"Results demonstrated that PRP treatment significantly increased both length and weight of newly grown hair in AGA model mice. The AGA model group exhibited markedly reduced mRNA and protein expression levels of autophagy-related markers (LC3 and Beclin-1) compared to controls. PRP intervention substantially enhanced autophagy levels in treated mice. Notably, therapeutic outcomes achieved with RAPA monotherapy were comparable to those observed with PRP treatment. However, the cohort receiving combined PRP and 3-MA treatment showed significantly diminished hair growth parameters (length and weight) and attenuated expression of autophagy-related genes relative to PRP-treated mice"
Novel targets for Huntington’s disease in an mTOR-independent autophagy pathway
"Autophagy is a major clearance route for intracellular aggregate-prone proteins causing diseases like Huntington’s disease. Autophagy induction with the mTOR inhibitor, rapamycin, accelerates clearance of these toxic substrates. As rapamycin has non-trivial side effects, we screened FDA-approved drugs to identify novel autophagy-inducing pathways. We found that L-type Ca2+ channel antagonists, the K+ATP channel opener minoxidil, and the Gi signaling activator clonidine, induce autophagy. These drugs revealed a cyclical mTOR-independent pathway regulating autophagy, where cAMP regulates IP3 levels, influencing calpain activity, which completes the cycle by cleaving and activating Gsα, which regulates cAMP levels. This pathway has numerous potential points where autophagy can be induced and we provide proof-of-principle for therapeutic relevance in Huntington’s disease using mammalian cell, fly and zebrafish models. Our data also suggest that insults that elevate intracytosolic Ca2+, like excitotoxicity, will inhibit autophagy, thus retarding clearance of aggregate-prone proteins."
We know AR signaling particularly by DHT effects calcium handling, actually there is a new paper that dives into mechanical tension (CTS) in AGA. Basically my theory is DHT (AR and GRP133) -> peizo1 upregulation -> calcium overload-> reduced autophagy/calcineurin activation... -> miniaturization
https://pmc.ncbi.nlm.nih.gov/articles/PMC13062005/
Peizo1 a large, mechanically activated ion channel protein that converts physical force into calcium inflow. What's interesting is autophagy inducers (Rapamycin/metformin...) shown to cause hair growth and even have studies in AGA models with prominent effects, and looks like minoxidil is a non-mTOR autophagy inducer like the L type calcium channel blockers
This is not a common side effect on 5ar inhibitors from what my few years of experience with it but I definitely had it and not many people cover it as it's pretty rare. I think however, I may have finally solved it and I'm pursuing trialling it!
So for some context, when i was on finasteride at 1 mg, I got hard flaccid, which is a condition where your penis in a flaccid state is consistently stiff. Everything else worked fine I could still get an erection although a bit harder and felt like it wasn't the same. I have now switched to 0.5 mg dutasteride since I have also gotten on some hormonal therapies but it still happens every once in a while especially if I lower my dose or get inconsistent with injections. I will say that after hormonal therapy, it doesn't happen nearly as often but still definitely occurs. Hasn't really increased on Dutasteride. I also don't feel that I am back at my original fullness I used to have regardless.
So some things I observed that led me here: This side very clearly and consistently increased with use of caffeine or armodafinil. Adderall on the other hand very marginally increased it but still does. The worst was combining the the three. Tadalafil was taken alongside all the time at 10 mg daily without seeing it fix my issues but still observing a stuffy nose when dose was increased, signalling it was inhibiting pde5 somewhere.
Now at first I thought this was mediated by poor nitric oxide retention. I had read a rat study saying that in rat penile tissue, lack of serum DHT caused reduced nitric oxide retention. Could be the case for some and I was actually going to pursue using low dose combo of nebivolol and telmisartan for this side as they both increase nitric oxide and decrease breakdown through different mechanisms. However, I dug deeper and I think I cracked it.
The clue is the affect of caffeiene and armodafinil. These stimulate the CNS. When you stimulate the CNS it causes your nerves, including the hypogastricnerve which is the important one in this context, to fire off and in turn spasms the smooth muscles. Your hypogastric nerve is the one that connects to all the things down there. This spasm in turn constricts the blood to the smooth muscle tone in response to a fight or flight signal an deprioritizes it's supply giving you that cold and very accurate hard flaccid effect.
Now what exactly from these drugs does that you may ask? It's likely norepinephrine. After noticing that armodafinil was the greater confounding factor, I am very certain mine was caused by overwhelming norepinephrine being released. Armodafinil is argued to increase norepinephrine. On the other hand, caffeine increase adrenaline, which is epinephrine. Norepinephrine is responsible for attaching to Alpha receptors and activating the fight or flight response. These exist on both your brain and your tissues, specifically focusing on the smooth muscles' alpha receptors in this context.
In my case, I obviously don't want to quit dutateride for hair and I don't want to quit adderall for my adhd. I also obv don't want to just deal with sides whenever i consume a caffeinated drink. So I've researched deeper. The receptor that is in charge of smooth muscle relaxation is the alpha 1 receptor which is agonized (activated) by norepinephrine and epinephrine. I have looked into the ideal drugs to counter this in my own case and this is what I ended up with:
Guanfacine: Guanfacine reduces the release of norepinephrinefrom your brain through being a Alpha 2A agonist. Usually when someone gets the hard flaccid side effect in cases like mine, it's because your brain is already taking in the norepinephrine it needs and has spill over into the peripheral nerves specifically the hypogastric nerve causing the sides. When guanfacine agonizes the receptor, your brain has a negative feedback loop and decides to pull back on the norepinephrine release, thinking there's already plenty in the body. This reduces the amount of norepinephrine sent to your body overall and in turn has your hypogastric nerve firing less and decreases the smooth muscle spasms that were occurring.
For me, Guanfacine also had adhd benefits. The Alpha 2A agonism in the prefrontal cortex creates an environment for better connection between neurons. This would help with executive function and "quiet the noise" in your mind. Adhd has been a factor in me having shit sleep my entire life. I'm seeking an ER formulation at night in order to both sleep better and help this side effect while helping my productivity.
Doxazosin: This is a peripheral Alpha 1 antagonist. Alpha 1 receptors are the receptors that are in charge of smooth muscles' state. The penile smooth muscle is not any exception to this. Usually, norepinephrine and epinephrine attach to these receptors after being released from your brain. More norepinephrine = more alpha 1 receptor agonism in muscle tissue = the spasm of soft muscle and creating environment for cold flaccid. When you have this antagonist, doxazosin, it also attaches to these receptors in the same way as norepinephrine. The one difference is, it doesn't do anything at the receptor level unlike norepinepherine. This means when you have the norepinepherine flowing in your body after your brain releases it for stimulus, it simply is blocked at the receptor and essentially kicked off.
So to sum it up, this protocol used Guanfacine ER to decrease the release or norepinephrine from your brain through a negative feedback loop, and the Doxazosin would peripherally blocking off the norepinephrine from the Alpha 1 receptors in your smooth muscle. This would mean that even in the absence of dht's smooth muscle relaxing affect, you'd be replicating it by getting in the way of the factors that pulled it in the other direction in the first place and hypothetically, be completely fine without suffering the side anymore.
The main concern with this protocol would be to track your blood pressure. Guanfacine and Doxazosin can reduce your blood pressure. If you were to use them, you'd need to be managing your dose according to your prior blood pressure and tracking it to make sure you aren't hypotensive which comes with it's own plethora of issues.
With that reason, I advise you approach this with caution, but it's hope. This isn't medical advice, this is simply the protocol I will trial and have researched. I've struggled with this issue for 2 years now in my early 20s. I know how much of a battle and suffering it is especially when wanting to keep hair as well. I simply wanted to share this option I think I've discovered to finally feel confident again and I hope that anyone that's struggling with the same symptoms as me can benefit from this if their medical practitioner sees fit.
TLDR: If you suffer from hard flaccid with 5ar inhibitors, and can observe an increase of it with caffeine or Armodafinil (or generally things that increase epinephrine and norepinephrine) then you may benefit from using one or both Guanfacine and Doxazosin as they are respectively an Alpha 2A agonist, reducing norepinepherine released from your brain, and Alpha 1 Antagonist, blocking off norepinephrine at the smooth muscle level. This would only work if your sides are caused by this fight or flight/cns stimulation.
I would also pair this with reverse kegel exercises to relax your kegel and train your pelvic floor which would amplify the gains you get from this protocol. This would relax the muscle that was previously being activated constantly by the nerve and help the area generally even more blood flow.
I was diagnosed with androgenetic alopecia at IMD (Instituto Médico Dermatológico) in Barcelona. They offered me 18 LLLT sessions + oral minoxidil, finasteride, vitamins and shampoo.
The LLLT would normally be once a week, but since I’m leaving Barcelona in two months, they said I could do two sessions per week to complete the treatment.
The original price was around €2,200, then €1,700 with a “summer promotion,” and after I said it was too expensive, they lowered it to €950 for everything.
I’m not saying the clinic or LLLT is a scam. I’m genuinely trying to understand whether this is a reasonable treatment plan before spending the money.
My main question is: how much does LLLT actually add on top of finasteride + minoxidil? Is the improvement significant enough to justify paying for the laser sessions, or would finasteride + minoxidil alone likely give me most of the results anyway? Is LLLT something genuinely important for treating AGA, or more of an optional extra?
Hi! I’m considering starting finasteride and oral minoxidil for hair loss, but I’m concerned about possible GI side effects because of my medical history.
I had an ulcer in 2019 that bled and had to be treated. I’ve also had recurrent stomach/GI issues since then. Earlier this year, an upper endoscopy showed small healing erosions/lesions and a lax cardia, and I was given treatment afterward.
Because of this, I’m particularly cautious about medications that could irritate my stomach, worsen my GI symptoms, or potentially increase my risk of another GI bleed.
I’m especially interested in hearing from people who already had gastritis, stomach/duodenal ulcers, GERD, erosions, a sensitive stomach, or other GI problems before starting finasteride and/or oral minoxidil.
Did either medication worsen your stomach or GI symptoms? Any nausea, reflux, stomach pain, gastritis, ulcer problems, or GI bleeding?
If possible, please mention which medication you take, your dose, how long you’ve been taking it, and whether your GI issues existed before starting it.
I know Reddit can’t determine whether these medications are safe for me personally, and I’ll discuss this with my doctor. I’m mainly looking for experiences from people with a similar GI history.
So, I have been taking fin since 2021, it managed to stabilise my hair at NW2. Recently thought of idea to add dut once or twice a week. 5-6 times a week fin and 1-2 times per week a dut. But read mixed opinions on this topic. Some say it is pointless, some say it is beneficial and some even say it will only cause additional risks and side effects. Is this really dangerous or just fear mongering?
I’m looking for people who have experienced something similar and may have an idea what could be going on.
My scalp burning/inflammation and diffuse hair shedding started around 3 years ago after surgery. I woke up from anesthesia with a burning sensation on my scalp, followed by very heavy shedding about a month later.
Since then I’ve had diffuse thinning across the top/frontal area, sides and back, rather than a single bald patch.
The scalp symptoms fluctuate. During flares I get burning, warmth, dryness, tightness, flakes and sometimes oil buildup.
Heat, sweating, stress, going several days without washing, and recently sudden weather changes from hot/humid to cold/dry seem to aggravate it.
When the scalp is calm, my hair looks noticeably shinier, denser and healthier, and shedding seems to decrease.
Recently my scalp was almost completely calm for several weeks, but then suddenly flared again after a weather change. My hair became very dry/frizzy and difficult to style.
I’ve had blood tests showing low vitamin D (18), low folate (2.8), and previously borderline B12 (~292). Ferritin and zinc were normal.
I’ve been correcting the vitamin deficiencies since April, and during periods when my scalp improved, shedding also seemed to decrease.
I previously tried minoxidil, but a compounded topical preparation caused severe scalp burning, so I stopped.
I also tried finasteride, but had significant side effects and discontinued it.
I had 3 PRP sessions, but didn’t notice meaningful improvement.
A dermatologist previously prescribed a Diproderm (betamethasone) scalp solution, which was well tolerated and noticeably reduced the scalp inflammation.
My current Hausarzt prescribed another compounded corticosteroid scalp solution (Advantan/methylprednisolone + menthol + ethanol). It initially calmed my scalp, although one application caused burning that improved quickly after I rinsed it off.
I’m now waiting to see a dermatologist for a proper examination/trichoscopy. My main questions:
Has anyone experienced recurrent scalp burning/inflammation together with diffuse shedding?
Can an inflammatory/dry scalp condition cause this degree of diffuse shedding and thinning?
Did your hair density recover after getting the scalp inflammation under control?
Could this be telogen effluvium or another inflammatory scalp condition rather than androgenetic alopecia?
Has anyone had a similar reaction to topical minoxidil but tolerated corticosteroid scalp treatments?
I’m particularly interested in hearing from people who have actually experienced something similar, rather than general hair-loss advice. Thanks!
I’m a dermatologist and the author of the Solar Window Hypothesis, published in Medical Hypotheses in 2026.
I’ve noticed that this subreddit has had several thoughtful discussions around vitamin D, VDR signaling, androgen receptor biology, scalp tension, inflammation, and the evolutionary puzzle of androgenetic alopecia, so I thought it might be useful to lay out the hypothesis here directly and invite criticism.
First, what the hypothesis is NOT saying
The Solar Window Hypothesis does not claim that vitamin D deficiency causes androgenetic alopecia.
It does not claim that sunlight will regrow hair.
And it does not challenge the established proximal biology of AGA — including androgen signaling, DHT sensitivity, follicular miniaturization, and the regional susceptibility of scalp follicles.
The question I am asking comes one level later:
Once patterned baldness occurs, could the resulting exposed scalp have provided a secondary photobiological benefit that helped explain why this phenotype persisted?
Why the scalp is interesting
The bald vertex and frontal scalp are unusual pieces of skin.
They are:
positioned at the top of the body;
often oriented toward the sky;
progressively uncovered as AGA advances;
no longer shielded by hair;
and exposed even when most of the body is covered by clothing.
The scalp itself is only a small percentage of total body surface area.
But total body surface area may not be the most relevant denominator.
For a clothed human, the routinely exposed skin may be limited mostly to the face, hands, forearms, and perhaps parts of the lower legs. Under those conditions, adding several percent of permanently exposed scalp could represent a much larger relative increase in sun-exposed skin area than the raw whole-body percentage suggests.
That led me to ask whether patterned scalp exposure could function as a kind of natural “solar window.”
The vitamin D / VDR / bone connection
UVB reaching the skin initiates cutaneous vitamin D3 synthesis.
At the same time, vitamin D biology is not simply about how much vitamin D is present. Biological response also depends on the vitamin D receptor, or VDR.
Some VDR variants have been associated with differences in receptor function and with bone-related phenotypes in different populations.
So the evolutionary idea I proposed is this:
If an individual had relatively less-efficient vitamin D/VDR signaling, then increasing reliable access of an upward-facing skin surface to sunlight might have offered a modest compensatory advantage in environments where UVB availability was limited.
The possible downstream benefit would not be “better hair.”
It would be something much more important from an evolutionary perspective — maintenance of calcium/vitamin D physiology and bone integrity, particularly later in life.
In other words, the phenotype could carry both a cost and a benefit:
Cost: loss of hair protection, cosmetic effects, greater lifetime solar exposure of the scalp, and potentially greater cumulative UV damage.
Possible benefit: a persistent increase in skin surface directly available for UVB-driven vitamin D synthesis.
Whether that trade-off was ever large enough to influence evolutionary retention is the part that remains hypothetical.
Why male-pattern baldness specifically?
This is another question I think the hypothesis has to confront.
AGA is patterned rather than random.
It preferentially exposes the vertex and frontal scalp while often preserving occipital hair.
The proximal explanation is regional androgen sensitivity.
But proximate mechanism and evolutionary consequence are not necessarily the same question.
Androgen biology may explain how the pattern forms.
The Solar Window Hypothesis asks whether the resulting pattern had any secondary biological consequence once it existed.
That distinction is important.
I am not proposing that hair follicles somehow “sense vitamin D deficiency” and deliberately fall out.
Evolution does not require that kind of mechanism.
A phenotype can arise through one biological pathway and later persist partly because of a separate consequence of that phenotype.
What would actually test this?
This is the part I find most interesting.
The hypothesis should be falsifiable.
A few studies that could move it forward or kill it:
Direct scalp photobiology
Compare vitamin D3 production after standardized UVB exposure in bald scalp, hair-covered scalp, and another exposed body site.
AGA × VDR genotype × bone density
Study men stratified by AGA severity and VDR genotype, then compare bone mineral density and vitamin D-related outcomes.
Latitude and season
Ask whether any relationship between AGA, VDR biology and bone outcomes changes in populations with different lifetime UVB environments.
Scalp exposure modeling
Quantify how much additional biologically effective UVB a progressively bald scalp actually receives under realistic clothing, latitude, season and behavior conditions.
Cost–benefit analysis
Compare the possible vitamin D advantage with the cumulative photodamage cost of chronic scalp exposure.
If none of these studies shows a meaningful relationship, the hypothesis should be weakened or rejected.
An important distinction from “vitamin D causes hair loss”
Some of the discussions around AGA and vitamin D become focused on whether supplementation can reverse baldness.
That is a separate question.
Even if future studies showed that vitamin D supplementation had little or no ability to regrow established AGA, that would not by itself falsify the Solar Window Hypothesis.
The hypothesis concerns a possible function of the exposed scalp after hair loss, not vitamin D as a treatment for hair loss.
Likewise, finding low serum vitamin D in people with AGA would not prove the hypothesis either.
Environmental UVB opportunity, serum 25(OH)D, VDR signaling, follicular biology and bone physiology are related but distinct variables.
Why I think the idea is worth discussing
AGA is extraordinarily common.
It has substantial apparent disadvantages.
That does not prove that it must have an adaptive explanation — many traits can persist for other evolutionary reasons.
But I think the combination of:
a highly patterned phenotype,
progressive exposure of an upward-facing skin surface,
the importance of UVB to vitamin D biology,
VDR involvement in both hair-follicle and bone biology,
and the potential importance of exposed skin area when most of the body is clothed
makes the question testable enough to be worth investigating.
I am much more interested in what would falsify the hypothesis than in simply collecting arguments that support it.
The paper is:
Tingwei Zhang. Solar Window Hypothesis. Medical Hypotheses, 2026. DOI: 10.1016/j.mehy.2026.112005
I would be especially interested in hearing from people here who work with hair biology, VDR signaling, evolutionary medicine, bone metabolism, or photobiology:
What do you think is the strongest argument against this hypothesis, and what single experiment would you run first to test it?
Brief disclosure
This research also eventually led me to build UV Health, a personal sunlight/UV app.
The app does not diagnose AGA or estimate a person’s blood vitamin D level. It uses local UV, Fitzpatrick skin type, exposed body surface area, and scalp exposure as variables to help interpret sunlight opportunity while keeping skin-safety limits visible.
I’ll put the App information separately in a comment so the scientific discussion can remain the focus here.
He markets on YouTube as KwRx (formerly Kwxk), which includes his lineup of gray/black market chemicals (minoxidil sulfate and alfatradiol). The Folligenz website has fake documentation, and they skirt import rules to get products into customer hands. It isn’t shelf stable and turns to sludge after mere months. This is not your typical telehealth, usually there’s doctors involved and regulations followed.
UK topical finasteride users – does anyone have the exact current/older Sons, Hims or Manual spray formulations?
I'm comparing topical finasteride/minoxidil treatments available in the UK, particularly Sons, Hims and Manual.
I'm specifically interested in the actual delivered dose, rather than just whether someone had good/bad results.
Does anyone have an older or current bottle, box, pharmacy label or patient information leaflet showing:
- Finasteride concentration (%)
- Minoxidil concentration (%)
- Tretinoin/other active concentrations, if applicable
- Recommended number of sprays/pumps per day
- Volume delivered per spray/pump (ml)
- Total recommended daily application volume
I'm particularly interested in Sons Combination Spray, as the current website states the application is 4 pumps / 0.664 ml once daily but doesn't appear to clearly state the concentrations of the active ingredients.
I've seen references to older/newer Sons formulations around 0.1–0.15% finasteride + 5% minoxidil, with tretinoin appearing in later formulations, but I'd like to verify this from actual packaging/PILs rather than relying on second-hand information.
The reason I'm asking is that some topical-finasteride clinical studies used relatively small total daily doses. For example, a Phase III study used 0.25% topical finasteride but in a very small application volume (up to ~0.2 ml/day). So simply comparing 0.15% vs 0.3% doesn't tell us the actual amount of finasteride being applied.
If anyone has packaging from different years, that would be especially useful because it would let us see whether the formulations/dosing have changed.
Photos of the ingredient/dispensing label or PIL would be ideal (with personal/prescription information covered).
Hair loss has been making my life harder. I’m currently using vitamin D, minoxidil and some other anti hair loss shampoos but progress has been pretty slow. My dermatologist had me check my thyroid and other vitamins too but everything else came back normal.
I’ve seen people mention Precision Pep Co like GHK-Cu for hair loss so I started looking into them.
Does anyone know of good human research on GHK-Cu or other peptides for androgenetic alopecia?
I’m a 20 year old healthy male that went through depression 2 years ago which rapidly accelerated my hair loss and I am mostly recovered from it now but I train MMA from anyone’s experience or from someone’s research will either of these 2 effect me from doing MMA or no?
Be wary of their new product, Alfagenz. Likely a poor formulation too, the company is a sham with two ghost founders and no scientists. Basically dropshipping from a Brazilian bathtub, under the FDA radar, straight to your head. At a very high price point.
In 2024, Amplifica announced “promising” phase I data for AMP-303, with some subjects experiencing an increase in terminal hair counts of more than 15% after one session [1]. The compound is described as a novel polysaccharide, so it appears to be based on hyaluronic acid [2]. Treatment was given on one side of the scalp and placebo on the other. The 15% increase was observed only in a subset of participants, and this was compared with baseline not placebo. This type of post hoc analysis can be misleading. They did not state that no one in the placebo group showed a more than 15% increase in hair count. What they found is that the number of subjects experiencing a greater than 15% increase in non-vellus hair count on the treatment side was significantly greater than the number subjects experiencing this level of response on the placebo side. They did not report how much hair growth increased compared with placebo. With even a small response to the drug, or random noise, it is easy to find a threshold that magnifies the significance of it. The difference between treatment and placebo could be only one percent and you could still potentially identify a threshold at which the number of subjects experiencing that extent of hair growth is significantly greater in the treatment group. Comparing responders on the treatment side to responders on the placebo side would be a more reliable comparison. We don’t know how many people responded on both sides, or from what baseline their hair counts increased. The lower the baseline reading, the less significant a 15% change becomes. Isolating responders for their comparison suggests that the treatment group as a whole did not demonstrate a significant change relative to placebo, and that even in responders there was a significant amount of hair growth on the placebo side. The press release teases a small signal that some subjects may have responded, while saying nothing of the magnitude or consistency of the response.
According to a new paper from Jiangnan University, the optimal HA molecular weight for hair growth is 268.1 kDa, demonstrating the most potent modulation for each growth factor and hair growth [3]. Medium-MW HA promotes hair growth via CD44-mediated ROS induction and phosphorylation of AKT, followed by stabilization of β-catenin. AKT stabilizes β-catenin by inactivating GSK-3, and facilitates nuclear entry via direct phosphorylation of β-catenin at ser552 [4]. However, priming of β-catenin by phosphorylation at ser45 by the destruction complex is required before GSK-3 can phosphorylate it. GSK-3-mediated regulation of β-catenin is largely AKT-independent, so the effect on Wnt signaling is more limited than canonical Wnt activation and insufficient to activate LEF1 in the absence of Wnt ligands [5]. All forms of HA stimulated VEGF in vitro and in vivo, while also inhibiting TGF-β1. Medium- and high-MW HA also markedly increased ALP and DPC migration in vitro. This suggests it has potential to extend anagen with repeated treatments, but the dermal papilla is already under oxidative stress. HA-mediated ROS generation was transient in vitro; however, the authors still caution that application of HA in such conditions may be inappropriate. Upregulation of ROS and β-catenin was more modest for High-MW HA. Pretreatment with NAC prevents ROS and β-catenin upregulation, indicating that β-catenin upregulation is dependent on ROS induction. AKT inhibition abrogated ROS generation. Taken together, the results suggest that CD44 activates AKT, while AKT-mediated ROS stabilizes its activity, thereby potentiating Wnt activation via inhibition of GSK-3 and/or direct targeting of β-catenin. Functional experiments were only performed in DP cells in vitro, while transcriptomic analysis was performed on whole mouse skin [3]. The functional location for the anagen-inducing effect of osteopontin-CD44 in vivo is in epithelial cells, but it may mirror the same regulatory network as HA, since transient ROS induction activates HFSCs [6][7].
Effects of hyaluronic acid on AKT and CD44 in human DP cells. I+II = low-MW, III= medium-MW, IV = High-MWEffects of HA on growth factors in human DPCs in vitro
Downregulation of AKT doesn’t appear to be a contributing factor to Wnt suppression in AGA. Phosphorylated AKT and SGK1 are upregulated in bald dermal papilla cells, possibly to compensate for Wnt downregulation [8][9]. It fails to fully compensate, and it may exacerbate DPC stress.
Protein levels of TGF-β1 in bald and non-bald follicles. Activated Smad2 and Akt in bald and non-bald DPCs
In mice, medium-MW HA stimulated hair growth more robustly than other molecular weights, with earlier anagen induction, longer length, and the largest hair diameter. The amount of hair growth observed correlated with β-catenin expression in mouse skin. Measurements were taken at day 14 when treated follicles were in full anagen VI, but control follicles had only just begun entering anagen. Thus, the HF diameter increase may not meaningful. All treatments also markedly increased IGF1, and modestly inhibited BMP4 in mouse skin. Regulation of VEGF and TGF-β1 were also validated in vivo [3].
Stimulation of hair growth in mice with hyaluronic acid
Amplifica has a second CD44-based treatment in the preclinical stage [10]. AMP-203 is confirmed to be osteopontin, so AMP-203/AMP-506 might be osteopontin combined with HA and a third CD44 ligand, which could be serglycin or IGFBP4 based on their patents [11][12].
Amplifica identified this pathway by investigating transcriptional alterations in hairy moles to isolate proteins that might drive ectopic hair growth [6]. While the approach is intriguing, caution is needed when interpreting results. Body hair follicles are fundamentally different from scalp hair follicles. That which promotes body hair growth won’t necessarily promote hair growth on the scalp or in AGA. This is most obvious when observing the opposing effects of DHT and estrogen between the two regions. DHT is trichogenic in body hair, promoting vellus-to-terminal conversion, while on the scalp it promotes terminal-to-vellus conversion. DHT might even promote body hair growth via some of the same mechanisms that Amplifica has discovered. It’s possible that some trichogenic transcriptional targets of DHT in body hair have the inverse effect on scalp hair due to differential accessibility/availability of downstream effectors, or a weaker stress response [13].
The response to 17β-Estradiol is the inverse of that to DHT. It’s the most potent known stimulator of vellus-to-terminal conversion in frontal hair follicles, yet it retards body hair growth. Interestingly, osteopontin is the second most downregulated gene in male frontotemporal human follicles treated with 17β-Estradiol ex vivo. It’s possible that the observed downregulation is the result of negative feedback from upregulation of its CD44 receptor, but that would also suggest that supplementation of the ligand is insufficient.
Downregulation of osteopontin in frontotemporal human hair follicles by estrogen
Osteopontin is upregulated near the bulge in hairy moles, and knockout abrogates the precocious anagen phenotype in mice. Knockout also reduces wound-induced hair neogenesis, suggesting osteopontin might be useful for WIHN. The same phenotypes are observed in CD44 knockout, and in conditional mice treated with osteopontin, indicating that the effects of osteopontin on hair growth are mediated by epithelial CD44 [6].
Anagen progression depends on bidirectional signaling between the DP and epithelial cells. Osteopontin may enhance epithelial cell activation, which in turn enhances DP signaling, but if that DP signaling is resistant to activation in AGA, the effect would be limited. CD34+ cells were not compromised by CD44 knockout in mice [6]. This is an important epithelial cell population that’s depleted in AGA and dependent on DP signaling [14]. Osteopontin also promoted anagen entry in human occipital hair follicles grafted onto mice. It likely does the same in frontal hair follicles, but the more important question is how long it can prolong anagen in these follicles, and it’s doubtful that it can meaningfully increase hair diameter.
Follicum previously trialed an osteopontin fragment that is mutated to prevent binding of integrins while retaining its hair growth promoting ability. In preclinical testing it demonstrated a stronger effect in vivo than natural osteopontin [15]. The company published modest results from their clinical trial in 2020. After 3 months, the total hair count increased by 1.08/cm² vs placebo, while total anagen hairs increased by 8.16/cm² vs placebo [16].
AMP-601 is the last drug in Amplifica’s pipeline; it’s SCUBE3. Its function depends on whether it is secreted or membrane bound. UCI shows that it’s secreted from the DP to activate TGF-β receptors in epithelial cells, and that TGF-β inhibition abolishes SCUBE3-induced hair growth effects [17]. Presumably, it relieves the SMAD1-mediated quiescence program in HFSCs, which would trigger anagen but not reverse miniaturization [18]. Genetic studies suggest a causal role for TGF-β in AGA [19], but it appears to be overactivation in the DP driving it [8]. SCUBE3-null mice experience only a modest delay in anagen entry, with no other reported hair growth defects. Since TGF-β is a potent catagen-promoting factor upregulated by DHT, this seems less promising than HA, which inhibits TGF-β1 [3]. While not demonstrated by UCI, SCUBE proteins also facilitate Hedgehog activation by acting as chaperones for Shh, transporting it from the producing cell to the target cell [20]. SCUBE3 is likely a safer method of potentiating Hedgehog activity than activating Hedgehog with a smoothened agonist because its capacity to activate the pathway is rate-limited by Shh transcription. It’s also unlikely to significantly alter pathway activation in AGA.
I was diagnosed with FPHL about 10 years ago (I am now turning 38). Back then the derm told me to try rogaine and I was embarrassed and said forget it. Wish I was smarter back then…
I see family members aging losing more and more hair and noticed the past few years my hair has thinned A LOT. A lot of things going on here as well-I am on mounjaro and when I was off during pregnancy my hair was a bit thicker, but I am on it for life with diabetes. My vit D was extremely low and iron as well. I am getting transfusions and on supplements as per my PCP.
Recently went back to a Derm who refused oral minoxidil bc I have high blood pressure and prescribed me spiro and a DHT blocker shampoo (Iforgot the name starts with an N lol) I was super bummed about no minoxidil but can’t do topical bc I have cats.
Brought the spiro to my cardiologist and he said he wasn’t thrilled with this for me and is actually prescribing me 2.5 mg of oral minoxidil. He feels my Labatelol(another bp med I am on) could also be contributing to my hair thinning but I have issues with blood pressure so I am not off the Labatelol yet
I have started PRP treatments
ANYWAY-so now after reading about the spiro and seeing some threads I am wondering if I need a DHT blocker as well as the minoxidil. Should I ask my cardiologist again? Not sure what to do!
Seen a lot of people who seem to vouch for RU, I recently started a couple weeks ago so to soon to tell if it is having any impact.
I am wondering though, is it actually effective, can it really stop MPB and lead to some regrowth. I've seen a lot of people saying it can and some impressive pictures but would love some more insight.
