Research on the regulation of 5a-reductase

I would like to dedicate this thread to papers on the regulation of 5a-reductase.

One possible cause of PFS is the persistent downregulation of 5a-reductase. I have written about the possible mechanisms on various occasions - ex. here, here and here, but also throughout this entire thread starting with this post.

One of the important components of this theory is the observation that 5a-reductase is positively regulated by DHT: higher concentrations of DHT induce 5a-reducase expression, which leads to even more DHT being produced. The opposite is also true - lack of DHT leads to the downregulation of 5a-reductase.

It is easy to see how this regulatory mechanism can lead to PFS and to the so called crash: lowering of DHT beyond some regulatory threshold can result in a bad equilibrium of low 5a-reductase expression from which it is difficult to climb back.

The first couple of papers will be on the effects of DHT on the expression of 5a-reductase.


Dihydrotestosterone stimulates 5 alpha-reductase activity in pubic skin fibroblasts.


In vivo, the 5 alpha-reduction of testosterone (T) to dihydrotestosterone (DHT) is androgen dependent in pubic skin but not in the skin of the external genitalia. The aim of the present study was to determine whether pubic skin fibroblasts (PSF) had retained this androgen dependency. PSF were prepared from explants of skin from normal subjects (four men, three women) and three patients with complete form of the testicular feminization syndrome. Culture medium containing 5% fetal calf serum and DHT was added 24 h after subculture (day 1) and renewed every other day. 5 alpha-Reductase was assayed on day 4 or day 8 by incubation of intact cell monolayers with [3H]T (2 nM), extraction of the medium, and chromatography of the metabolites; DNA was assayed in the cell pellets; 5 alpha-reductase was expressed as fmol/micrograms DNA . h. Controls were untreated plates from the same subcultures. DHT had no effect on cell DNA, whereas it resulted in a dose-dependent increase in 5 alpha-reductase activity. In seven PSF strains tested, DHT (10(-7) M) increased 5 alpha-reductase activity 2- to 4-fold over the control levels. This effect was abolished by the simultaneous addition of cyproterone acetate (2 X 10(-6) M) and was not observed in PSF from testicular feminization syndrome patients, suggesting that it was indeed mediated via the androgen receptor. T but not estradiol or cortisol also increased 5 alpha-reductase activity in PSF. The effect of androgens was suppressed by protein synthesis inhibitors. These data provide strong evidence that PSF respond to androgens via a receptor mediated mechanism, and that 5 alpha-reductase can be used as a marker of androgen action in pubic skin in vitro as well as in vivo.


Regulation of androgen receptor and 5 alpha-reductase in the skin of normal and hirsute women.


The hormonal activity of androgens is mediated in target cells, particularly in human skin, by two kinds of proteins: the androgen receptor and the enzyme 5 alpha-reductase. In well differentiated androgen target cells, 5 alpha-reductase achieves the transformation of testosterone (T) into dihydrotestosterone (DHT), a more active androgen than T, because of its higher affinity for the receptor. In other words, 5 alpha-reductase acts as an amplifier of the androgen signal but is not absolutely required for androgen action. Regarding the regulation of the androgen receptor, minimal information is available. However, in genital skin, the receptor seems to be predominantly localized in the cytosolic compartment before puberty in males and in the nuclear compartment after puberty. In hirsute patients, recent data on genital skin fibroblasts do not show significant differences between the binding capacity of fibroblasts from normal and hirsute women whereas there is no difference between normal men and women. 5 alpha-Reductase activity seems to be a very important step in the processes involved in androgen action. While 5 alpha-reductase activity present in the skin of external genitalia does not seem to be androgen dependent, this is not the case for the enzyme located in pubic skin. In this area, a sex difference between males and females may be observed both in skin homogenates and in cultured fibroblasts. In addition DHT added to a medium of pubic skin fibroblasts is capable of increasing 5 alpha-reductase activity. This increase is not observed when cyproterone acetate is added to the medium and in patients with testicular feminization syndrome without receptors. Pubic 5 alpha-reductase activity is an androgen receptor mediated phenomenon. In patients with hirsutism, and particularly idiopathic hirsutism, 5 alpha-reductase activity is high without an increase in circulating androgens. This may be observed both in pubic skin homogenates and in cultured fibroblasts. Thus, an excess of skin 5 alpha-reductase activity may be considered as a cause of hirsutism but both the exact level of the abnormality in the regulation of the enzyme and its genetic control remain to be elucidated.

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Note: TGF-beta 1 appears to be very important in the regulation of 5a-reductase. I will post more papers about this later.

Effects of transforming growth factor beta and epidermal growth factor on steroid 5 alpha-reductase activity in genital skin fibroblasts.


Regulation of steroid 5 alpha-reductase (5 alpha R) activity and dihydrotestosterone (DHT) formation is central to prostate and sexual skin (hair) growth and cell function. Transforming growth factor-beta 1 (TGF-beta 1) is a ubiquitous peptide present in skin and scrotal tissue and its receptor is universally expressed. We have explored the role of TGF-beta 1 and -beta 2 on androgen formation in skin. Rat or human sexual skin fibroblasts were grown in primary cultures (passage 3-7). 5 alpha-Reductase activity was measured by the %-conversion of tracer 3H-testosterone to dihydrotestosterone over a 4 h period. Incubation of scrotal fibroblasts (2 x 10(5) cells) in serum and growth factor free media with androgen, such as DHT for two days significantly stimulates 5 alpha R in these cells (1.6-fold, p < 0.05 vs control). TGF-beta 1 alone at picomolar concentrations (2 x 10(-11) M to 2 x 10(-10) M) was a potent inducer of 5 alpha R activity in both rat (1.8-fold and 2.8-fold, respectively, p < 0.001 vs control at both doses) and human cells (TGF-beta 1 2 x 10(-10) M 3.3-fold, p < 0.001 vs control). Combined exposure of these fibroblasts to TGF-beta 1 (2 x 10(-10) M) and androgen (10(-7) M) further potentiated 5 alpha R activity (rat cells 6.5-fold, human cells 6.4-fold, p < 0.001 vs DHT or TGF-beta 1 alone).(ABSTRACT TRUNCATED AT 250 WORDS).

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Note: IGF-I is important for 5a-reductase expression!

Androgen induction of steroid 5 alpha-reductase may be mediated via insulin-like growth factor-I


The action of added insulin-like growth factor-I (IGF-I) and dihydrotestosterone (DHT) on steroid 5 alpha-reductase (5 alpha R) activity was studied using primary cultures of rat or human scrotal skin fibroblasts. Agents were added to cultured cells (2 x 10(5) cells) for 2 days, and enzyme activity was measured by the percent conversion of [3H] testosterone to DHT over a 4-h period in the absence of fetal calf serum or other growth factors. DHT, but not testosterone, at 10(-7) M significantly increased 5 alpha R activity (rat, 1.5 +/- 0.3% to 3.0 +/- 0.4%; human, 7.6 +/- 1.7% to 11.4 +/- 2.9%; P < 0.01). IGF-I (10(-9)-6.4 x 10(-9) M), but not IGF-II (10(-9)-10(-8) M) or insulin (10(-9)-10(-7) M), increased enzyme activity in a dose-related fashion [i.e. 1.5 +/- 0.5 to 10 +/- 2 in rat and 6.0 +/- 1.1 to 9.8 +/- 1.6% (P < 0.01) in human cells]. No change in cell numbers was observed in any experiment. Since the effect of IGF-I was about 100 times that of androgen, we studied the possibility that androgen induction of the enzyme activity could be via IGF-I production. Addition of a monoclonal antibody against IGF-I significantly reduced the effect of DHT, and simultaneous addition of a specific IGF-I receptor antibody blocked the expected induction of 5 alpha R activity (control, 4.9 +/- 0.5; DHT, 8.0 +/- 1.9; DHT plus IGF-I receptor antibody, 3.7 +/- 0.4%). No effect on 3 alpha-reduction of [3H]DHT to 3 alpha-androstanediol was detected in separate experiments. These studies indicate that IGF-I may be an important regulator of skin 5 alpha R activity and, thus, may influence DHT formation. The previously known androgen induction of this peripheral steroidogenic enzyme may be via paracrine/autocrine production of an IGF-I-type growth factor.

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Activin and inhibin have opposite effects on steroid 5 alpha-reductase activity in genital skin fibroblasts.


The transforming growth factor beta (TGF-beta) superfamily includes several closely related peptides including the activins and inhibins. Since we recently reported that TGF-beta 1 and beta 2 are potent inducers of steroid 5 alpha-reductase (5 alpha R), we have now studied the effects of these other peptides using primary cultures of human scrotal skin fibroblasts. Recombinant human activin A or inhibin A were added to cultured cells (2 x 10(5) cells) for 2 days in a serum free media and 5 alpha R activity was measured by the %-conversion of tracer [3H]-testosterone to dihydrotestosterone (DHT) over a 4-h period. Activin significantly stimulated 5 alpha R activity in a dose related manner (control 3.0 +/- 0.4%, activin (1.2 x 10(-9) M) 6 +/- 0.7%, P < 0.01, (2.4 x 10(-9) M) 8.5 +/- 0.6%, P < 0.001). In comparison, androgen (DHT 10(-7) M) induction of 5 alpha R was 4.7 +/- 0.2%, P < 0.05. Combined exposure of fibroblasts to activin (1.2 x 10(-9) M) and androgen (10(-7) M) did not result in additive or synergistic effect on 5 alpha R activity. In contrast, exposure of cells to an androgen (10(-7) M) and TGF-beta (2 x 10(-10) M) led to synergistic effects on 5 alpha R activity (control 1.5 +/- 0.1%, DHT 2.6 +/- 0.2% TGF-beta 1 4.8 +/- 0.5, TGF-beta 1 + DHT 9.2 +/- 1.2%).


This paper was originally posted here in 2007. I wrote a comment about it in July 2019.

Feed-forward control of prostate growth: dihydrotestosterone induces expression of its own biosynthetic enzyme, steroid 5 alpha-reductase.


Dihydrotestosterone, the primary mediator of prostate growth, is synthesized in target tissues from the circulating androgen testosterone through the action of steroid 5 alpha-reductase (EC The expression of 5 alpha-reductase and the level of 5 alpha-reductase messenger RNA in rat ventral prostate are regulated by androgens. To determine whether this control is mediated by dihydrotestosterone or testosterone, we investigated the effect of finasteride, a potent inhibitor of steroid 5 alpha-reductase, on the expression of 5 alpha-reductase in the prostate. The administration of finasteride to intact rats for 7 days caused a 55% decrease in prostate weight and an 87% decrease in 5 alpha-reductase enzyme activity. Furthermore, the restoration of prostate growth after castration and the enhancement in 5 alpha-reductase enzyme activity and 5 alpha-reductase messenger RNA level by testosterone administration were blocked by finasteride, whereas the inhibitor had no effect on dihydrotestosterone-mediated increases in 5 alpha-reductase activity or messenger RNA level. These findings indicate that dihydrotestosterone itself controls prostate growth and 5 alpha-reductase activity. They further suggest that prostate growth is controlled by a feed-forward mechanism by which formation of trace amounts of dihydrotestosterone induces 5 alpha-reductase, thereby increasing dihydrotestosterone synthesis and triggering a positive developmental cascade.

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Androgen regulation of 5α-reductase isoenzymes in prostate cancer: implications for prostate cancer prevention.


The enzyme 5α-reductase, which converts testosterone to dihydrotestosterone (DHT), performs key functions in the androgen receptor (AR) signaling pathway. The three isoenzymes of 5α-reductase identified to date are encoded by different genes: SRD5A1, SRD5A2, and SRD5A3. In this study, we investigated mechanisms underlying androgen regulation of 5α-reductase isoenzyme expression in human prostate cells. We found that androgen regulates the mRNA level of 5α-reductase isoenzymes in a cell type-specific manner, that such regulation occurs at the transcriptional level, and that AR is necessary for this regulation. In addition, our results suggest that AR is recruited to a negative androgen response element (nARE) on the promoter of SRD5A3 in vivo and directly binds to the nARE in vitro. The different expression levels of 5α-reductase isoenzymes may confer response or resistance to 5α-reductase inhibitors and thus may have importance in prostate cancer prevention.

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Hello Sibelio,

I would like to thank you for your diligent work putting all these together.

I wonder if you got away with any clearer picture of what could be going on with our bodies.

I’ve been trying to put together a comprehensive summary of all the different theories that have been discussed on here from 5ar-reduxtase regulation to demethylation of certain genes. However, I am far from even grasping the fundamental concepts yet.

There’s some sort of foolish hope that if I grasp the depth of the problem, that I can come up with some way to reverse it. But the reality is we are still dependent on probably years of research to get a decent understanding of the pathways this is affecting. It’s almost as if our problems lie on the intersection of life’s mysteries themselves.

I’d like to try to be useful. Let me know if there’s a way I can help.

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At the beginning of the thread I have listed a couple of posts and threads where I describe in some detail my opinion on the etiology of PFS. I continue to believe all evidence supports this theory and no evidence contradicts it.

I also believe it would not take years of research and many millions of dollars but one small, cheap study to test this theory - a test for DHT and 5ar expression in penis skin from 30 PFS sufferers and 30 controls. In the 30 years since PFS has existed, no such study has ever been done.

Unfortunately I am not allowed to try to organize or fundraise for such a study on PH, and the PFS Foundation or the site admins don’t seem to believe this is the right kind of research to pursue. Based on what I am hearing about current ideas for research, I personally don’t expect much meaningful progress to come soon.


Wasn’t the Harvard study supposed to take a tissue biopsy of the penis and ended up not doing it and took a tissue sample of the skin on the back of patients? I feel like this would be such a simple test, Harvard has deep ties with Merck so it doesn’t surprise me that they wouldn’t go with what was in the contract.

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Not true. The Di Loreto study was done six years ago comparing PFS foreskin vs. control foreskin. They aimed to look at the difference between androgen receptor density and nerve density, not the 5ar/DHT density you wish to measure.

It’s impossible to cater to everyone’s research desires. Resources are limited to say the least so I’m sorry we’re not spending money on your approach. But a similar study to yours has already been done.

Please correct me if I’m wrong. I’m genuinely trying to understand your perspective of PFS. You believe that PFS is an issue of persistent down regulation of 5 alpha reductase? Some members on here with labwork show that their DHT is in normal range, or even in high range. Wouldn’t that suggest that 5 alpha reductase is back and producing DHT? The only other thing I can think of is that local regions don’t have the proper amount of 5alpha reductase. For example, the prostate didn’t get back its usual amount of 5 alpha reductase and therefore local DHT is low.

@Sibelio I have read your first post. Although, I don’t have the scientific knowledge to comment critically on your theory, it definitely feels plausible. I think the Melcangi study shows that PFS patients do tend do display different methylation pattern, but I think it’s definitely possible that we were already displaying that difference before starting Finasteride (which would explain why there are people who use this pill without significant sides). It could be a combination of the methylation pattern with the decreased DHT that sends us in the crash. Whereas, for example, someone with regular methylation pattern would only experience the symptoms (the other 44% of the PFS patients from Melcangi’s study) due to a different dosing/longer exposure to the drug. I can’t recall if the study took into consideration the duration and dosage of Fin usage in the PFS study group.

I think one of the questions is what kind of effect/damage do the crashes have? Are they simply a potentially-temporary imbalance in hormones that the body cannot balance out on its own? Or even if the drug itself is not inducing some “permanent” alteration, are the cascaseds of the 5ar inhibition potentially leading to other epigenetic changes.

It is interesting that we have a user who claims to have recovered by cycling Proviron. But we also have many people who argue they have seen no effects from it (I’m not aware if anyone has been negatively affected after trying it). Is this simply a function of the method of dosing & cycling? Or are people suffering from PFS in a multitude of original pathways? I notice in the Proviron thread you discuss PFS type 1 and type 2, but I am not clear on what the distinctons are.

@AaronF As new as I am here, I did read some other poster ranting about that (using skin from the back, and being potentially compromised by Merck) in another thread. As much as we need to be adverse to conspiratorial thinking, I don’t have doubt Big Pharma has the power to often influence research. Especially, considering Merck’s shady past.

Does anyone know if the Harvard study was funded or petitioned for by PH or PFSFoundation?

@Greek Unfortunately, I don’t think I have any specific skills. I’m a mechanical engineer. I was thinking along the lines of what you have stated about being somewhat scientifically literate and reasonably intelligent. I also have some free time and would be willing to donate a reasonable amount of money. Although, I realize it’s reactionary, I’ve been trying to understand the scientific fundamentals and framing presented in the various studies being shared around here.


@inbrugge I think it’s natural to want to try and work it all out, I know I did. I came to the conclusion it was just too hard for me, but I’m not knocking anyone else.

Keep hold of your money, I’m sure it’ll be obvious when the right time is, beware people who might want to help you spend it.

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@Jaime Your response puzzles me.

In response to my statement that no study has ever measured 5ar/DHT in foreskin, you say “not true”, and then proceed to say that Di Loreto measured “androgen receptor density and nerve density” in foreskin but then you conclude that’s “not the 5ar/DHT density [I] wish to measure”? I am confused. Is it true or is it not true that 5ar/DHT has never been measured before?

I hope you realize these two types of tests are not the same and are not interchangeable vis-a-vis testing the theory I advocate for. An upreguated AR, while still consistent with my theory, could in theory co-exist with a normal level of DHT/5ar and be caused by something else - as I guess the admins’ theory would postulate.

Likewise, you say you are sorry you are not spending money on my approach, because you can’t cater to everyone’s research desires, but it seems in making that determination you have not bothered to read much of my theory. The objection you raise, along many others raised by other moderators, has been answered multiple times by me - with support from the literature.

The answer is as you said - and as I have written many times - serum levels of DHT are not predictive of local (prostate or other sex organ) tissue levels of DHT. The prostate and the other tissues responsible for sexual function (penis, pudendal nerve, etc) are a miniscule fraction of the total tissues producing DHT which include the skin and the liver.

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Sorry, I didn’t mean to confuse you. I was saying that human prepuce has indeed been studied in PFS, but not how you want it to be analyzed. I’m very aware of the differences between DHT, AR, and 5 alpha reductase.

In my above question, I was referring to this portion of your theory on PFS.I was asking how are normal levels of DHT consistent with a downregulation of 5a-reductase? Wouldn’t downregulated 5a-reductase mean lower levels of DHT in the body? Many men on here, however, have normal or even high levels of DHT. I’m not trying to argue, I was genuinely asking this as a question.

This was the answer I was looking for and now you’ve answered my question. Thanks. I have not read your entire theory on PFS. You posted it a couple of days ago. Between work and school, I haven’t had the time to read through all those papers.

Doesn’t make sense. People have gotten worse and/or ended up here from drugs that have no effect on 5ar.

Your theory chooses to ignore most of these people’s experiences, and before you say you’ve provided answers to it multiple times, you really haven’t. Just cited a bunch of papers that said one thing, and asked the people reading to jump to another conclusion from that (like you saying that 50% of people in the Melcangi study had methylated 5AR2 probably meant that there were two types of PFS. Or maybe, just maybe, it meant that not everyone with PFS has a methylated 5AR2 gene? You’re big on philosophy, so I’m sure you’ve heard of Occam’s razor. I don’t mean this as a slight, but I think you should apply it more.) If this problem was what you were saying, things would be so much easier in terms of fixing it. Why would any of us not want it to be that? Why is it that some people here have severe exercise intolerance? Why did I experience genital pain, worsening of sexual symptoms, insomnia, etc. from trying to work out? Why are there people here from other drugs that do not affect 5AR (who are experiencing a nearly identical symptom profile)?

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Androgens negatively regulate 5-ar type-I in certain areas of the brain (in rats, probably in humans):

J. M. Torres and E. Ortega, “Differential regulation of steroid 5α-reductase isozymes expression by androgens in the adult rat brain,” FASEB J , vol. 17, no. 11, pp. 1428–1433, Aug. 2003

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Great paper, thanks! What did they find about 5-ar type II, which is the predominant type present in sex organs, and also the one Finasteride affects the most?

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They also found positive regulation of 5-ar-II by androgens, contrary to type I.

Castrated animals had significantly lower 5α-R2 mRNA levels than intact animals. After T treatment, there was a significant increase in 5α-R2 mRNA levels in both intact and castrated animals compared with their pretreatment levels, with a greater effect in the latter group. After DHT treatment, there was a significant increase in 5α-R2 mRNA levels in both intact and castrated animals vs. their respective pretreatment levels.