By Aly W. | First published August 30, 2019 | Last modified October 22, 2021
This is a commentary and fact check of version 5.3 of Dr. Will Powers’s transgender care presentation and lecture. It has been incrementally updated and revised since it was originally published.
First and foremost, I’ll briefly explain who Powers is for anyone who isn’t aware. William Powers, D.O., or Dr. Will Powers, is a physician in Farmington Hills, Michigan in the United States. His medical specialization is in family medicine but in his clinical practice he now primarily does hormone therapy for transgender people. He is well-known by the online transgender community due to his own web presence and participation in our community. This includes on Reddit with his account u/DrWillPowers and his subreddit r/DrWillPowers. Powers has a downloadable transgender care lecture/presentation that describes his personal clinical approach and has been widely shared. Powers’s clinic website can be found here and his clinic’s Facebook profile can be found here.
A video of Powers presenting his transgender care lecture was uploaded to YouTube in mid-June 2019. This video was posted on Reddit and elsewhere on the web and has enjoyed an explosive degree of popularity. It was also submitted to our subreddit, but we chose to remove it due to concerns about the quality of the information (more on that later). Powers’s transgender care presentation has been around on the web in the form of a PowerPoint for a couple of years now, but this is the first time that it’s been presented by Powers himself in the form of a video.
I commend Powers’s commitment to the medical care of the transgender community. He says that approximately 75% of his patients are transgender, and per his own words, he has “basically dedicated [his] life to taking care of transgender people” (Reddit). I also commend Powers’s willingness to experiment and defy the status quo in terms of his clinical care. Particularly the following aspects of his approach to transgender hormone therapy:
- His use of high-dose parenteral estradiol therapy to more effectively and safely suppress testosterone levels in transfeminine people.
- His use of rectal administration of oral micronized progesterone capsules to more effectively deliver progesterone and suppress testosterone levels in transfeminine people (Aly W., 2019).
- Others deserve credit for originating this idea prior to Powers, but Powers deserves credit for thoroughly evaluating oral progesterone by this route and helping to popularize its use.
- His use of bicalutamide as a better antiandrogen in transfeminine people.
- Especially the results for liver function tests with bicalutamide in 400 transgender women that he has accumulated and reported, which substantiate bicalutamide as a safe treatment modality in this patient population (slide 47 of lecture).
- Various additional ideas, like his experimentation with very-high-dose custom-compounded topical estradiol gel as an alternative to estradiol ester injections in transgender women, or use of topical testosterone gel to enlarge and maintain the size of the genitals in transfeminine people prior to vaginoplasty (important for vaginal depth), among others.
Powers continuously strives towards innovation in terms of hormone therapy for transgender people and clearly wants to help improve the state of transgender hormone therapy as a clinical discipline. He has also shown himself to be willing to listen to and learn from transgender people. I find all of this great. It’d be helpful if there were more clinicians like him in this regard.
With all of that said however, there are also many problems with Powers and what he says. Many of his ideas about sex-hormone endocrinology and transgender hormone therapy are inaccurate or poorly supported. In addition, many of his claims are highly anecdotal, conjectural, and/or otherwise not evidence-based. I take the greatest issue with his claims regarding estrone, oral estradiol, spironolactone, and progesterone, particularly in relation to topics like breast development and adverse effects. I discuss these issues in-depth below.
Powers has requested critique and suggestions for his presentation many times before on Reddit (Reddit; Reddit; Reddit; More). Yet I’ve never provided feedback of my own for his presentation. This isn’t because I don’t care, but rather due to time and motivation constraints—in considerable part related to the sheer volume of material in his presentation needing coverage. In any case, I regret that I haven’t done this until now. With the popularity of his presentation and ideas surging on account of his recently posted video however, I’ve decided to finally write a commentary and fact check of Powers’s presentation (as well as lecture video). This write up follows my watching of the video/presentation and is roughly chronological.
Powers claims that diethylstilbestrol (DES) has 600 times the potency of estradiol. This is incorrect. It has about 2 to 4 times the clinical potency of oral estradiol in terms of FSH suppression and endometrial proliferation (or general estrogenicity) in women (Kuhl, 2005; Table). In other words, 1 mg oral DES is similar in general estrogenicity to 2 to 4 mg oral estradiol. Oral DES does have on the order of 20- to 25-fold the clinical potency of oral estradiol in terms of influence on liver protein synthesis due to its resistance to hepatic metabolism however. Although not much greater in potency than oral estradiol, it is the case that oral DES was used at high to very high doses in pregnant women; typically 5 mg/day in early pregnancy with the dosage gradually increased to 125 mg/day by the end of pregnancy (Reed & Fenton, 2013).
High-dose DES was previously used to help support pregnancy—before it was found that it was associated with birth defects and wasn’t actually effective. Powers claims that DES exposure in utero increases the likelihood of being transgender. This notion is controversial and the evidence in support of this notion is limited however. There is weak evidence from animal studies to suggest that prenatal DES exposure may produce limited intersex changes, but there is no quality clinical research to support the notion that prenatal DES exposure increases the likelihood of intersex or transgenderism in humans (Robinson, 2018; Wiki). Until this research is conducted, we won’t know the true influence of prenatal DES exposure on transgender identity in humans.
Update: New clinical data on prenatal DES exposure and AMAB transgenderism incidence here (i.e., Troisi et al., 2020). TL;DR: This is the best available data we have on this topic. The incidence of AMAB transgenderism was very low (~0.2%). This was too low to allow for determination of whether the risk was increased relative to non-exposed AMAB people in the sample. In any case, it was sufficient to indicate that any such effect of DES would be small at best and that the incidence of AMAB transgenderism with prenatal DES exposure is very rare (>99% end up cisgender).
Powers uses anastrozole to block puberty in adolescent transgender males. Surprisingly however, aromatase inhibitors like anastrozole don’t prevent gynecomastia induced by antiandrogens in men (Fagerlund et al., 2015; Bedognetti et al., 2010). As such, it may not a good idea to use them to block puberty in transgender males, because they may not actually prevent breast development. On the other hand, aromatase inhibitors can be used to inhibit estradiol production and thereby delay epiphyseal closure and increase height in short children (Lanes & Briceño, 2017). They would probably be effective for increasing height in pubertal transgender males as well, although most of the studies have used them in combination with growth hormone. But the issue of gynecomastia is still a problem.
Powers said that oral testosterone isn’t available in the United States. However, oral testosterone was recently approved for use in the United States under the brand name Jatenzo. Whether it’s an optimal choice for use in testosterone therapy is another matter that I won’t touch on here however. A number of other approved testosterone formulations besides those that Powers mentioned are also available (see here), both in the United States and elsewhere.
Powers mentioned that many of his transgender male patients have scalp hair loss due to testosterone therapy. Nandrolone decanoate, a prodrug of nandrolone (a.k.a. 19-nortestosterone), is a promising potential alternative to testosterone for avoiding scalp hair loss in transgender men. See my article on this topic here. The TL;DR is that whereas testosterone is potentiated by 5α-reduction into DHT, nandrolone is inactivated by 5α-reduction into 5α-dihydronandrolone, a weak AR agonist. So in theory you should largely avoid the issue of scalp hair loss with testosterone by using nandrolone decanoate instead (since 5α-reductase potentiation is critical for androgen-dependent scalp hair loss in men). There’s a lack of clinical research on nandrolone decanoate for androgen replacement in cisgender and transgender men at present however.
Powers claims that he hasn’t encountered irreversible infertility in transfeminine people. He says that he hasn’t had a single patient he couldn’t fix with use of clomifene to stimulate the gonads.
I think that this is something that would be a good candidate for publication. And this would be quite easy to do, via blood work results and semen analysis results. A meta-analysis of clomifene for infertility in men showed that it significantly improved spermatogenesis and pregnancy rates (Chua et al., 2013). Hence, clomifene very well might be beneficial for transfeminine people with fertility issues.
With that said however, I think that we should be cautious here. How many transfeminine people has Powers done this in? I imagine it’s a very small sample. Clinical studies have shown azoospermia in many transfeminine people even with prolonged discontinuation of hormone therapy (Schneider et al., 2017). Although a study with clomifene does not appear to have been done in transfeminine people to date, we currently don’t have any published clinical data to support its effectiveness, or particularly the notion that it will always be successful. We don’t want transfeminine people to assume that they can just start hormone therapy and not worry in the slightest about fertility since they can just get it back later. Because the evidence isn’t there to validate such a notion yet.
It’s well-established that infertility in AMAB people caused by progestogens, androgens/anabolic steroids, and GnRH agonists/antagonists is completely reversible. But the same may not be true in the case of infertility associated with high-dose estrogen therapy, which may result in long-lasting or even permanent impairment of testicular sex-hormone production and/or spermatogenesis (Wiki—last paragraph and refs; Salam, 2003):
Estrogens act primarily through negative feedback at the hypothalamic-pituitary level to reduce LH secretion and testicular androgen synthesis. […] Interestingly, if the treatment with estrogens is discontinued after 3 [years] of uninterrupted exposure, serum testosterone may remain at castration levels for up to another 3 [years]. This prolonged suppression is thought to result from a direct effect of estrogens on the Leydig cells.
This is thought to be because estrogens have direct toxic effects on the testes. Studies have been mixed regarding fertility in transfeminine people, with many having azoospermia despite discontinuation of hormone therapy but others successfully recovering their fertility following discontinuation of hormone therapy. Duration of therapy and estrogen dosage are probable moderating factors involved in this variation.
Powers claims that estrone only has 4 to 8% of the effect of estradiol as an estrogen and, therefore, estrone antagonizes estradiol at the ERs. However, Powers is mistaken. Estrone has, according to one study, about 4% of the affinity of estradiol for the human ERs (Escande et al., 2006). But multiple studies using human proteins, including that study, have shown that despite their far lower affinity for the ERs, both estriol and estrone are full or near-full agonists of the ERs, capable of inducing maximal responses similar to those of estradiol (Escande et al., 2006; Kloosterboer, Schoonen, & Verheul, 2008; Perkins, Louw-du Toit, & Africander, 2017; Perkins, Louw-du Toit, & Africander, 2018). In relation to this, estrone likely does not have the capacity to competitively antagonize estradiol to a meaningful degree.
Some transfeminine people claim to experience poor results with oral estradiol and it’s been argued that estrone antagonism is responsible for this. This is because estrone levels are much higher with oral estradiol than with non-oral estradiol routes. Although estrone antagonism is unlikely to be the case per the above, simple inactivation of estradiol via excessive conversion into estrone, and consequent low levels of estradiol, could certainly explain poor clinical results such as inadequate testosterone suppression, feminization, and breast development with oral estradiol in some transfeminine people.
Powers claims that estrone is implicated in the development of breast cancer and blood clots with estradiol. He essentially believes that estrone generated by estradiol is more important for these risks than is estradiol itself. But evidence in support of this notion is poor, and it is very likely a false notion.
Circulating levels of estradiol, estrone, and estrone sulfate have all been strongly associated with breast cancer risk in clinical studies (Rezvanpour & Don-Wauchope, 2017). Estradiol is thought to be ultimately responsible for this increase in risk of breast cancer, and estrone and estrone sulfate are merely surrogates or indirect measures of estradiol exposure. This is because estradiol is a potent ER agonist, whereas estrone and estrone sulfate themselves have very low potency as ER agonists (that is, require higher concentrations for the same effect) and derive their estrogenic activity largely from conversion into estradiol. Moreover, estradiol is metabolized into estrone and estrone sulfate, and hence breast cancer risk correlates not only with estradiol levels but also with levels of its metabolites. There is little in the way of evidence to specifically implicate estrone or estrone sulfate over estradiol in terms of breast cancer risk, and certainly no causational evidence. Large RCTs with selective estrogen receptor modulators demonstrate that breast cancer risk in postmenopausal women is strongly dependent on ER activation (Li et al., 2016). Accordingly, oral estradiol and transdermal estradiol show no difference in breast cancer risk in large observational studies (CGHFBC, 2019; Table).
The notion that estrone is more important for blood clots than estradiol is based on the findings of a single small correlational study with flawed conclusions. I’ve written a debunk of this study here.
Powers states that “There is a mounting level of evidence against estrone.” But there really isn’t. There is no reason to think that estrone is specifically harmful.
Powers claims that using oral estradiol alone or adding oral estradiol to estradiol ester injections results in better breast development than estradiol ester injections alone.
Powers claims this to be true based on his anecdotal observations in transfeminine people. He appears to have originally derived this notion from anecdotes and speculation by Redditor u/samkelley_ (Reddit). These claims are based on subjective observations and are not based on any actual objective measurements. Anecdotes are very often unreliable and should be considered with a great deal of skepticism. The idea in question has not been expressed or discussed in the scientific literature, and there is no published clinical or other evidence to support it. There is also no decent theoretical or preclinical research to support the notion.
Powers claims that he’s mimicking thelarche—the onset of breast development in pubertal cisgender girls—by using oral estradiol instead of non-oral estradiol, because estrone levels are higher than estradiol levels during early puberty and oral estradiol results in higher estrone levels than estradiol levels due to the first pass through the liver. He speculates that the higher estrone levels are the reason for his observations of better breast development. u/samkelley_ speculated that her observations of better breast development with oral estradiol had something to do with estrone sulfate. There is however no plausible mechanism by which higher levels of either estrone or estrone sulfate would result in better breast development.
Despite his claims, Powers is not mimicking thelarche by using oral estradiol. Previously Powers was using low-dose oral estradiol (e.g., 2 mg/day) for such purposes but has mentioned that he’s now using 10 to 12 mg/day oral estradiol for this indication. See the following table for approximate estrogen levels in pubertal girls, premenopausal adult women, postmenopausal women, and after a single 2 mg dose of oral estradiol in postmenopausal women to understand why oral estradiol doesn’t mimic normal female puberty (note: E2 = estradiol, E1 = estrone, E1S = estrone sulfate):
|Estrogen||Pubertal girls (Tanner stage 2)||Premenopausal women||Postmenopausal women||2 mg oral E2 post-menopausal women|
|E2||15 pg/mL||100 pg/mL||10 pg/mL||50 pg/mL|
|E1||20 pg/mL||50 pg/mL||50 pg/mL||350 pg/mL|
|E1S||≤700 pg/mL||1,000 pg/mL||500 pg/mL||12,000 pg/mL|
As can be seen in the above table, levels of estrone and estrone sulfate with a single 2 mg dose of oral estradiol are massively higher than normal physiological circumstances in normal female puberty and even in adult premenopausal women. Levels of these estrogens are even higher with continuous administration (as opposed to a single dose) and of course higher still with larger doses (e.g., 10–12 mg/day). Continuous oral estradiol at 2 mg/day generally achieves early pregnancy levels of estrone. For these reasons, Powers is producing astronomically high levels of estrone and estrone sulfate that are extremely unphysiological and massively in excess of what occurs during normal female puberty. Moreover, estradiol levels and estrone levels are in fact quite similar to each other during puberty when assessed with modern high-quality blood work assays (LC–MS/MS) (Aly W., 2020). Hence, there is little basis for making estrone levels higher than estradiol levels in the first place.
Powers also mentioned estrone sulfate as possibly being responsible for his observations of better breast development with oral estradiol, because estrone sulfate “is taken up into cells more easily than estradiol and is then converted into estradiol” (paraphrased). However, estradiol is lipophilic and readily crosses cell membranes via passive diffusion, whereas estrone sulfate is hydrophilic and cannot cross cell membranes on its own. Hence, estrone sulfate requires active transport via a variety of carriers to enter cells (Wiki). As such, estrone sulfate likely has a harder time entering cells than does estradiol. In addition, it can only enter cells in tissues that express the requisite transporters and can only be converted into estradiol in cells that express steroid sulfatase and 17β-HSD.
It’s very unlikely that higher estrogen exposure would result in any better breast development than physiological exposure. There is considerable published literature relevant to this subject which I’ve been collecting and will post at some point in the future. (See also the next major section below—”High-dose estrogen and breast development”.)
In accordance with the lack of theoretical support, available clinical studies have found similar breast development with oral estradiol versus transdermal estradiol in transfeminine people and hypogonadal cisgender girls (Shah et al., 2014; Wierckx et al., 2014; de Blok et al., 2018; Sam S., 2020; de Blok et al., 2021). In addition, a preliminary study reported no association of estrone levels with breast development in transfeminine people (Tebbens, 2020). These findings suggest that route of administration of estradiol is of no importance for breast development in transfeminine people.
Powers also claims in the video that thelarche is primarily due to production of weak androgens like DHEA and androstenedione by the adrenal glands, which are subsequently aromatized into estrone in peripheral tissues. However, he is incorrect here. It’s well-known that breast development does not occur in prepubertally ovariectomized or hypogonadal cisgender girls and requires induction with exogenous estrogen therapy (Klein et al., 2018).
Powers presents a “neurodevelopmental estrone therapy” in which he argues that estrone causes gender dysphoria. Essentially, he argues that disproportionate conversion of estradiol into estrone due to 17β-HSD polymorphisms results in massive build up of estrone and excessive exposure of the fetal brain to estrogenic signaling, in turn resulting in feminization and transgenderism. He claims that this is “exactly what happens with diethylstilbestrol” as well—that is, excessive neurological estrogen exposure resulting in fetal brain feminization. This theory is complete conjecture and has no basis or support. It’s a rather naive idea honestly and I don’t think that such speculations should be shared. Powers does at least say to take the idea with a “grain of salt” in any case. With that said however, per recent findings, AMAB transgenderism with prenatal DES exposure is very rare, and hence this notion can be regarded as dubious likewise.
Powers thinks that transfeminine people tend to have mutations that cause them to have very high estrone levels with oral estradiol. However, there is high interindividual variability in the pharmacokinetics of oral estradiol, and excessive conversion of estradiol into estrone is not at all unusual. The average ratio of estradiol to estrone with oral estradiol is 5:1 (Kuhl, 2005) and some studies have found mean ratios as high as 10:1 to 20:1 (Kuhnz, Gansau, & Mahler, 1993). Hence, it’s unlikely that there’s anything unique about transfeminine people in this area.
Powers claims that “sore boob is more boob” and that if the breasts are sore, that means they’re growing. This is not true. High-dose estrogen therapy in cisgender women, resulting in estradiol levels of more than 150 pg/mL (Sitruk-Ware et al., 1984), is associated with breast pain/tenderness. Temporary or exposure-dependent breast enlargement also occurs due to fluid retention but this reverses with discontinuation and there is no lasting breast development. Breast pain/tenderness will generally occur with estradiol levels that are high enough, and are not necessarily indicative of growth. See here for some more information and discussion on this topic between Powers and I.
Powers mentions his experimentation with topical estradiol on the breasts to increase breast size in a single transfeminine patient. I thought I’d mention that published clinical experience in cisgender women has found that topical estrogens applied to the breasts result in only modest and temporary breast enlargement (Kaiser & Leidenberger, 1991; Cernea, 1944; Ribas, 2010). For example, “Estrogen-containing ointments, contrary to the often cherished expectations of the patient, at best lead to a temporary and unimpressive result” (Keller, 1984). Similar results have been observed with high-dose parenteral estradiol therapy in cisgender women. I’ll be posting an article on this topic in the future.
Powers claims that spironolactone impairs breast development. He says that this is based on clinical research in which “they took every trans woman in Europe, thousands…” (paraphrased) and found that breast development was poorer in transfeminine people given spironolactone than those not given spironolactone. This is a highly inaccurate claim.
The notion that spironolactone impairs breast development derives from a single small retrospective study by Seal et al. (2012) for a single transgender hormone therapy clinic in London, United Kingdom. The study found that use of spironolactone in transfeminine people was associated with a significantly higher rate of breast augmentation than use of other antiandrogens in transfeminine people (specifically GnRH analogues, cyproterone acetate, and/or 5α-reductase inhibitors). As this study was only correlational, it does not show that spironolactone causes a higher rate of breast augmentation, only that the two happened to co-occur in this particular patient sample. Moreover, the researchers did not physically measure breast development. Hence, it’s unknown whether breast development was actually less in those on spironolactone—the behavioral inclination of a person to opt for breast augmentation and a person’s actual physical breast development are two very different things that may or may not correspond to one another in a given situation.
The total sample size was 330 transfeminine people, but the spironolactone group only had 22 transfeminine people in it. Of them, 16 (73%) had breast augmentation and 6 (27%) did not. This was the basis for the association. It’s not very many cases to go on and isn’t a robust result, but statistical significance was in any case achieved with the difference (p = 0.025) (Table). However, a very large number of statistical tests were conducted in this study (36 t-tests, to be exact), and there was no adjustment for multiple comparisons to control for the risk of false positives (see also p-hacking). When you’re doing this many t-tests, something is bound to be statistically significant simply as a matter of probability (5% or 1/20 likelihood with a p = 0.05 test level). As such, chance may have been responsible for their findings, and until replicated, the results should be regarded very cautiously. It’s notable that the use of GnRH analogues trended in the direction of statistical significance for higher likelihood of breast augmentation similarly to spironolactone in spite of no biological plausibility for such a result and a much larger sample size (51/91 or 56% BA vs. 40/91 or 44% no BA; p = 0.155).
As the study was not a randomized comparison, confounding variables that were not controlled for may have mediated the association of spironolactone use with likelihood of getting breast augmentation rather than spironolactone itself. Indeed, Seal et al. (2012) additionally found that DIY/self-medication was associated with a significantly higher rate of breast augmentation than non-DIY/self-medication (38/58 or 66% BA vs. 20/58 or 34% no BA; p < 0.01). This is notable as Seal’s clinic does not prescribe any antiandrogens except GnRH analogues. Hence, spironolactone use may have been concentrated in or exclusive to the DIY/self-medication group. This is a clear potential confounding factor that could instead explain the association observed with spironolactone. For example, estradiol levels were also higher in DIY/self-medicating users, and this might have instead been involved in suboptimal breast development. Alternatively, the association might have really been due to behavioral impulsivity—those who were more impulsive might have been both more likely to DIY/self-medicate and more inclined to opt for breast augmentation. These hypotheticals are intended more as examples for illustrational purposes rather than as real explanations, but it’s possibilities of this nature that are why causation can’t be attributed to spironolactone.
It’s also important to note that even if spironolactone were causally responsible for the difference, it still might not be that spironolactone actually results in less breast development. As an example, spironolactone is a mineralocorticoid receptor antagonist, with significant brain and behavioral effects. Hypothetically, it could have influenced participants’ behavior and inclination to get breast augmentation without having any actual effect on physical breast development. This is likewise intended for purposes of illustration rather than real explanation, but it’s another reason why it can’t be assumed that spironolactone actually causes poor breast development.
Seal et al. (2012) is the sole reason that the notion spironolactone impairs breast development in transfeminine people exists. It’s low-quality data—small sample size, arguable p-hacking, retrospective correlational study, no control for extraneous variables, indirect/surrogate measure of breast development, etc.—and says nothing about causation or even about actual breast development.
Powers claims that the reason for poor breast development with spironolactone is due to “premature nipple plate fusion”. This also is from Seal et al. (2012). They claimed that spironolactone has intrinsic estrogenic activity of its own and that taking spironolactone resulted in excessive estrogenic exposure, which in turn caused “premature breast bud fusion and poor breast development”. In actuality, spironolactone has very low affinity for the estrogen receptors, and there is in general pretty considerable indication against the notion that it has clinically important intrinsic estrogenic activity. I am working on an article with this specific topic discussed. Hence, the mechanism proposed by Seal et al. (2012) is poor reasoning and shouldn’t be given credence. Assuming that spironolactone really did result in lesser breast development compared to the other antiandrogens, a much better hypothesis for the mechanism would be that spironolactone doesn’t “stunt” breast development but rather simply inadequately blocks/suppresses testosterone due to being a relatively weak antiandrogen. As for the antimineralocorticoid activity of spironolactone, there is little biological plausibility for the notion that it might in some way be harmful for breast development.
A randomized controlled trial of spironolactone versus cyproterone acetate and breast development in transfeminine people is currently underway in Australia and may give us more insight on the issue of spironolactone and breast development relative to other antiandrogens (ANZCTR).
Update: Powers has since modified his position on spironolactone and breast development here.
Powers claims that spironolactone causes increased visceral fat. This notion is derived from this transgender woman. She claims that it is due to increased cortisol levels induced by spironolactone. There is no clinical support for the idea that spironolactone causes visceral adiposity however. In fact, there is evidence both from preclinical and clinical research that spironolactone doesn’t cause visceral fat accumulation but rather may produce the very opposite effect.
It’s true that spironolactone increases cortisol levels, and elevations in cortisol levels of similar magnitude may indeed have been correlated with increased visceral fat in other studies. But cortisol is both a GR and MR agonist, and both of these receptors are involved in visceral fat accumulation with cortisol. The strong MR blockade of spironolactone—and hence a presumable mixed profile of relatively weak GR agonism and strong MR antagonism with spironolactone—appears to produce a very different result than one might expect if they assumed that cortisol only acted through the GR to mediate its effects on visceral fat (e.g., Mammi et al., 2016). I’ll be writing a comprehensive article on this topic at some point in the future.
One can’t simply extrapolate and assume that spironolactone will indeed cause increased visceral fat based on the fact that some studies have found increased cortisol levels with it. Actual clinical studies on spironolactone and visceral fat are needed to evaluate and confirm such ideas.
Update: See here for some more on spironolactone and visceral fat for now.
Powers claims that spironolactone causes depression and fatigue. There is little clinical support for the notion that spironolactone causes depression (Otte et al., 2010). Some sources state that spironolactone may produce fatigue or lethargy as an effect secondary to lowered blood pressure however. In any case, the incidence of this side effect appears to be very low (Table).
With all of the preceding said about spironolactone, I agree with Powers that bicalutamide is an excellent and superior alternative to spironolactone. It is a far better antiandrogen than spironolactone in terms of both efficacy and tolerability. Spironolactone shows inconsistent effects on testosterone levels (Aly W., 2018; Aly W., 2020), is a relatively weak AR antagonist (Wiki), and has undesirable off-target potent MR antagonism that results in antimineralocorticoid side effects and risks. Conversely, bicalutamide is far more potent in comparison and is highly selective as an AR antagonist (although it also has a small risk of liver toxicity that is not shared with spironolactone; Aly W., 2020). When it comes to spironolactone, I just care about factual accuracy.
Powers claims that people experience severe depression with finasteride. Some small clinical studies have indeed reported alarmingly high rates of depression with finasteride, and depression risk with 5α-reductase inhibitors might indeed be related to inhibition of neurosteroid biosynthesis. But these clinical studies have been poor-quality uncontrolled studies. A large and better-quality epidemiological study found that risk of depression was significantly higher with 5α-reductase inhibitors than without, but that the risk was quite small and was confined to the first year of treatment (Wiki). Additional research is necessary to further characterize the influence of 5α-reductase inhibitors on mood, but their risk of depression is unlikely to be substantial.
It is in any case entirely true that 5α-reductase inhibitors are often used unnecessarily in transfeminine people. If testosterone levels are in the normal female range, then there is likely no need for a 5α-reductase inhibitor, which just adds unnecessary costs and small but significant risks of adverse effects. Oral 5α-reductase inhibitors can still be very useful and convenient for combatting scalp hair loss in cisgender and transgender men however and I think it’s unfortunate that Powers doesn’t provide them to his transmasculine patients. Emotional consequences of hair loss can be severe, and not giving a 5α-reductase inhibitor could arguably be much worse in terms of risk-benefit ratio than not prescribing one given their quite small risk of depression. Powers does prescribe compounded topical 5α-reductase inhibitors. But I don’t know that their efficacy by this route has been adequately shown, and this route is not as convenient as taking them orally.
Powers claims that transfeminine people who aren’t given progesterone will develop “pointy boobs”, which he has referred to as “trans cone boobs syndrome”. He claims that this is because transfeminine people will be stuck in Tanner stage 4 breast development without progesterone. As I have discussed elsewhere however, there is no evidence that progesterone is involved in or required for complete breast development or feminization (Aly W., 2019; Aly W., 2020; Aly W., 2020). Moreover, women with complete androgen insensitivity syndrome, who have no progesterone, have excellent and full breast development and feminization, strongly suggesting that progesterone is dispensable for these characteristics. It’s also notable that premature introduction of progesterone might actually have adverse effects on breast development, although this notion is theoretical and remains to be demonstrated in humans (Aly W., 2019).
Powers claims that drospirenone, a progestin used in birth control pills and menopausal hormone therapy, is “eight times more deadly than every other progestin out there” (paraphrased). This is not accurate however. See the first paragraph here on a past version of the drospirenone Wikipedia page, which I imagine might actually be where Powers got the notion from.
When used in birth control pills, progestins with less androgenicity, like gestodene and norgestimate, as well as antiandrogenic progestins, like cyproterone acetate and dienogest, have likewise been found to have a higher risk of blood clots than levonorgestrel, a relatively androgenic progestin. It’s notable in this regard that drospirenone is a progestin with relatively high antiandrogenicity. It is thought that activation of the AR in the liver opposes estrogen-induced changes in production of coagulation factors, in turn reducing ethinylestradiol-mediated increases in coagulation and blood-clot risk. This would explain the different relative risks for venous thromboembolism with the different progestins, including that of drospirenone.
Also, the greater risk of blood clots with drospirenone and other recent-generation progestins relative to first-generation progestins is actually very controversial and may not be the case (Wiki).
Powers argues that oral progesterone should be used in birth control pills due to the adverse effects of progestins (e.g., risk of blood clots with drospirenone). I describe below in the “Progesterone and health risks” section that progesterone may not fundamentally differ from progestins in terms of various risks and hence that this idea may be misguided however. Moreover, researchers actually did try to use oral progesterone in birth control pills. But it was very weak in potency and they couldn’t achieve adequate inhibition of ovulation with it (Wiki). So they abandoned progesterone for oral birth control and developed progestins instead. And this is all not to mention the neurosteroid side effects of progesterone, especially at the very high doses that would be required for oral progesterone to be useful for birth control (Wiki; Wiki).
In any case, progesterone has been successfully developed for use as non-oral birth control, including as a vaginal ring and as an intrauterine device. These formulations have been plagued by the low potency of progesterone and hence by limited durations however. As a result, their use and availability has been very limited and the intrauterine device was discontinued decades ago.
The “Powers Method”—in terms of using a combination of estrogen and a progestogen to suppress testosterone levels—is not new and is actually how transfeminine hormone therapy is largely done in Europe and elsewhere outside of the United States. This is specifically with the combination of oral or transdermal estradiol and high-dose cyproterone acetate (CPA). However, Powers’s particular regimen—high-dose parenteral estradiol esters and rectal progesterone—although much less convenient, is likely to be more physiological and safe. An argument can still be made for use of low-dose CPA however, which is just as effective but has reduced risks compared to the fairly extreme doses of CPA typically used in transfeminine people (Aly W., 2019). The combination of estradiol with an adequately dosed progestogen is a more effective means of suppressing testosterone levels in transfeminine people than the estradiol plus spironolactone strategy often used in the United States (Angus et al., 2019; Graph).
Powers claims that progesterone makes people hungry and causes weight gain. Although extremely high doses of certain progestins like medroxyprogesterone acetate (MPA) and megestrol acetate (MGA) are known to markedly stimulate appetite and weight, progesterone and other progestogens are not known to have this action. Studies on depot MPA as a progestogen-only contraceptive in women are mixed and inconclusive in terms of weight gain, with similar rates of both weight gain and weight loss observed (Nelson, 2010). A 2018 systematic review of almost 20 clinical studies found that estrogen plus bioidentical progesterone did not influence weight or BMI in postmenopausal women and that these findings with progesterone were similar to studies with progestins (Coquoz, Gruetter, & Stute, 2019).
Powers claims that the addition of progesterone to estrogen therapy does not increase the risk of blood clots, cardiovascular disease, or breast cancer. He claims that progesterone actually decreases the risk of breast cancer. Conversely, he claims that progestins (synthetic progestogens) increase the risks in question.
Addition of progestins to estrogen therapy has been associated with significantly higher incidence of blood clots, cardiovascular disease, and breast cancer relative to estrogen alone in observational studies. This was shown to be causal in the case of MPA in the Women’s Health Initiative RCTs. Conversely, causation has not been demonstrated for any other progestins. In any case, the risk associations for blood clots and breast cancer are consistent among virtually all progestins, strongly suggesting that PR activation is responsible. Conversely, increased risk of coronary heart disease (clogged arteries) may be specific to androgenic progestins like MPA and norethisterone and hence may not apply to all progestogens. In contrast to progestins, oral progesterone has not been associated with increased risk of blood clots or cardiovascular disease nor with unfavorable cardiovascular biomarker changes. On the other hand, associations of oral progesterone with breast cancer risk in the short-term (<5 years) are less than those of progestins but in the long-term breast cancer risk is increased similarly. For sources on all of the preceding statements, see elsewhere (Wiki; Wiki; Aly W., 2018; Stanczyk et al., 2013).
It is difficult to explain why progestins, with diverse chemical structures and actions, would all increase risks of the aforementioned health issues while progesterone would not. They’re all PR agonists, so either all progestins would have to be doing something additional to PR agonism to produce the risks in question or progesterone would have to be doing something additional to partially cancel out its own PR agonism so as to neutralize said risks. Both scenarios are technically possible but stretch the limits of plausibility. Moreover, preclinical and epidemiological research implicate progesterone in the risks in question, for instance breast cancer (Kuhl & Schneider, 2013; Trabert et al., 2020; Aly W., 2020).
Originally, oral progesterone was thought to produce high, luteal-phase levels of progesterone. But this was based on studies with flawed analytic methodology. Subsequent research with superior and more accurate quantification methods has since shown that oral progesterone actually results in very low progesterone levels that are far below normal physiological luteal-phase levels (Aly W., 2018; Wiki). When this is considered, it’s not exactly surprising that estrogen plus oral progesterone therapy is associated with minimally different risks relative to estrogen alone (aside from breast cancer risk)—it’s because oral progesterone is almost like taking a sugar pill. The very low progesterone levels with oral progesterone simply aren’t enough to influence risks for the most part.
In contrast to oral progesterone, non-oral routes for progesterone, such as vaginal administration, rectal administration, and injections, are not widely used in hormone therapy and have never been assessed in adequately powered studies in terms of blood clots, cardiovascular disease, or breast cancer. So we have essentially no data on how non-oral progesterone would influence such risks. Based on these routes producing high progesterone levels however, the risks may prove to be similar to those of progestins. In any case, only more research will answer this question.
There are no clinical trials to indicate that addition of progesterone to an estrogen decreases the risk of breast cancer relative to an estrogen-only therapy. Although E3N, a large observational study, found a numerically higher rate of breast cancer with estrogen alone (RR = 1.29) than with the combination of estrogen and oral progesterone (RR = 1.00) (L’Hermite et al., 2008), this was only for short-term use (<5 years) and the difference was not statistically significant (Trabert et al., 2020). E3N found that long-term (>5 years) oral progesterone was in fact associated with increased breast cancer risk (Wiki). Other large observational studies have since replicated these findings and this topic was recently subject to large-scale meta-analysis, with no increase in risk in the short-term but significantly greater risk in the long-term (CGHFBC, 2019; Table).
There is actually one exception among progestins in terms of health risks—the retroprogesterone derivative dydrogesterone. It has been associated with lower risks similarly to oral progesterone (Wiki). However, dydrogesterone is an atypical progestogen and has unusual properties, even relative to progesterone—for instance it has no hyperthermic effect or ovulation inhibition—standard progestogenic effects—even at very high doses (Wiki). The reason for the atypicality of dydrogesterone is unknown. In any case, it has the lowest bioavailability of any clinically used progestin and may have analogous issues with levels and pharmacokinetics relative to oral progesterone (Wiki). Accordingly, dydrogesterone is associated with inadequate endometrial protection in contrast to all other clinically used progestins but similarly to oral progesterone (Wiki; Wiki).
Powers claims that a lack of testosterone in women will result in cognitive and memory impairment. He also claims that low-dose testosterone has beneficial effects on well-being, bone density, and other factors. However, there is a lack of support for beneficial effects of testosterone in women at present, per systematic reviews, meta-analyses, and clinical guidelines (Wiki; Aly W., 2020).
Powers made a number of errors in terminology and pronunciation in the video:
- Powers pronounces “bicalutamide” as “bih-kah-loo-tah-myde”. This is incorrect. It’s pronounced “bye-kah-loo-tah-myde”. The first two syllables of “bicalutamide” are derived from the term “bicyclic” which relates to the fact that bicalutamide is a bicyclic compound (Wiki).
- While discussing allopregnanolone in the context of 5α-reductase inhibitors, Powers referred to it as a “neurocorticosteroid” and “neurocorticoid”. These terms don’t actually exist however. And “corticosteroid” / “corticoid” refers to corticosteroid receptor agonists such as glucocorticoids and mineralocorticoids. Allopregnanolone has no such action or relation. The correct term that Powers was looking for is simply “neurosteroid” or “neuroactive steroid”.
- Powers refers to progesterone as a “GnRH agonist”, but this is technically incorrect. “GnRH agonist” is a specific term that refers to agonists of the GnRH receptor, like leuprorelin (Lupron). Progesterone has no such action—it is not an agonist of the GnRH receptor. Rather, progesterone and other progestogens, as well as estrogens, androgens/anabolic steroids, and prolactin, are antigonadotropins—agents which suppress the GnRH-induced secretion of gonadotropins secondary to their sex-hormonal effects (e.g., PR agonism).
- Powers at one point referred to the ER as a “cell-surface” receptor. This may have just been a momentary slip up, but it’s incorrect. The ER is a nuclear receptor. That is, it resides in the cell nucleus and upon binding to and being activated by an estrogen the receptor binds to and modulates gene expression, which is how estrogens mediate their effects. (However, a small portion of “nuclear” ERs are actually associated with cell membranes as membrane estrogen receptors. Although not the dominant mode of estrogen action, these membrane-associated “nuclear” ERs have their own physiological effects as well.)
Use of correct terminology is important to avoid misunderstandings and confusion.
As I touched on in the introduction, I think that Powers’s efforts in terms of improving care in the space of transgender hormone therapy are commendable. His adoption and advocacy of high-dose parenteral estradiol, rectal progesterone, and bicalutamide, among others, are all great, and I think he deserves credit and praise for them. I’ll readily give credit where I think it’s due. Accordingly, I’ve posted in the past on Powers’s clinical experience with rectal progesterone in transfeminine people (Aly W., 2018). This was based on his blood work results, which I think are adequately objective measures and hence acceptable for this subreddit (though of course unpublished).
In many regards however, Powers’s approach shows a significant deficiency of scientific rigor. He is not careful enough with factual claims, often making statements that are inaccurate or poorly supported. He engages in highly speculative theorizing that is poorly formulated and frequently contradicted by the published literature. He distributes his ideas widely online and elsewhere, regardless of how inadequately supported many of them may be. And due to his position of prestige and authority as a popular transgender hormone therapy physician, an alarming number of people uncritically accept and believe such ideas, often with little or nothing in the way of questioning. I think that Powers needs to think about the influence he has and be more careful about the things he says in his position.
Aside from blood work, Powers rarely if ever uses objective measurements, largely relying instead on unreliable and unsubstantiated anecdotal/subjective observations. This is an approach that is riddled with pitfalls. He hasn’t had any of his findings or ideas peer-reviewed or published. Hence, none of his claims are currently subject to any verification. It’s plausible that a clinician in such a position could be making cognitive and perceptual errors in their judgements and seeing trends that would disappear upon actual objective quantification. I don’t know if that’s the case or not here but I have significant suspicions. As a matter of principle, it’s a possibility that needs to be considered. There are good reasons for why things like evidence standards, peer review, and publication exist. For these reasons, great caution is warranted with Powers’s unpublished clinical anecdotes.
Powers’s current approach to scientific research isn’t how it is nor should be done. It should be conducted first, then peer-reviewed and published, and only then people should learn about it—once there’s objective data to support it, it’s certain to be accurate, and it’s been appropriately vetted.
I hope that Powers adopts a more scientifically rigorous approach in the future. I would be pleased to see him employ objective measures to substantiate his observations and ideas. As an example, objective measures of breast development, breast hemicircumference, breast–chest difference, and areolar diameter, are some possibilities for objective measurements that could very easily be employed (Aly W., 2020; Meyer et al., 1986; de Blok et al., 2018). If he used standardized objective measures, his findings, whatever they may be, could prove to be quite valuable. I can envision myself going from skepticism to commendation with adequate quality measures and data. And I’d be pleased to see Powers’s work be peer-reviewed and published. But until such changes, we should remain skeptical regarding his anecdotal/observational claims.
See here for some later discussion on Powers and “WPATH”.
And see here for some uncanny historical parallels to Powers.