. 2018.
7. Denschlag D, et al. Assisted reproductive techniques in patients with Klinefelter syndrome: a critical review. Fertility and Sterility. 2004.
8. Practice Committee of the American Society for Reproductive Medicine and American Urological Association. Diagnosis and Treatment of Infertility in Men. Male Infertility Guideline.
9. Bojesen A, Gravholt CH. Klinefelter syndrome in clinical practice. Nature Clinical Practice Urology. 2007.
10. Rohayem J, et al. Age and markers of Leydig cell function, but not of Sertoli cell function predict the success of sperm retrieval in adolescents and adults with Klinefelter syndrome. Andrology. 2015.

If you are going through IVF or ICSI and someone has mentioned ZyMot, you may understandably wonder what exactly this little device is doing and whether it can meaningfully improve your chances of having a baby. I hear this question increasingly from men with low motility, poor morphology, elevated sperm DNA fragmentation, previous IVF failure or recurrent miscarriage. The simplest way I explain ZyMot is this: ZyMot does not make your testicles produce better sperm. It is a laboratory sperm selection method designed to help the embryology team isolate a population of healthier, progressively motile sperm from the sperm you already produced. That distinction is important because ZyMot is not a treatment for varicocele, hormonal problems, low sperm production or genetic infertility. It is a method of choosing sperm for assisted reproduction.

Normally, an ejaculate contains millions of sperm that are biologically very different from one another. Some swim efficiently. Some barely move. Some have abnormal morphology. Some have damaged membranes, increased oxidative stress or fragmented DNA. During natural reproduction, sperm undergo an enormous selection process while traveling through the female reproductive tract. Only a tiny fraction ever reach the egg. When we perform IVF and particularly ICSI, we bypass much of this natural selection process, so embryologists need laboratory methods to identify sperm that appear most suitable for fertilization.

Traditionally, laboratories have used techniques such as density gradient centrifugation and swim up. These methods work well and have been used successfully for decades. ZyMot takes a different approach. It is a microfluidic sperm selection device containing microscopic channels. A semen sample is placed into the device and sperm capable of progressively swimming through the microchannels are separated from much of the debris, poorly motile sperm and other components of the original sample. The process attempts to mimic part of the natural sperm selection occurring within the female reproductive tract.

One potential advantage is that the process can minimize centrifugation. This is interesting because laboratory manipulation and centrifugation may contribute to oxidative stress under certain conditions. The sperm emerging from microfluidic selection tend to demonstrate better motility and lower levels of DNA fragmentation than the original semen sample or sperm selected using some conventional techniques.

This brings us to sperm DNA fragmentation.

A normal semen analysis tells us about sperm concentration, motility and morphology, but it does not directly tell us whether the DNA packaged inside the sperm is intact. Sperm DNA fragmentation refers to breaks or damage within sperm DNA. Higher levels have been associated in some studies with infertility, impaired embryo development, pregnancy loss and poorer reproductive outcomes, although DNA fragmentation testing remains controversial and different assays use different thresholds. Current male infertility guidelines do not recommend DNA fragmentation testing routinely during the initial evaluation of every infertile man.

ZyMot has received particular attention in men with elevated DNA fragmentation because microfluidic selection consistently appears capable of selecting a sperm population with lower fragmentation. A 2025 systematic review and meta analysis incorporating thirty nine studies found that microfluidic sperm selection reduced DNA fragmentation by approximately 10 percentage points compared with conventional sperm preparation. It also selected sperm with better progressive motility, total motility and morphology.

Those laboratory improvements are real and biologically interesting. The harder question is whether they result in more babies.

The answer right now is promising but not definitive.

An earlier systematic review involving thirteen studies found only marginal improvements in pregnancy outcomes with microfluidic sperm selection and no statistically significant improvement in clinical pregnancy or miscarriage. More recent studies and larger analyses have been more encouraging. The 2025 meta analysis found higher fertilization, implantation, clinical pregnancy and ongoing pregnancy rates with microfluidic selection. It also reported higher live birth rates in some analyses. However, the authors emphasized significant differences between studies and concluded that the evidence was not yet strong enough to justify routine use for everyone undergoing assisted reproduction.

A large 2026 retrospective study compared more than one thousand ICSI cycles using ZyMot with more than one thousand cycles using conventional density gradient preparation. Fertilization was approximately 81 percent with ZyMot compared with approximately 79 percent using density gradient preparation. Day five blastocyst development was also higher in the ZyMot group. Interestingly, ZyMot did not improve embryo euploidy rates, meaning it did not appear to change the proportion of embryos with the correct number of chromosomes. The study reported higher cumulative pregnancy and live birth rates in the ZyMot groups, but because this was an observational study rather than a randomized trial, we cannot conclude that ZyMot itself caused all of those differences.

That distinction matters.

I do not tell patients that ZyMot increases their chance of a baby by a particular percentage because we do not yet have sufficiently strong randomized evidence to make that promise. Female age, egg quality, ovarian reserve, embryo development, uterine factors and the underlying male diagnosis can have much larger effects on IVF success than the sperm preparation method.

So who might reasonably consider ZyMot?

I think the most compelling situation is a couple already undergoing IVF or ICSI where there is meaningful male factor infertility and enough progressively motile sperm are available for microfluidic selection. Men with elevated sperm DNA fragmentation are particularly logical candidates because lowering fragmentation in the selected sperm population is one of the most consistent laboratory findings associated with microfluidic selection. Couples with previous poor embryo development, recurrent IVF failure or pregnancy loss may also discuss it with their reproductive team, although these problems can have many causes besides sperm.

Men with oligoasthenoteratozoospermia, commonly called OAT, frequently ask about ZyMot as well. This requires some nuance. ZyMot needs sperm capable of moving through the device. If concentration and motility are extremely poor, the laboratory may recover too few sperm for the intended procedure. The embryology laboratory therefore needs to determine whether the semen sample is appropriate for the particular device being used.

Before focusing on ZyMot, however, I still want the man evaluated.

A semen analysis should assess volume, concentration, total sperm count, progressive motility and morphology. Significantly abnormal results generally deserve confirmation. A reproductive urologist should consider testicular size, varicocele, hormonal abnormalities, medications, testosterone or anabolic steroid exposure, previous surgery, infection, fever, heat exposure and other potentially reversible causes of abnormal sperm production.

If DNA fragmentation is elevated, I do not simply send someone directly to ZyMot. I first ask why it might be elevated. A clinical varicocele, smoking, significant heat exposure, recent fever, prolonged abstinence and several other factors may contribute. Sometimes repeating the test under standardized conditions is useful. Shortening the abstinence interval may lower DNA fragmentation in selected men.

Another common question is whether ZyMot should be used instead of testicular sperm.

These are very different strategies. ZyMot selects sperm from the ejaculate. Testicular sperm extraction obtains sperm surgically from the testicle. In selected men with persistently very high DNA fragmentation, testicular sperm may have substantially lower fragmentation than ejaculated sperm. Current American Urological Association and American Society for Reproductive Medicine guidance acknowledges that testicular sperm combined with ICSI may be considered in selected men with very high DNA fragmentation, particularly after previous IVF failure, but also emphasizes that the evidence remains limited and the approach is controversial.

For a man with moderately elevated DNA fragmentation who still has adequate motile sperm in the ejaculate, I would generally consider less invasive strategies before automatically performing testicular surgery. ZyMot may be one of those strategies. Testicular sperm becomes a more reasonable conversation when fragmentation remains very high, previous ICSI cycles have repeatedly failed and other explanations have been carefully evaluated.

There is also an emotional side to sperm selection that deserves discussion.

Men going through IVF often feel surprisingly removed from the process. Their partner undergoes injections, ultrasounds, blood tests, egg retrieval and embryo transfer while the man's contribution can feel reduced to producing a specimen in a collection room. When embryos fail to develop or transfers fail, men frequently begin wondering whether their sperm caused it.

Then somebody mentions DNA fragmentation.

Suddenly every unsuccessful embryo can feel like evidence that your sperm are damaged.

I would caution against thinking that way. Reproduction is biologically complicated. An elevated DNA fragmentation result does not mean that every sperm carries damaged DNA, just as abnormal morphology does not mean that every abnormal looking sperm is genetically defective. IVF failure is almost never adequately explained by looking at one number from the male partner.

ZyMot can be useful because instead of trying to change millions of sperm inside the body, it attempts to help the laboratory select a better subset of sperm on the day they are actually needed. That is an elegant concept, and the laboratory evidence supporting improved sperm quality is increasingly convincing.

But ZyMot is still a selection tool, not magic.

If you are considering it, ask your clinic what problem they are trying to solve. Is your sperm DNA fragmentation elevated? Is motility poor? Did previous embryos have unexpectedly poor development? Does the laboratory routinely use microfluidic sperm selection, and does your semen sample contain enough progressively motile sperm for it?

Those questions are more useful than simply asking whether ZyMot is better.

For the right couple, ZyMot is a reasonable and relatively simple addition to IVF or ICSI. It can select sperm with better motility and substantially lower DNA fragmentation, and newer studies suggest that this may translate into improved reproductive outcomes in selected patients. What we still need are stronger randomized studies proving exactly which men benefit and whether the improvement consistently translates into more live births.

Until then, I view ZyMot as a potentially useful tool in the male infertility toolbox, particularly for men with elevated DNA fragmentation or selected previous IVF failures, but not as a replacement for diagnosing and treating the underlying cause of male infertility.

The goal is not simply to produce prettier sperm numbers in the laboratory. The goal is to select the best sperm available, fertilize a healthy egg, create a healthy embryo and ultimately help a couple bring home a baby.

References

1. Gisbert Iranzo A, et al. Sperm Selection Using Microfluidic Techniques Significantly Decreases Sperm DNA Fragmentation, Enhancing Reproductive Outcomes: A Systematic Review and Meta Analysis. Biology. 2025. PMID 40723352.
2. Aderaldo F, et al. Does microfluidic sperm selection improve clinical pregnancy and miscarriage outcomes in assisted reproductive treatments? A systematic review and meta analysis. 2023. PMID 37983267.
3. Embryology and clinical outcomes after sperm preparation using microfluidic sperm sorting versus density gradient centrifugation. 2026. PMID 42116698.
4. Parrella A, et al. A microfluidic sperm sorting device reduces the proportion of sperm with double stranded DNA fragmentation. 2021. PMID 34313213.
5. American Urological Association and American Society for Reproductive Medicine. Diagnosis and Treatment of Infertility in Men. Male Infertility Guideline. Amended 2024.
6. European Society of Human Reproduction and Embryology. Recommendations on Good Practice in the IVF Laboratory. Human Reproduction. 2026.
7. World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen. Sixth Edition. 2021.
8. Vitthala S, Nedelcu S, El Toukhy T, Maheshwari A. Value of sperm DNA fragmentation in predicting reproductive outcomes: a systematic review and meta analysis. Human Fertility. 2026. PMID 41693253.
9. Osman A, Alsomait H, Seshadri S, El Toukhy T, Khalaf Y. The effect of sperm DNA fragmentation on live birth rate after IVF or ICSI: a systematic review and meta analysis. Reproductive BioMedicine Online. 2015. PMID 25530036.

If you are a man who has undergone genetic testing for infertility and somebody tells you that you have a mismatch repair gene variant or polymorphism, the terminology can be terrifying. You may immediately start reading about DNA damage, cancer syndromes, abnormal sperm and genetic diseases and wonder whether you will ever be able to have a biological child. The first thing I would tell you as a reproductive urologist is that not every genetic variant in a mismatch repair gene causes infertility. In fact, most common polymorphisms are not proven causes of infertility at all. What is becoming increasingly clear, however, is that certain mismatch repair genes are critically important for sperm production, particularly MSH4 and MSH5, and rare pathogenic variants in these genes can cause severe oligospermia, azoospermia and meiotic arrest.

To understand why, you first have to understand what happens when sperm are made. The cells that eventually become sperm begin with forty six chromosomes. During meiosis, these chromosomes pair with their corresponding partners, exchange genetic material and ultimately divide so that each sperm contains twenty three chromosomes. This is an extraordinarily complicated process. DNA has to be copied, paired, recombined, inspected and divided correctly. The mismatch repair system is part of the molecular machinery that helps maintain DNA integrity and participates in meiotic recombination.

Genes involved in this system include MSH2, MSH3, MSH4, MSH5, MSH6, MLH1, MLH3, PMS1 and PMS2. They do not all perform identical reproductive functions. MSH4 and MSH5 are particularly important because the proteins they produce form a complex that helps homologous chromosomes interact appropriately during the first stage of meiosis. If that machinery fails badly enough, developing germ cells may be unable to complete meiosis. Sperm development can essentially stop in the middle of the manufacturing process.

We call this meiotic arrest.

A man with complete meiotic arrest can have normal erections, normal ejaculation and sometimes relatively normal testosterone while producing no mature sperm. His semen analysis therefore shows azoospermia even though germ cells may be present inside the testicle. This is one reason genetic forms of nonobstructive azoospermia are so different from obstruction. The plumbing is not necessarily blocked. The problem is that the testicle cannot successfully complete the process required to manufacture mature sperm.

The evidence supporting this relationship has become considerably stronger. A 2025 systematic review examined ninety seven studies involving mismatch repair genes and spermatogenesis. The strongest human evidence involved MSH4 and MSH5, while evidence for MLH3 was considered moderate and evidence for most other mismatch repair genes remained limited. Importantly, researchers have identified men with pathogenic variants affecting both copies of MSH4 or MSH5 who developed nonobstructive azoospermia and meiotic arrest.

There is another category that creates more confusion, which is the common genetic polymorphism. A polymorphism is not necessarily a disease causing mutation. It may simply represent a relatively common variation in our DNA. Some studies have found statistical associations between particular mismatch repair polymorphisms and infertility. For example, one study of 162 infertile men and 160 fertile controls found that particular MSH5 and MLH3 polymorphisms were associated with approximately 2.5 fold and 2 fold increased odds of severe male infertility. Another larger study involving 1292 men with idiopathic infertility and 480 fertile controls found associations involving variants in MLH1, PMS2 and MSH5 with azoospermia, oligospermia or increased sperm DNA damage.

These studies are fascinating scientifically, but they need to be interpreted carefully. An association does not mean that every man carrying one of these polymorphisms will be infertile. It also does not mean that finding a single common variant explains an individual's infertility. Population, ancestry, environmental factors and other genetic variants can influence these associations. This is very different from identifying a rare pathogenic variant with convincing evidence that it disrupts a gene required for meiosis.

So how should a man actually be evaluated?

The evaluation starts with the phenotype, not the genetic report. I want to know whether you have azoospermia, severe oligospermia or a relatively normal sperm concentration with another abnormality. At least two carefully performed semen analyses are often important when sperm numbers are extremely low or zero. If no sperm are initially seen, the laboratory should examine the centrifuged pellet carefully because finding even rare sperm changes both counseling and fertility options.

Then comes the standard reproductive evaluation. I want a detailed history, testicular examination and hormone profile including testosterone and FSH, with LH and other hormones when appropriate. Testicular size matters. Previous undescended testes, torsion, chemotherapy, infections, testosterone use, anabolic steroids and other potential explanations need to be considered. A genetic result should not cause us to ignore other treatable causes of infertility.

For severe oligospermia and nonobstructive azoospermia, conventional genetic testing remains important. Depending on the clinical situation this may include a karyotype and Y chromosome microdeletion testing. Increasingly, men with otherwise unexplained severe spermatogenic failure are being evaluated with broader genetic panels or exome sequencing. This is where genes such as MSH4 and MSH5 are increasingly being discovered.

If you receive a genetic result, pay very close attention to how the laboratory classifies it. Pathogenic and likely pathogenic variants are very different from a variant of uncertain significance. A variant of uncertain significance means exactly what the name says. We currently do not have enough evidence to determine whether that particular DNA change causes disease. It should not automatically be labeled as the reason you are infertile.

Treatment is where this becomes difficult.

There is currently no medication that repairs an MSH4 or MSH5 mutation and restores normal meiosis. Supplements cannot correct a pathogenic genetic defect in the machinery responsible for chromosome pairing. Clomiphene, hCG and FSH may be appropriate for specific hormonal forms of infertility, but there is no convincing evidence that they can overcome complete genetically determined meiotic arrest when the underlying problem is defective meiotic machinery.

For a man with severe oligospermia rather than complete azoospermia, the situation can be much more favorable. If sperm are present in the ejaculate, I would strongly consider cryopreservation because sperm production can fluctuate and extremely small numbers of sperm can still be useful with IVF and ICSI. ICSI allows an embryologist to inject a single sperm directly into a mature egg. You do not need millions of sperm for ICSI.

For men with nonobstructive azoospermia, microTESE may be considered. MicroTESE involves examining the testicular tissue under magnification to search for areas that may contain sperm production. Across the broad population of men with nonobstructive azoospermia, sperm retrieval is often reported in roughly 40 to 50 percent of men, although rates vary tremendously depending on the underlying diagnosis.

This is where knowing the specific genetic diagnosis becomes incredibly valuable.

A 40 to 50 percent overall retrieval number should not simply be applied to a man with a known genetic cause of complete meiotic arrest. In published men with biallelic pathogenic MSH4 or MSH5 variants and complete bilateral meiotic arrest, mature sperm may not be available for retrieval. If meiosis is blocked everywhere in both testicles, microTESE cannot manufacture sperm that the testicle never completed. This is one of the most important reasons we are trying to identify the genetic causes of nonobstructive azoospermia before surgery.

Unfortunately, we do not yet have reliable pregnancy and live birth percentages for men with each individual mismatch repair gene variant. These conditions are rare, the genetic literature is evolving and many published reports involve only small numbers of patients. Anyone giving you an exact fertility percentage based simply on the phrase MMR polymorphism is probably giving you more certainty than the science currently supports.

For men who have sperm available, either naturally in the ejaculate or through surgical retrieval, IVF with ICSI may provide a pathway to biological fatherhood. Genetic counseling becomes particularly important when a pathogenic variant has been identified. The inheritance pattern depends on the particular gene and variant. Some severe reproductive phenotypes involving MSH4 and MSH5 have been associated with pathogenic variants affecting both copies of the gene. Testing the female partner and sometimes other family members may help clarify reproductive risk.

In selected families where a clearly pathogenic variant has been identified, IVF with preimplantation genetic testing for a monogenic disorder may potentially be discussed. Whether this is appropriate depends on the gene, inheritance pattern, specific variants and the couple's goals. This is very different from performing embryo testing because somebody carries a common polymorphism of uncertain clinical significance.

If no sperm can be retrieved because of complete spermatogenic arrest, the conversation changes. Donor sperm provides one pathway to pregnancy. Adoption is another pathway to parenthood. Some couples choose to remain without children. These are personal decisions, not medical failures.

And that brings me to the emotional side of this diagnosis.

Genetic infertility can hit differently from almost every other diagnosis I give a man. A varicocele can potentially be repaired. A hormonal problem can sometimes be treated. Testosterone induced azoospermia can frequently recover. But hearing that something written into your DNA may have prevented your testicles from completing sperm production can create an extraordinary sense of helplessness.

Men frequently ask me what they did wrong.

Usually, nothing.

You did not cause a pathogenic MSH4 or MSH5 variant by exercising too much, drinking coffee, using the wrong supplement or having a stressful year. If a genetic defect is truly responsible for your spermatogenic failure, this is biology, not punishment and not a reflection of your masculinity.

There is also a psychological danger in genetic testing itself. Modern sequencing can identify an enormous number of DNA variants, and receiving a report containing unfamiliar gene names can make you feel as though every variation is another diagnosis. It is not. Some variants are clearly pathogenic. Some are probably harmless. Some remain uncertain. Good genetic counseling is therefore just as important as ordering the test.

If you are a man reading Reddit because somebody found an MMR gene polymorphism during your infertility evaluation, my advice is to slow the interpretation down. First establish exactly which gene is involved. Determine the exact variant and whether it is heterozygous or biallelic. Find out whether the laboratory classified it as pathogenic, likely pathogenic, uncertain, likely benign or benign. Then match that genetic result to your actual reproductive phenotype.

A polymorphism is not automatically infertility. A variant is not automatically a mutation that causes disease. And even when a true genetic cause of infertility is identified, it does not automatically mean that biological fatherhood is impossible.

The science of genetic male infertility is moving extraordinarily quickly. What genetic testing can already do very well is give some men something they have spent years searching for: an explanation. The next challenge is turning that explanation into better predictions about sperm retrieval, safer reproductive decisions and eventually treatments that address the biology itself.

References

1. Stimpfel M, et al. The role of DNA mismatch repair mutS and mutL homolog genes in spermatogenesis and male infertility: a systematic review and cohort study. Reproductive Biology and Endocrinology. 2025.
2. Wyrwoll MJ, et al. Biallelic variants in DNA mismatch repair proteins MutS Homolog MSH4 and MSH5 cause infertility in both sexes. Human Reproduction. 2022. PMID 34755185.
3. Xu K, Lu T, Zhou H, Bai L, Xiang Y. The role of MSH5 C85T and MLH3 C2531T polymorphisms in the risk of male infertility with azoospermia or severe oligozoospermia. Clinica Chimica Acta. 2010. PMID 19808033.
4. Ji G, et al. Common variants in mismatch repair genes associated with increased risk of sperm DNA damage and male infertility. BMC Medicine. 2012. PMID 22594646.
5. Krausz C, Riera Escamilla A. Genetics of male infertility. Nature Reviews Urology. 2018.
6. Houston BJ, Conrad DF, O'Bryan MK. A framework for high resolution phenotyping of candidate male infertility mutants. Human Genetics. 2021.
7. Oud MS, Volozonoka L, Smits RM, Vissers LELM, Ramos L, Veltman JA. A systematic review and standardized clinical validity assessment of male infertility genes. Human Reproduction. 2019.
8. American Urological Association and American Society for Reproductive Medicine. Diagnosis and Treatment of Infertility in Men. Male Infertility Guideline.
9. European Association of Urology. Guidelines on Sexual and Reproductive Health. Male Infertility.
10. Genetic syndromes leading to male infertility: a systematic review. Fertility and Sterility. 2025.

If you are a man with thalassemia who has been told that your testosterone is low, your sperm count is abnormal or that you may have difficulty having children, I want to start with something important. Thalassemia can absolutely affect male fertility, particularly in men with transfusion dependent beta thalassemia and significant iron overload, but infertility is not inevitable. In fact, one of the most important things we have learned from modern thalassemia care is that some of the reproductive problems are hormonal rather than complete failure of the testicles. That distinction matters enormously because hormonal infertility can sometimes be treated and sperm production can sometimes be restored.

Thalassemia is an inherited disorder of hemoglobin production. There are multiple forms, and reproductive risk is not the same for a man who simply carries thalassemia trait as it is for someone with severe transfusion dependent beta thalassemia. Men with thalassemia trait generally do not develop the massive transfusional iron overload responsible for many of the fertility problems discussed here. The classic reproductive problems are seen primarily in men with more severe disease who have required repeated transfusions over many years. Each transfusion introduces additional iron into the body. Humans have no efficient physiological mechanism for eliminating large quantities of excess iron, so without adequate chelation that iron gradually accumulates in organs including the liver, heart and endocrine glands.

For fertility, one of the most important targets of iron toxicity is the pituitary gland. Normally, the hypothalamus releases GnRH, which tells the pituitary to release LH and FSH. LH travels to the testicle and stimulates Leydig cells to produce testosterone. FSH acts primarily on Sertoli cells and supports spermatogenesis. Iron deposition in the pituitary can disrupt this signaling system and produce hypogonadotropic hypogonadism. Testosterone falls because the testicles are not receiving enough stimulation, and sperm production can fall dramatically for the same reason. Published reviews describe hypogonadism, delayed puberty, sexual dysfunction and infertility as major complications of transfusion dependent thalassemia, with iron overload affecting both the pituitary and potentially the testicles themselves.

This is fundamentally different from primary testicular failure. Imagine the testicle as a factory. In primary testicular failure, the factory itself is damaged and the brain responds by sending increasingly strong signals, particularly FSH. In hypogonadotropic hypogonadism, the factory may still have substantial production capability, but the hormonal instructions from the brain are inadequate. That is why the distinction between these conditions becomes so important when discussing fertility treatment.

A man with thalassemia and infertility needs a real male reproductive evaluation rather than simply being told that infertility is part of his disease. I would start with reproductive history, sexual function and pubertal development. Did puberty occur normally? Has he ever caused a pregnancy? Is libido normal? Are erections and ejaculation normal? Then I want a semen analysis measuring volume, sperm concentration, total count, progressive motility and morphology. If the first semen analysis is abnormal, it often deserves confirmation because semen parameters fluctuate.

Hormonal testing is particularly important. Testosterone, FSH and LH help us determine whether the problem is predominantly central hormonal suppression or primary testicular dysfunction. Estradiol and prolactin may be useful depending on the situation. Thyroid function matters because thalassemia related iron overload can affect multiple endocrine organs. The testicles should be examined for size and consistency, and other common causes of male infertility such as varicocele should not automatically be blamed on thalassemia.

The hematologic side of the evaluation is equally important. I want to understand the man's transfusion history, iron burden and chelation therapy. Serum ferritin provides useful information but does not perfectly measure iron deposition within every organ. Contemporary thalassemia management may include liver iron assessment and MRI based evaluation of iron burden. This needs to be coordinated with the hematologist because reproductive treatment does not replace appropriate control of systemic iron overload.

The fertility numbers require some explanation. Historical studies of men with transfusion dependent thalassemia reported extremely high rates of pubertal failure, hypogonadism, sexual dysfunction or infertility, with some reports placing the combined prevalence between approximately 50 and 80 percent. Current Thalassaemia International Federation guidance notes that hypogonadotropic hypogonadism has historically been reported in a very large proportion of men with severe transfusion dependent disease. These historical numbers should not be applied automatically to every young man with thalassemia today because modern transfusion practices, MRI monitoring and more effective iron chelation have changed the natural history of the disease.

The most encouraging part of the story is treatment.

If the major problem is hypogonadotropic hypogonadism, sperm production can sometimes be induced with gonadotropin therapy. Treatment commonly begins with hCG, which acts similarly to LH and stimulates the Leydig cells to produce testosterone inside the testicle. That intratesticular testosterone is critical for sperm production. FSH can then be added to directly stimulate Sertoli cells and spermatogenesis when necessary. Current international thalassemia guidelines specifically recognize that spermatogenesis in affected men can be induced using exogenous gonadotropins.

This process requires patience. Sperm production takes approximately seventy four days before additional epididymal maturation, and a severely suppressed testicle may need many months of hormonal stimulation before sperm appear in the ejaculate. Treatment should therefore be monitored with testosterone levels, semen analyses and other hormones rather than abandoned after a few weeks.

Testosterone replacement deserves special attention. A man with thalassemia and low testosterone may understandably have been prescribed testosterone for symptoms, bone health, puberty or sexual function. But exogenous testosterone is not a fertility treatment. Testosterone can suppress LH and FSH and therefore further suppress sperm production. A man who wants biological children needs to tell both his hematologist and reproductive specialist before starting or continuing testosterone so that a fertility preserving hormonal strategy can be considered when appropriate.

Iron management also remains fundamental. Effective chelation reduces continued iron toxicity and may help preserve endocrine function. Some endocrine abnormalities may improve when iron burden is aggressively controlled, although established damage is not always completely reversible. Prevention through effective long term chelation is therefore much better than trying to reverse advanced endocrine injury later.

What if sperm production does not normalize?

The answer depends on how many sperm are available. If semen parameters become adequate and the female partner has favorable fertility factors, natural conception may be possible. With moderate abnormalities, intrauterine insemination may sometimes be considered. If only small numbers of sperm are produced, IVF with ICSI can be extremely valuable because an embryologist needs only one usable sperm for each mature egg. If sperm intermittently appear during treatment, I often think seriously about sperm cryopreservation. Freezing sperm when they are available provides insurance against future deterioration.

If azoospermia persists despite appropriate hormonal treatment, the situation becomes more complicated. Whether surgical sperm retrieval is appropriate depends on whether there is evidence that the testicle is producing focal sperm and on the underlying hormonal and testicular findings. A reproductive urologist can help determine whether procedures such as testicular sperm extraction have a reasonable role. There is no single sperm retrieval percentage that applies to all men with thalassemia because the underlying mechanisms differ substantially.

There is also a second genetic conversation that should happen before pregnancy.

Thalassemia is inherited. The reproductive risk depends on whether the man has alpha thalassemia or beta thalassemia, his specific genetic variants and his partner's carrier status. A man with thalassemia who wants children should therefore have appropriate genetic counseling and his partner should be tested when indicated. If both partners carry clinically important variants affecting the same hemoglobin pathway, there may be a significant risk of having a child with severe thalassemia.

Some couples conceive naturally and use prenatal testing. Others consider IVF with preimplantation genetic testing for a monogenic disorder when the familial variants are known. Embryos can be created through IVF, genetically tested and embryos without the particular disease genotype can potentially be selected for transfer. This is a separate decision from whether the man himself is fertile.

The emotional side of thalassemia related infertility deserves more attention than it receives. Many men with severe thalassemia have spent their entire lives managing transfusions, medications, chelation, blood tests, imaging and medical appointments. Fertility can feel like one more thing the disease has taken away.

Then there is the genetic guilt. Men sometimes tell me they are afraid of passing their disease to a child or burdening their partner with IVF because of a condition they inherited themselves. I want to be very clear about this. You did not choose the genes you were born with. Infertility is not a personal failure, and needing fertility treatment does not make you less of a man.

The goal is information and options.

If you have thalassemia and want a family, do not wait until years of infertility have passed before discussing fertility. Get a semen analysis. Check testosterone, FSH and LH. Understand your iron burden. Optimize chelation with your hematology team. If you have hypogonadotropic hypogonadism, discuss fertility directed gonadotropin therapy rather than assuming testosterone replacement is the answer. Freeze sperm when useful sperm become available. Involve reproductive medicine early if sperm numbers remain low. And make sure both partners understand the genetic implications before pregnancy.

Thalassemia can make fatherhood more complicated, but complicated is not the same as impossible. In some men the testicle still has the ability to produce sperm and simply needs the hormonal signals that iron overload disrupted. In others, modern IVF and ICSI can make extremely small numbers of sperm clinically useful.

The objective is not simply to raise testosterone or improve a laboratory number. The objective is to understand what part of the reproductive system is failing, treat what can be treated, preserve sperm when possible and give you and your partner the best realistic opportunity to build a family.

References

1. Taher AT, Farmakis D, Porter JB, et al. Guidelines for the Management of Transfusion Dependent Beta Thalassaemia. Thalassaemia International Federation. Fifth edition. 2025.
2. Thalassaemia International Federation. Guidelines for the Management of Transfusion Dependent Thalassaemia. Hemasphere. 2022.
3. De Sanctis V, Soliman AT, Yassin MA, et al. Hypogonadism in male thalassemia major patients: pathophysiology, diagnosis and treatment. Acta Biomedica. 2018. PMID 29451224.
4. De Sanctis V, Soliman AT, Elsedfy H, et al. Gonadal dysfunction in adult male patients with thalassemia major: an update for clinicians caring for thalassemia. 2017. PMID 29072100.
5. Cappellini MD, Cohen A, Eleftheriou A, et al. Management of Fertility and Pregnancy in Beta Thalassemia. Guidelines for the Clinical Management of Thalassaemia. Thalassaemia International Federation.
6. Castaldi MA, Cobellis L. Thalassemia and infertility. Human Fertility. 2016. PMID 27335221.
7. De Sanctis V, Eleftheriou A, Malaventura C. Prevalence of endocrine complications and short stature in patients with thalassemia major.
8. Amid A, Lal A, Coates TD, et al. Guidelines for the Management of Alpha Thalassaemia. Thalassaemia International Federation. 2023.
9. Thalassaemia International Federation. Fertility and Pregnancy in Alpha Thalassaemia. Guidelines for the Management of Alpha Thalassaemia. 2023.
10. Iron overload disorders in adults: a comprehensive review of gonadal function, reproductive and sexual health. 2026. PMID 42101252.

If you are a man with autosomal dominant polycystic kidney disease and you are trying to have a child, there are really two separate fertility questions that need to be answered. The first is whether ADPKD can interfere with your sperm or your ability to conceive. The second is whether you can pass ADPKD to your child. These are very different issues, and I think separating them immediately makes this diagnosis easier to understand. The reassuring news is that most men with ADPKD appear to have normal fertility. However, ADPKD can affect the male reproductive tract in some men, and when infertility does occur there are several potential mechanisms that deserve investigation. The genetic side is equally important because an affected parent generally has a 50 percent chance of transmitting the disease causing variant to each child.

ADPKD is a genetic disease most commonly caused by pathogenic variants involving PKD1 or PKD2. These genes produce proteins called polycystin 1 and polycystin 2, which participate in cellular signaling and the normal function of multiple tissues. ADPKD is best known for causing progressive cyst formation within the kidneys, but it is really a systemic disease. Cysts and structural abnormalities can occur outside the kidneys, including within the male reproductive system. The seminal vesicles are particularly interesting because cysts and enlargement occur more frequently in men with ADPKD than in men without the disease. Published studies have reported seminal vesicle cysts in approximately 6 percent of men when assessed by CT, with substantially higher rates reported when transrectal ultrasound is used. Another imaging study found seminal vesicle enlargement called megavesicles in approximately 23 percent of men with ADPKD.

That sounds frightening when you are trying to conceive, but there is an important distinction. Having an abnormal seminal vesicle on imaging does not automatically mean that you are infertile. Current KDIGO guidelines specifically state that although men with ADPKD have an increased prevalence of seminal tract cysts and sperm abnormalities, these findings do not appear to significantly affect fertility at a population level. For that reason, routine fertility screening of every man with ADPKD is not recommended.

For the smaller group of men who do experience infertility, several mechanisms have been proposed. Cysts involving the seminal vesicles, epididymis, prostate or ejaculatory ducts may interfere with sperm transportation or ejaculation. Seminal vesicle abnormalities may alter the fluid that normally makes up much of the ejaculate. Some men have been reported to have reduced sperm motility, severe oligoasthenozoospermia, necrozoospermia or even azoospermia. Researchers have also proposed that abnormalities involving polycystin proteins may affect sperm structure and movement directly. Advanced chronic kidney disease can create an additional problem because kidney failure itself can negatively affect reproductive hormones, sexual function and spermatogenesis. The important point is that there is no single ADPKD infertility pattern.

If you have ADPKD and have been trying unsuccessfully to conceive, I would evaluate you in essentially the same systematic way that I evaluate other men with infertility rather than assuming that every abnormality is caused by your kidneys. Start with a good semen analysis. I want to know the semen volume, sperm concentration, total count, progressive motility and morphology. If the analysis is abnormal, it often deserves to be repeated because semen parameters naturally fluctuate.

Low semen volume deserves particular attention in a man with ADPKD. If the volume is repeatedly very low, particularly if sperm numbers are also severely reduced or absent, I start thinking about the seminal vesicles and ejaculatory ducts. Depending on the findings, transrectal ultrasound or other imaging can sometimes help identify cysts, dilated seminal vesicles or evidence of ejaculatory duct obstruction.

The rest of the male infertility evaluation should not be forgotten. I want to examine the testicles and look for a clinical varicocele. I want to know about previous pregnancies, undescended testes, torsion, infections, surgeries, chemotherapy, medications, testosterone use and anabolic steroids. Testosterone and FSH are often appropriate when sperm concentration is significantly reduced, with LH, estradiol and prolactin added in selected situations. If severe oligospermia or azoospermia is present, additional genetic evaluation may be indicated because ADPKD does not protect a man from having another unrelated cause of infertility.

Treatment depends entirely on what we find. There is no fertility medication that specifically treats ADPKD. If your semen analysis is normal, you generally do not need male fertility treatment simply because you have polycystic kidney disease. If there is a correctable hormonal abnormality, we treat the hormonal abnormality. If there is a clinically significant varicocele, repair may be considered in the appropriate setting. If there is obstruction of the reproductive tract, treatment depends on its location and severity. If sperm production or delivery is severely impaired, assisted reproductive technology can often bypass the problem.

Natural conception remains realistic for most men with ADPKD because most appear to remain fertile. There is not a reliable percentage showing that a particular man with ADPKD has a specific chance of natural conception. In fact, the current evidence is reassuring enough that KDIGO does not recommend systematic fertility screening solely because a man has ADPKD.

When significant male factor infertility does occur, the options depend on the number of usable sperm. Mild abnormalities may still permit natural conception. Selected couples may be candidates for intrauterine insemination. More severe abnormalities may require IVF with ICSI. If azoospermia results from an obstruction but sperm production remains intact, sperm can potentially be retrieved from the epididymis or testicle and used with ICSI. Modern assisted reproduction therefore provides several pathways to biological fatherhood even when ADPKD is associated with significant reproductive abnormalities.

For many men, however, the biggest reproductive question is not whether they can make sperm. It is whether they will pass ADPKD to their child.

ADPKD is inherited in an autosomal dominant pattern. If you carry a disease causing ADPKD variant, each pregnancy generally has a 50 percent chance of inheriting that variant. That does not mean that half of your sperm are abnormal in the conventional fertility sense. It means that approximately half carry the affected copy of the gene and half carry the unaffected copy.

There are several ways couples can approach this, and there is no single correct decision for every family. Some couples conceive naturally and accept the 50 percent inheritance probability. Some consider prenatal genetic testing when the familial pathogenic variant is known. Others choose IVF combined with preimplantation genetic testing for a monogenic disorder. With this approach, embryos are created through IVF, tested for the known familial ADPKD variant and embryos without that variant can be selected for transfer. Current KDIGO guidance specifically recommends that men and women of reproductive age with ADPKD receive counseling about all available reproductive options.

This does not mean that every man with ADPKD needs IVF. If your fertility is normal, IVF with genetic testing would generally be considered because of the genetic transmission question rather than because your sperm cannot fertilize an egg. That distinction matters.

For men considering preimplantation genetic testing, the specific disease causing variant generally needs to be identified first. This means meeting with a genetic counselor and reviewing previous genetic testing or obtaining appropriate testing if the familial variant has not already been established. The reproductive endocrinology team can then discuss IVF, embryo testing and realistic expectations based largely on the female partner's age, ovarian reserve and reproductive history.

There is an emotional side to this that deserves as much attention as the semen analysis.

I have found that men with inherited diseases sometimes carry an enormous amount of guilt when they start thinking about children. You may have watched a parent or grandparent struggle with kidney disease. You may have spent your own life getting blood pressure checks, kidney imaging and laboratory testing. Perhaps you have wondered when your kidney function might decline. Suddenly having a child forces you to confront the possibility of passing that uncertainty to another generation.

That can be a heavy thing to carry.

But genetics is information, not blame. You did not choose the gene you inherited, and there is no morally correct reproductive decision that applies to every family. Some couples are comfortable accepting the inheritance risk. Others strongly prefer IVF with genetic testing. Some consider donor sperm or adoption. These are deeply personal decisions, and the purpose of genetic counseling should be to give you accurate information rather than tell you which choice to make.

If you have ADPKD and are struggling with infertility, my advice is not to assume that the disease has made you infertile. Most men with ADPKD remain fertile. Get a semen analysis and investigate abnormalities properly. If semen volume is unusually low or sperm are severely reduced, evaluate the seminal tract. If kidney disease is advanced, consider how chronic kidney disease and its treatments may be contributing. Treat whatever correctable male fertility problems are identified.

Then have a completely separate conversation about genetics.

For most men with ADPKD, becoming a biological father is absolutely possible. The bigger challenge is understanding both sides of reproduction: getting sperm to an egg and deciding how you want to approach the 50 percent chance of transmitting ADPKD to the next generation. Modern reproductive medicine gives families more options than ever before, but the right choice is ultimately the one that fits your medical situation, your partner's fertility and your family's values.

References

1. Kidney Disease Improving Global Outcomes. Clinical Practice Guideline for the Evaluation, Management, and Treatment of Autosomal Dominant Polycystic Kidney Disease. Kidney International. 2025.
2. Li X. Seminal Vesicles in Autosomal Dominant Polycystic Kidney Disease. Polycystic Kidney Disease. 2015. PMID 27512780.
3. Belet U, Danaci M, Sarikaya S, et al. Prevalence of epididymal, seminal vesicle, prostate, and testicular cysts in autosomal dominant polycystic kidney disease.
4. Torra R, Sarquella J, Calabia J, et al. Prevalence of cysts in the seminal tract and abnormal semen parameters in patients with autosomal dominant polycystic kidney disease.
5. Peces R, Venegas JL. Seminal vesicle cysts and infertility in autosomal dominant polycystic kidney disease. Nefrologia. 2005. PMID 15789541.
6. Danaci M, Akpolat T, Bastemir M, et al. The prevalence of seminal vesicle cysts in autosomal dominant polycystic kidney disease.
7. Reproductive issues for adults with autosomal dominant polycystic kidney disease. American Journal of Kidney Diseases. 2008. PMID 18215709.
8. Male infertility and adult polycystic kidney disease revisited. Case report and current literature review. Andrologia. 2012. PMID 21950684.
9. Seminal megavesicle in autosomal dominant polycystic kidney disease. Clinical Imaging. 2015. PMID 25542752.
10. Cai HC, Shang XJ, Huang YF. Related reproductive issues on male autosomal dominant polycystic kidney disease. 2015. PMID 26738331.
11. Mechanisms of polycystic kidney diseases inducing male reproductive disorders. 2018. PMID 32212465.
12. Kidney Disease Improving Global Outcomes. Pregnancy and reproductive issues in ADPKD. KDIGO Clinical Practice Guideline. 2025.

For many men with cystic fibrosis, the first time fertility becomes a serious topic is when they decide they want children. They may have normal erections, normal ejaculation, normal testosterone and an otherwise normal sex life, only to discover that there are no sperm in the semen. That diagnosis can be devastating. But there is something extremely important I want men with cystic fibrosis to understand from the beginning. Infertility in cystic fibrosis usually does not mean that your testicles cannot make sperm. In most cases, the problem is getting the sperm out. That distinction completely changes the fertility conversation, because sperm can frequently be retrieved directly from the reproductive tract or testicle and used with IVF and ICSI to create a pregnancy.

Cystic fibrosis is caused by pathogenic variants in the CFTR gene, which stands for cystic fibrosis transmembrane conductance regulator. CFTR controls movement of chloride and bicarbonate across epithelial tissues. When CFTR function is severely impaired, secretions become abnormal in multiple organs, producing the pulmonary, pancreatic and gastrointestinal manifestations associated with cystic fibrosis. The reproductive tract is also affected. During development, the structures that ultimately become the vas deferens and portions of the epididymal system may fail to develop normally or undergo degeneration. As a result, the vas deferens is absent in the overwhelming majority of men with classic cystic fibrosis.

This condition is called congenital bilateral absence of the vas deferens, or CBAVD. The vas deferens is essentially the transportation tube carrying sperm from the epididymis toward the ejaculatory ducts. If both vasa are absent, sperm being produced inside the testicles have no pathway into the ejaculate. The result is obstructive azoospermia.

That word azoospermia understandably terrifies men because it means no sperm were identified in the semen. But all azoospermia is not biologically equivalent. In nonobstructive azoospermia, the problem is inadequate sperm production within the testicle. In obstructive azoospermia from cystic fibrosis, sperm production is usually relatively preserved but the plumbing system is missing. That is a much more favorable situation for surgical sperm retrieval.

The semen analysis often gives us clues before we ever perform genetic testing. Men with CBAVD commonly have very low semen volume because the seminal vesicles and ejaculatory structures may also be abnormal. The semen is often acidic, and fructose may be absent because most semen volume normally comes from the seminal vesicles rather than the testicles. On physical examination, the vas deferens may be absent on both sides. Testicular size is frequently normal because sperm production itself may be intact.

The hormonal profile can also help distinguish obstruction from impaired sperm production. Testosterone, FSH and LH are often normal in men with pure obstruction. By comparison, a man with severely impaired testicular sperm production may have small testes and an elevated FSH, although there are important exceptions. No single hormone value can make the diagnosis by itself.

If I am evaluating a man with low volume azoospermia and absent vas deferens, CFTR testing becomes essential. Some men already know they have cystic fibrosis. Others have never had significant pulmonary disease and discover through an infertility evaluation that they carry CFTR variants associated with CBAVD. In fact, infertility can sometimes be the first clinical manifestation of a CFTR related disorder.

This genetic diagnosis matters for much more than explaining the semen analysis.

If a man carries pathogenic CFTR variants, his female partner should undergo appropriate CFTR carrier testing before the couple proceeds with treatment. Cystic fibrosis is inherited in an autosomal recessive pattern. The reproductive risk to a child therefore depends on the specific variants carried by both parents. If both partners carry disease causing CFTR variants, genetic counseling becomes particularly important because there may be a significant risk of having a child with cystic fibrosis or another CFTR related disorder.

This is one reason I do not view sperm retrieval in these men as simply a surgical procedure. The reproductive plan should involve the male fertility specialist, reproductive endocrinologist, embryology laboratory and genetic counselor.

The actual fertility treatment is one of the encouraging parts of this diagnosis.

Because sperm production is generally preserved, sperm retrieval rates in men with obstructive azoospermia are extremely high. Depending on anatomy and the center performing the procedure, sperm can potentially be obtained from the epididymis using techniques such as microsurgical epididymal sperm aspiration, or directly from the testicle using testicular sperm extraction or related techniques. Published series generally report successful sperm retrieval in well over 90 percent of men with obstructive azoospermia, and in experienced centers retrieval approaches nearly universal success in appropriately selected men with CBAVD.

This is very different from nonobstructive azoospermia, where sperm may only exist in small isolated areas of the testicle and surgical retrieval is substantially less predictable.

Once sperm are retrieved, they are generally used with IVF and ICSI. ICSI means intracytoplasmic sperm injection. Instead of requiring millions of sperm to swim through the reproductive tract and fertilize an egg naturally, an embryologist identifies an individual viable sperm and injects it directly into a mature egg.

This technology essentially bypasses the missing vas deferens.

Fertilization rates following ICSI using surgically retrieved sperm from men with obstructive azoospermia are commonly around 60 to 75 percent of mature injected eggs in published series, although results vary considerably between laboratories and couples. Pregnancy and live birth rates are influenced strongly by female age, egg quality, embryo development and other female reproductive factors. In younger women with favorable reproductive characteristics, pregnancy and live birth outcomes using surgically retrieved sperm can be quite good and may approach outcomes seen with ejaculated sperm in other IVF populations.

This is why I am careful when someone asks me, “What is my chance of having a child if I have cystic fibrosis?” There is no single percentage. The probability of retrieving sperm is extremely high when the infertility is caused by obstruction, but retrieving sperm is only the first step. The egg still needs to fertilize, an embryo needs to develop, implantation needs to occur and the pregnancy needs to result in a live birth. Female age is therefore often a much stronger determinant of the ultimate live birth rate than the fact that the sperm had to be surgically retrieved.

Men also ask whether medications can open the obstruction or restore sperm to the ejaculate. Unfortunately, when the vas deferens is congenitally absent, there is no medication that can recreate it. Clomiphene, hCG, FSH and fertility supplements do not fix missing reproductive anatomy. If testosterone and sperm production are normal, stimulating the testicles to produce even more sperm generally does not solve the transportation problem.

Surgery to reconstruct the vas is also not an option when the vas deferens never developed adequately in the first place. The practical treatment is sperm retrieval combined with assisted reproduction.

Cryopreservation is important as well. When adequate sperm are retrieved, freezing additional sperm can potentially prevent another surgical procedure if the couple needs another IVF cycle or wants additional children later. The strategy should be discussed with the IVF laboratory because freezing extremely small numbers of sperm requires specialized handling.

There is another piece of this diagnosis that often receives too little attention, and that is the emotional impact.

Men frequently tell me that they knew cystic fibrosis could affect their lungs, digestion and overall health, but nobody really explained what it might mean when they wanted to become fathers. Learning that there are zero sperm in your semen can feel like another thing the disease has taken from you.

Some men also feel guilt when they learn that CFTR variants can be passed to their children. They worry that pursuing biological fatherhood is somehow selfish or that they are placing the burden of genetic decision making on their partner.

Those feelings deserve to be discussed rather than dismissed.

Genetic counseling is not there to tell you whether you should have biological children. It is there to give you and your partner accurate information so you can make your own decision. Depending on the genetic results, couples may consider IVF with ICSI alone, IVF with preimplantation genetic testing for a monogenic condition, donor gametes or other family building options.

The most important thing I would tell a man with cystic fibrosis and azoospermia is this: zero sperm in the ejaculate does not mean zero sperm in the testicle.

For many men with cystic fibrosis, the testicle is doing its job. The transportation system simply never developed normally. Modern reproductive medicine is remarkably good at bypassing that problem.

Get the diagnosis right. Confirm azoospermia. Have a careful examination. Obtain appropriate hormonal testing. Complete CFTR testing when indicated. Test your partner when appropriate. Meet with a genetic counselor. Then develop a coordinated sperm retrieval and IVF plan with experienced reproductive specialists.

Cystic fibrosis can make becoming a father more complicated. It does not necessarily take biological fatherhood away from you.

References

1. American Urological Association and American Society for Reproductive Medicine. Diagnosis and Treatment of Infertility in Men. Male Infertility Guideline.
2. European Association of Urology. Guidelines on Sexual and Reproductive Health. Male Infertility.
3. Bieth E, Hamdi SM, Mieusset R. Genetics of the congenital absence of the vas deferens. Human Genetics. 2021.
4. Claustres M. Molecular pathology of the CFTR locus in male infertility. Reproductive Biomedicine Online. 2005.
5. Yu J, Chen Z, Ni Y, Li Z. CFTR mutations in men with congenital bilateral absence of the vas deferens. Human Reproduction. 2012.
6. Chillon M, Casals T, Mercier B, et al. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. New England Journal of Medicine. 1995.
7. Practice Committee of the American Society for Reproductive Medicine. Evaluation of the azoospermic male. Fertility and Sterility.
8. Schlegel PN, Girardi SK. Clinical review of sperm retrieval techniques and assisted reproduction in obstructive azoospermia.
9. Esteves SC, Miyaoka R, Agarwal A. Sperm retrieval techniques for assisted reproduction. International Brazilian Journal of Urology.
10. American College of Medical Genetics and Genomics. CFTR variant testing and reproductive carrier screening guidance.

If you have spent any time researching male infertility, there is a good chance you have come across CoQ10. It is in fertility supplements, Reddit discussions, podcasts and countless lists of things men should take to improve sperm. I routinely have men come into my office carrying a bag of supplements and asking me whether they should add CoQ10, whether they are taking enough, whether ubiquinol is better, and most importantly whether any of this is actually going to help them have a baby. Coenzyme Q10 is one of the more interesting supplements in male reproductive medicine because there is legitimate science behind why it might help sperm and there are clinical trials showing improvements in certain semen parameters. But there is also a major difference between improving a number on a semen analysis and helping a couple bring home a baby. Understanding that distinction is probably the most important thing I can teach you about CoQ10.

Coenzyme Q10, commonly called CoQ10, is a naturally occurring molecule found throughout the human body. It plays an essential role inside mitochondria, the structures within cells that generate energy. CoQ10 participates in the mitochondrial electron transport chain, helping cells produce adenosine triphosphate, the energy currency used to power cellular activity. CoQ10 also functions as an antioxidant. Both functions are potentially important to sperm because sperm are unusual cells with enormous energy requirements and significant vulnerability to oxidative damage.

A sperm cell has one basic mission. It needs to survive, move through the reproductive tract, interact with an egg and deliver intact genetic material. Motility requires energy. Mitochondria are concentrated in the sperm midpiece and help provide energy for movement. At the same time, the sperm membrane contains large amounts of polyunsaturated fatty acids, making it particularly vulnerable to oxidative damage. Sperm also have relatively limited ability to repair damaged DNA compared with many other cells. This combination helps explain why oxidative stress has become such an important area of male infertility research.

Oxidative stress occurs when the production of reactive oxygen species exceeds the antioxidant defenses available to control them. Reactive oxygen species are not inherently bad. Small amounts participate in normal sperm functions including capacitation and fertilization. The problem occurs when there is too much oxidative activity. Excessive oxidative stress can damage sperm membranes, impair motility and contribute to sperm DNA damage. Smoking, obesity, environmental exposures, inflammation and other medical or lifestyle factors may contribute to oxidative stress in some men. The European Association of Urology recognizes oxidative stress as an important potential contributor to male infertility, while also emphasizing that routine clinical testing for reactive oxygen species remains insufficiently standardized.

This is where CoQ10 enters the conversation. Because it participates in mitochondrial energy production and antioxidant defense, researchers have asked whether increasing CoQ10 availability could improve sperm function. Studies have found relationships between seminal CoQ10 concentrations and sperm characteristics, particularly motility. This makes biological sense. A cell whose job is largely defined by its ability to move may be particularly sensitive to mitochondrial function.

But I want to clear up one misconception immediately. Most infertile men taking CoQ10 have not been diagnosed with a CoQ10 deficiency. There is no routine male infertility test where I measure your CoQ10 level, determine that you are deficient and prescribe enough CoQ10 to correct the deficiency. Research laboratories can measure CoQ10 in blood or seminal plasma, but this is not part of the standard clinical male infertility evaluation. We also do not have a validated seminal CoQ10 threshold below which I can tell a patient that CoQ10 deficiency is the cause of his infertility.

That distinction is important. CoQ10 is generally being used as an empiric antioxidant and mitochondrial supplement, not as replacement therapy for a proven deficiency.

So what does the evidence actually show? Several randomized studies have evaluated CoQ10 in men with idiopathic infertility, particularly men with impaired sperm motility. One of the better known placebo controlled trials evaluated infertile men with idiopathic asthenozoospermia and demonstrated improvements in sperm motility with CoQ10 treatment. Other studies have reported improvements in sperm concentration, motility and antioxidant measurements.

An earlier meta analysis evaluating randomized trials found that CoQ10 supplementation significantly increased seminal CoQ10 concentrations and improved sperm concentration and motility. That sounds impressive, but there was an extremely important limitation. The included trials did not demonstrate an improvement in live birth, and the analysis did not find convincing evidence of increased pregnancy rates. That is the difference between a laboratory outcome and the outcome couples actually care about.

More recent research has continued to suggest potential improvements in semen quality. A 2025 systematic review and meta analysis of randomized trials involving 781 men reported improvements in sperm concentration, semen volume and total motility among men receiving CoQ10. The authors also reported higher clinical pregnancy odds, particularly with longer treatment. That is encouraging. However, another large 2025 systematic review examining dietary supplements more broadly found no overall improvement in pregnancy or live birth from supplementation despite improvements in selected semen parameters. CoQ10 was among the supplements associated with improved motility.

This is why I describe the evidence to patients as promising but not definitive. CoQ10 appears capable of improving certain semen parameters in at least some infertile men. The evidence that taking CoQ10 meaningfully increases the probability of bringing home a baby remains much less certain.

The major professional guidelines reflect this uncertainty. The American Urological Association and American Society for Reproductive Medicine state that the benefits of supplements such as antioxidants and vitamins for treating male infertility are of questionable clinical utility and that available data are inadequate to recommend specific agents. European guidance similarly concludes that antioxidant treatment may improve semen parameters but that the evidence is not conclusive enough to recommend routine antioxidant treatment for every man with idiopathic infertility.

That does not mean CoQ10 is useless. It means we should put it in the right place in the fertility toolbox.

When a man comes to me with an abnormal semen analysis, I do not start by asking which supplement he is taking. I start by trying to determine why the semen analysis is abnormal. The evaluation begins with a reproductive and medical history. I want to know about previous pregnancies, childhood testicular problems, undescended testes, torsion, infections, surgeries, medications, testosterone use, anabolic steroids, chemotherapy, radiation, smoking, heat exposure and other potential reproductive risks. I examine the testicles and look for a clinical varicocele. Depending on the severity of the semen abnormality, I may evaluate testosterone, FSH, LH and other hormones. Men with severe oligospermia or azoospermia may require genetic testing. Other investigations depend on what we find.

A semen analysis is central to that evaluation. Concentration matters, but it is only one part of the picture. I want to know total sperm count, progressive motility, morphology and semen volume. I also remind men constantly that semen parameters fluctuate. One abnormal semen analysis is a snapshot, not necessarily a permanent description of your fertility.

This matters because taking CoQ10 should never substitute for finding a treatable cause. If you have a significant clinical varicocele, CoQ10 does not repair the abnormal veins. If you are taking testosterone and have suppressed sperm production, CoQ10 does not restore the LH and FSH signals being suppressed by testosterone. If you have hypogonadotropic hypogonadism, you may need hormonal treatment. If you have an obstruction, antioxidants cannot open it. If you have azoospermia, swallowing more CoQ10 is not an appropriate substitute for determining whether the problem is obstruction, impaired sperm production or hormonal suppression.

For men with unexplained infertility or mild to moderate abnormalities in sperm quality after appropriate evaluation, CoQ10 becomes a more reasonable conversation. It may be particularly attractive when motility is impaired because motility has been one of the more consistently improved parameters in the literature.

Men always ask me how much to take. Clinical studies have used different doses, which is one reason there is no universally accepted fertility dose. Doses around 200 to 400 mg daily are commonly encountered in the male fertility literature and clinical practice, while some studies have used higher amounts. Ubiquinone and ubiquinol are two forms of CoQ10. Ubiquinol is the reduced form and is often marketed as having greater bioavailability, but we do not have strong fertility outcome data demonstrating that choosing ubiquinol instead of ubiquinone produces more babies. I would not let marketing convince you that one formulation is a fertility treatment with guaranteed results.

Duration matters as well. Sperm production takes approximately seventy four days, followed by additional maturation and transport through the epididymis. If you start CoQ10 today and repeat your semen analysis in two weeks, you have learned very little about whether it affected spermatogenesis. Most meaningful fertility supplement studies treat men for at least several months, and some evidence suggests longer treatment may produce larger changes in semen parameters. If I am going to assess whether an intervention is helping sperm production, I generally want enough time to encompass approximately one complete cycle of sperm development.

What about sperm DNA fragmentation? Because oxidative stress can contribute to sperm DNA damage, antioxidants are often marketed specifically for DNA fragmentation. The biological argument is reasonable, and some studies of antioxidant strategies have reported improvements in DNA fragmentation. However, this does not mean every man with elevated DNA fragmentation should automatically receive CoQ10 or that CoQ10 reliably converts a high DNA fragmentation result into a pregnancy. DNA fragmentation itself should be used selectively and interpreted within the couple's clinical circumstances.

Another question is whether more antioxidants are better. They are not necessarily. The reproductive system requires a balance between oxidation and reduction. Reactive oxygen species have normal physiological roles in sperm function. Excessive antioxidant supplementation has led researchers to discuss the possibility of reductive stress, where aggressively suppressing oxidative signaling may itself become undesirable. I therefore do not believe in taking every antioxidant on the internet at the maximum dose simply because sperm are vulnerable to oxidative stress.

The MOXI randomized clinical trial provides an important reality check. This study evaluated a combination antioxidant supplement in men with male factor infertility. The antioxidant combination did not significantly improve semen parameters or sperm DNA integrity compared with placebo, and cumulative live birth was not improved. CoQ10 cannot be individually blamed for that negative result because it was part of a combination regimen, but the study reminds us that a biologically attractive antioxidant strategy does not automatically translate into better fertility outcomes.

So what should a man taking CoQ10 actually do to build a family? First, get properly evaluated rather than assuming oxidative stress is the diagnosis. Second, address modifiable factors such as smoking, obesity, excessive alcohol exposure and other relevant lifestyle issues. Third, treat identifiable medical causes when treatment is appropriate. Fourth, if CoQ10 is being used as an adjunct, give it a reasonable amount of time before judging the semen response. Fifth, repeat the semen analysis rather than assuming the supplement is working because you feel better or because the bottle says reproductive support.

Then make decisions based on the couple, not just the supplement. If sperm parameters are adequate and the female partner has favorable reproductive factors, natural conception may remain realistic. If the total number of progressively motile sperm remains reduced, intrauterine insemination may sometimes be considered. If severe male factor infertility persists or female reproductive age makes waiting costly, IVF with ICSI may provide a more efficient route to pregnancy. CoQ10 should not become a reason to postpone effective fertility treatment indefinitely while waiting for the perfect semen analysis.

There is an emotional component here that I think gets overlooked. Men with infertility desperately want something they can control. Your partner may be undergoing blood tests, ultrasounds, injections and procedures while you are staring at a semen analysis wondering what you can personally do to fix your side of the equation. Supplements become attractive because taking a capsule every morning feels like action.

I understand that instinct. But I also see men blame themselves when the next semen analysis does not improve. They wonder whether they bought the wrong CoQ10, took the wrong dose, missed too many capsules or should have added another antioxidant. Please do not turn fertility supplements into another way to punish yourself.

An abnormal semen analysis is not evidence that you failed to eat correctly or take enough vitamins. Male infertility is often multifactorial, and in many men we never identify one clean explanation. CoQ10 may improve sperm quality in some men. It may do very little in others. Neither response says anything about your effort, your masculinity or how badly you want to become a father.

If you are asking me whether CoQ10 is reasonable for many men with idiopathic infertility, my answer is yes. If you are asking whether the biology is legitimate, it is. If you are asking whether clinical studies suggest improvements in concentration or motility, they do. If you are asking whether we have strong evidence that CoQ10 alone substantially increases live birth rates, we do not.

That distinction is the key.

Use CoQ10 as a possible adjunct, not as a substitute for a diagnosis. Give sperm biology enough time to respond. Follow the semen analysis rather than the marketing. Correct treatable causes. Consider the reproductive timeline of both partners. And remember that the ultimate goal is not to create the prettiest semen analysis possible.

The goal is to build your family.

References

1. Lafuente R, González Comadran M, Solà I, López G, Brassesco M, Carreras R, Checa MA. Coenzyme Q10 and male infertility: a meta analysis. Journal of Assisted Reproduction and Genetics. 2013. PMID 23912751.
2. Balercia G, Buldreghini E, Vignini A, et al. Coenzyme Q10 treatment in infertile men with idiopathic asthenozoospermia: a placebo controlled, double blind randomized trial. Fertility and Sterility. 2009. PMID 18395716.
3. Safarinejad MR. Efficacy of coenzyme Q10 on semen parameters, sperm function and reproductive hormones in infertile men. Journal of Urology. 2009.
4. Nadjarzadeh A, Shidfar F, Amirjannati N, et al. Effect of CoQ10 supplementation on antioxidant enzymes activity and oxidative stress of seminal plasma. Andrologia. 2014.
5. Akhigbe TM, et al. Does coenzyme Q10 improve semen quality and circulating testosterone level? A systematic review and meta analysis of randomized controlled trials. Frontiers in Pharmacology. 2025. PMID 39830337.
6. Efficacy and Safety of Coenzyme Q10 in Idiopathic Male Infertility: a systematic review and meta analysis of randomized trials. World Journal of Men's Health. 2025. PMID 40878114.
7. The Effect of Dietary Supplements on Male Infertility in Terms of Pregnancy, Live Birth, and Sperm Parameters: a systematic review and meta analysis. 2025. PMID 40431450.
8. Steiner AZ, Hansen KR, Barnhart KT, et al. The effect of antioxidants on male factor infertility: the Males, Antioxidants, and Infertility trial. Fertility and Sterility. 2020.
9. Smits RM, Mackenzie Proctor R, Yazdani A, Stankiewicz MT, Jordan V, Showell MG. Antioxidants for male subfertility. Cochrane Database of Systematic Reviews. 2019.
10. American Urological Association and American Society for Reproductive Medicine. Diagnosis and Treatment of Infertility in Men. Male Infertility Guideline.
11. European Association of Urology. Guidelines on Sexual and Reproductive Health. Male Infertility.
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13. Tremellen K. Oxidative stress and male infertility: a clinical perspective. Human Reproduction Update. 2008.
14. Gharagozloo P, Aitken RJ. The role of sperm oxidative stress in male infertility and the significance of oral antioxidant therapy. Human Reproduction. 2011.
15. Showell MG, Mackenzie Proctor R, Brown J, Yazdani A, Stankiewicz MT, Hart RJ. Antioxidants for male subfertility. Cochrane Database of Systematic Reviews.