By Aly W. | First published August 30, 2019 | Last modified May 17, 2022
This is a commentary and fact check of version 5.3 of Dr. Will Powers’s transgender care presentation and video. This page is slightly out-of-date as Powers’s presentation is now at version 6.0. This article was originally a bullet-point list of the present author’s thoughts that was written up and casually posted on social media. However, it has since been adapted to a degree into the format of an article and moved to this site. The article has been incrementally updated and revised since it was originally published. Nonetheless, this content may be partly outdated and is in need of further revision.
William Powers, D.O., or Dr. Will Powers, is a family medicine physician near Detroit, Michigan in the United States. He was formerly employed by Be Well Medical Center in Berkley, Michigan, but has since left that clinic and launched his own practice called Powers Family Medicine in Farmington Hills, Michigan. Although his medical specialization is in family medicine, Powers’s clinic primarily provides hormone therapy for transgender people. The website for Powers’s clinic is at powersfamilymedicine.com and his clinic’s Facebook page can be found at facebook.com/DrWillPowers. Powers is well-known by the online transgender community due to his extensive 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 called Healthcare of the Transgender Patient: The Powers Method of Hormonal Transitioning (direct link to “version 6.0”) which he initially released in 2017 and has maintained since. This PowerPoint presentation describes Powers’s personal clinical approach to transgender care and has been widely shared in the online transgender community. A video recording of Powers presenting his transgender care lecture at the Oakland University William Beaumont School of Medicine in Michigan was uploaded to YouTube in mid-June 2019. This video was subsequently posted on Reddit and elsewhere on the web and quickly garnered an explosive degree of popularity in the online transgender community. Powers’s transgender care presentation had been around on the web for a couple of years prior, but this was the first time that it had been presented by Powers in the more easily digestible and apparently viral-phenomenon-inclined format of a video.
It must be noted that Powers is not an endocrinologist, is not a scientific researcher or academic, and is not a recognized expert in the professional transgender health community. At this time, he hasn’t conducted any research or published any scientific papers and he doesn’t participate in the transgender medical community—for instance by joining the World Professional Association for Transgender Health (WPATH) or attending transgender health conferences. Powers himself is very straightforward about all of this online. However, many transgender people nonetheless misunderstand who he is and assume that he’s an expert and groundbreaking researcher in the field of transgender hormone therapy. Considering the medical information that transgender people receive from Powers and his presentation, it’s important for people to be aware of who he is and his standing in the field of transgender health.
It’s great to see clinicians like Powers who are strongly dedicated to the transgender medicine. It’s also very nice to see clinicians trying to contribute to innovation in transgender medicine. Some of Powers’s approaches to transgender hormone therapy I think have definite clinical value, such as his use of high-dose parenteral estradiol to suppress testosterone levels in transfeminine people, his use of rectal administration of oral progesterone capsules to more effectively deliver progesterone and help suppress testosterone levels in transfeminine people (see also Aly W., 2019), and his use of bicalutamide as a more favorable antiandrogen in transfeminine people (see Aly W., 2020 for more on this topic), among others. However, there are also important safety concerns when it comes to such approaches that must be recognized. In any case, it’s clear that Powers wants to help improve the care of transgender people. He has also shown himself to be unusually willing to listen to and learn from transgender people. All of that is very commendable, and I think it’d be helpful if more clinicians were like him in these regards.
At the same time however, there are many problems with Powers, his transgender care presentation, and the information he disseminates online in general. Powers’s clinical approaches in terms of transgender hormone therapy deviate strongly from accepted clinical practices and expert recommendations by transgender care guidelines, with little data to substantiate them. The present author considers many of Powers’s ideas about sex-hormone endocrinology and transgender hormone therapy to be inaccurate and poorly supported. Many of Powers’s claims are anecdotal or are based on highly theoretical musings rather than on quality scientific data. He seems to have little care for evidence-based medicine or practice or for the hierarchy of evidence, little proficiency with scientific research methods and statistics, and little respect for clinical practice standards and norms. However, formal research methods and medical standards exist to ensure the effectiveness and safety of medical interventions and to protect the health and well-being of patients. In these regards, they are of critical importance.
Powers has requested critique and suggestions for his transgender care presentation from transgender people many times before on Reddit (Reddit; Reddit; Reddit; More). To date, I have not provided feedback of my own for his PowerPoint. This has mainly been due to time and motivation constraints, in considerable part related to the sheer volume of material in the presentation that needed to be covered. In any case, with the popularity of his presentation surging on account of the recently posted video of him giving the presentation, I’ve opted to finally write up and provide feedback. This article is a commentary and fact check of both the presentation and video which follows my watching of the video and subsequent reading-through of the PowerPoint. It is roughly chronological.
Diethylstilbestrol (DES) is a potent synthetic estrogen which was widely used in medicine in the past, for instance to support pregnancy via estrogen supplementation. Powers claims that DES has 600 times the potency of estradiol. This is not true. It has about 2 to 4 times the clinical potency of oral estradiol in terms of follicle-stimulating hormone (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 estrogen-sensitive liver 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).
Although DES was previously used to help support pregnancy, it was eventually found to cause birth defects and to not actually be effective in preventing miscarriage and other adverse pregnancy outcomes (Barter et al., 1986; Bamigboye & Morris, 2003). The toxic effects of DES appear to be related to overactivation of the estrogen receptors (Korach & McLachlan, 1985). Powers claims that DES exposure in utero increases the likelihood of being transgender. However, this notion is very controversial, and the evidence in support of it is limited and based on very low-quality data (DES Action). There is indication that prenatal DES exposure may produce reproductive abnormalities in both animals and humans and there is research finding limited intersex changes with prenatal DES exposure in male animals (Stillman, 1982; Glaze, 1984; Swan, 2000; Newbold, 2004; Sinclair et al., 2016). However, there is no quality clinical research at this time to support the idea that prenatal DES exposure increases the likelihood of being intersex or transgender in humans. Until this research is conducted, we won’t know the true influence of prenatal DES exposure on gender variance and transgender identity in humans.
Update: The first formal observational study of prenatal DES exposure and likelihood of being transgender in people assigned male at birth was published subsequent to the writing of this article. The study was Troisi et al. (2020) and it has been covered on Transfeminine Science here. This study is by far the best-quality evidence available on this topic. In the study, the incidence of being transgender in people assigned male at birth who were exposed to DES prenatally was only about 0.2% (1 in 500) and hence was very low. This rate was too low to allow for determination of whether the likelihood was significantly increased relative to non-DES-exposed people who were assigned male at birth. Hence, it’s still unknown whether DES increases the likelihood of being transgender in people assigned male at birth or not. In any case, the low percentage of cases was sufficient to indicate that any such effect of DES would be very small at best and that the incidence of transgender identity in people assigned male at birth with prenatal DES exposure is very rare (>99% end up being cisgender).
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-hydroxysteroid dehydrogenase (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 being transgender. 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 however conjecture, and there is no basis or support for it that the present author is aware of. Honestly, it’s a fairly naive idea, and I think that Powers should reconsider his sharing of such speculations. He does at least say to take the idea with a “grain of salt”. In any case, per recent findings, transgender identity with prenatal DES exposure in people assigned male at birth is very rare, and as with the notion of DES causing people to be transgender, this notion can be regarded as unlikely similarly.
Powers uses anastrozole (brand name Arimidex), an aromatase inhibitor (estrogen synthesis inhibitor), to block puberty in adolescent transgender males. This type of medication is not normally used to block puberty in transgender youth nor to block puberty in the context of precocious puberty (except under special circumstances—specifically, gonadotropin-independent precocious puberty). Surprisingly, aromatase inhibitors like anastrozole don’t prevent gynecomastia caused by antiandrogens in cisgender men (Fagerlund et al., 2015; Bedognetti et al., 2010) or in cisgender boys with precocious puberty (Reiter et al., 2010; Wiki). Considering this, they should probably not be routinely used to block puberty in transgender males as they likely would not prevent breast development in this context.
On the other hand, aromatase inhibitors can be used to delay epiphyseal closure and increase final height in unusually short children (Lanes & Briceño, 2017). They would probably be effective for increasing height in pubertal transgender males as well, although most of the studies of aromatase inhibitors for such purposes have used them in combination with growth hormone. But this would be an experimental use that has yet to be studied. And the issue of gynecomastia is still a problem.
Powers said that oral testosterone isn’t available in the United States. However, oral testosterone actually has been approved for use in the United States under the brand name Jatenzo. A number of other approved testosterone formulations besides those that Powers mentioned are also available (see here).
Clomifene (brand name Clomid) is a selective estrogen receptor modulator (SERM) with predominantly antiestrogenic effects on the hypothalamic–pituitary–gonadal (HPG) axis. It disinhibits the release of the gonadotropins from the pituitary gland and thereby stimulates the gonads. Powers claims that he hasn’t encountered irreversible infertility in transfeminine people. Specifically, he says that he hasn’t had a single patient he couldn’t fix with use of clomifene to stimulate the gonads. In accordance with these claims, a meta-analysis of clomifene for infertility in cisgender men showed that it significantly improved spermatogenesis and pregnancy rates (Chua et al., 2013). Hence, clomifene very well may be beneficial for helping to restore fertility in transfeminine people.
With that said however, caution is warranted here. It’s unclear how many transfeminine people Powers has actually tried this approach in. I’d imagine that it’s a very small number of individuals. Clinical studies have shown azoospermia (absent sperm in semen) 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 shed light on its effectiveness in this context, and it’s unknown how often it will be successful. We don’t want transfeminine people to assume that they can start hormone therapy and not worry about fertility since they can just get it back later—which may not actually be the case.
Infertility in cisgender men caused by progestogens, androgens and anabolic steroids, and gonadotropin-releasing hormone (GnRH) modulators is temporary and reversible. But the same may not be true in the case of infertility associated with estrogen therapy, which may result in long-lasting or even permanent impairment of testicular sex-hormone production and/or spermatogenesis (Wiki; Salam, 2003):
Estrogens act primarily through negative feedback at the hypothalamic-pituitary level to reduce [luteinizing hormone] 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. More research is needed to clarify these issues.
Powers claims that estrone only has 4 to 8% of the effect of estradiol as an estrogen and, therefore, estrone antagonizes estradiol at the estrogen receptors. However, Powers is mistaken. Estrone has, according to one study, about 4% of the affinity of estradiol for the human estrogen receptors (Escande et al., 2006). But multiple studies using human proteins, including that study, have shown that despite their far lower affinity for the estrogen receptors, both estriol and estrone are full or near-full agonists of the estrogen receptors, capable of inducing maximal effects 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 meaningfully antagonize estradiol—at least in terms of classical competitive receptor antagonism.
Some transfeminine people claim to experience poor results with oral estradiol, and it has been argued that antagonism of estradiol by estrone is responsible for this. This is because estrone levels are much higher with oral estradiol than with non-oral estradiol routes and because of notions that estrone is partially antagonistic at the estrogen receptors. 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 and suboptimal feminization with oral estradiol in some transfeminine people.
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 a transfeminine Redditor (Reddit). These claims are based on subjective observations and are not based on any actual objective measurements. Anecdotes are notoriously unreliable and should be interpreted with heavy 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 that this author is aware of.
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 anecdotal observations of better breast development with oral estradiol in transfeminine people. The Redditor 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 of estrogen levels in different contexts to understand why oral estradiol doesn’t mimic normal female puberty:
Table: Approximate estradiol (E2), estrone (E1), and estrone sulfate (E1S) levels and ratios in pubertal girls, pre- and postmenopausal adult women, and after a single 2 mg dose of oral estradiol a:
|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||30 pg/mL||350 pg/mL|
|E1S||? (≤700 pg/mL)||1,000 pg/mL||500 pg/mL||12,000 pg/mL|
|E2:E1:E1S||1 : 1.3 : ? (≤47)||1 : 0.5 : 10||1 : 3 : 50||1 : 7 : 240|
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 probably 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 is unlikely that higher estrogen exposure would result in any better breast development than physiological levels. There is considerable published literature relevant to this subject. (See also the High-Dose Estrogen and Breast Development section below.)
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 study looking at the role of estrone in feminization found no relationship between estrone levels and breast development or changes in body fat in transfeminine people during hormone therapy with either oral or transdermal estradiol (Tebbens et al., 2022; Tebbens, 2020). These findings suggest that route of administration of estradiol is not important in terms of breast development.
Powers also claims in the video that thelarche is primarily due to production of weak androgens like dehydroepiandrosterone (DHEA) and androstenedione by the adrenal glands, which are subsequently aromatized into estrone in peripheral tissues. This is however incorrect. It is well-known that breast development does not occur in cisgender girls who are hypogonadal or have their ovaries removed before puberty, and requires induction with exogenous estrogen therapy (Laron, Kauli, & Pertzelan, 1989; Laurence, Monaghan, & Gusterson, 1991; Klein et al., 2018). Hence, breast development depends exclusively on gonadal estrogen production, and adrenally derived estrogens do not initiate it. An interesting exception to this is some girls with complete androgen insensitivity syndrome (CAIS) who have their testes removed in childhood (Sobrinho, Kase, & Grunt, 1971; Andler & Zachmann, 1979).
Powers thinks that transfeminine people tend to have mutations that cause them to have very high estrone levels with oral estradiol. He often refers to these individuals as “estrone mutants”. However, there is high variability between individuals in the pharmacokinetics of oral estradiol as well as other estradiol forms, and robust 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 unclear that there is anything unique about transfeminine people in this area. Accordingly, clinical studies have reported similar average ratios of estrone to estradiol between cisgender women and transfeminine people:
|Estrogen route||Cisgender women||Transfeminine people|
|Oral estrone sulfate||5:1||?|
|Estradiol pellet implant||1:1.5||1:3|
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 false.
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, by activating estrogen receptors, 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 (1) estradiol is a potent agonist of the estrogen receptors, whereas estrone and estrone sulfate themselves have very low potency in this regard (that is, require much higher concentrations to produce the same effect) (Kuhl, 2005); and (2) estradiol is metabolized into estrone and estrone sulfate, in turn causing levels of estrone and estrone sulfate to be closely associated with those of estradiol even though they themselves have little or no direct role in breast cancer risk. Instead of acting as estrogen receptor agonists themselves, estrone and estrone sulfate largely derive their estrogenic activity from re-conversion back into estradiol (Kuhl, 2005; Rezvanpour & Don-Wauchope, 2017).
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 clinical trials with SERMs, which are essentially estrogen receptor partial agonists with predominantly antagonistic actions in the breasts, have shown that these agents decrease breast cancer risk, and causally demonstrate that breast cancer risk in postmenopausal women is strongly dependent on estrogen receptor activation (Li et al., 2016). Moreover, oral estradiol and transdermal estradiol in menopausal hormone therapy show no difference in breast cancer risk in large observational studies in spite of the fact that estrone and estrone sulfate levels are dramatically higher with oral estradiol than with non-oral routes (CGHFBC, 2019 [Table]). It is also notable that drugs that inhibit the conversion of estrone and estrone sulfate into estradiol have been under investigation for the potential treatment of breast cancer for many years owing to the fact that they block the re-activation of estradiol and hence are able to reduce estrogenic signaling in the breasts (Sasano et al., 2006; Purohit & Foster, 2012; Hilborn, Stål, & Jansson, 2017).
The notion that estrone is more important for blood clots than estradiol is based essentially on the findings of a single correlational study with arguably flawed conclusions (Bagot et al., 2010). I’ve written a critique of this study here. Briefly, the study found that oral estradiol increased coagulation and that estrone levels correlated more robustly with the increase in coagulation than did estradiol levels. However, as both estrogen-mediated procoagulation and conversion of estradiol into estrone with oral administration (as measured by estrone levels) derive from the presence of estradiol in the liver, these two things would be expected to correlate. Moreover, logically—although perhaps counterintuitively at first—estrone levels would have the potential to be a better biomarker for procoagulation in this context than would estradiol levels as this estrone reflects what had formerly been estradiol in the liver. As with estrogen-mediated breast cancer risk, increased coagulation and blood clot risk with estrogens is clearly related to estrogen receptor activation rather than to formation of weakly estrogenic metabolites like estrone (Aly W., 2020). Hence, what the researchers may have really detected, and what may have ultimately been causative of the correlation, was simply the exposure of the liver to estradiol.
Powers states that “There is a mounting level of evidence against estrone.” But there really isn’t. Everything that has supposedly implicated estrone in health risks has merely been correlational, and there is little reason to assume that estrone is causative or specifically harmful. In any case, there is substantial indication that transdermal estradiol is safer than oral estradiol in terms of coagulation, blood clot risk, and risk of associated cardiovascular complications for other mechanistic reasons—namely, avoidance of the first pass of estradiol through the liver that occurs with oral administration.
Powers claims that “sore boob is more boob” and that if the breasts are sore, that means they’re growing. This is not true. Estrogens are concentration-dependently associated with increased breast pain/tenderness independently of breast development, and high-dose estrogen therapy in cisgender women, resulting in estradiol levels of more than approximately 150 pg/mL, is particularly associated with breast pain/tenderness (de Lignières & Mauvais-Jarvis, 1981; Sitruk-Ware et al., 1984). Temporary or exposure-dependent breast enlargement also occurs due to fluid retention and increased blood flow, 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.
Powers mentions his experimentation with topical estradiol on the breasts to increase breast size in a single transfeminine patient. However, published clinical experience in cisgender women has found that topical estrogens applied to the breasts result in only modest and temporary breast enlargement (e.g., 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. It is also unknown whether direct application of estrogens to the breasts is safe, for instance in terms of breast cancer risk. For this reason, transdermal forms of estradiol explicitly state in their packaging information that they should not be applied to the breasts (e.g., Climara FDA Label).
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 heavily 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 modulators, 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 different things that are clearly related but 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 in rates (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 this many t-tests are being performed, something is bound to be statistically significant simply as a matter of chance (5% or 1/20 likelihood with a p = 0.05 test level). As such, the finding may easily have been spurious, and until replicated, the results should be regarded very cautiously.
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 modulators. Hence, spironolactone use may have been concentrated in or exclusive to the DIY/self-medication group. Estradiol levels were also higher in DIY/self-medicating users, and higher estradiol levels may instead have resulted in less breast development and greater rates of breast augmentation. Alternatively, the association might have really been due to behavioral impulsivity—those who were more impulsive and hence willing to take risks might have been both more likely to DIY/self-medicate and more inclined to opt for breast augmentation. Such hypotheticals are very uncertain and are intended more for illustrative purposes rather than as real explanations, but it’s possibilities of this nature that are why causation can’t be attributed to spironolactone here.
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 idea is also from Seal et al. (2012). They claimed that spironolactone has intrinsic estrogenic activity of its own and that taking spironolactone results in excessive estrogenic exposure, which in turn causes “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. As an example, spironolactone does not increase sex hormone-binding globulin (SHBG) levels, which is an essentially universal effect of estrogens as well as of SERMs. Hence, the mechanism proposed by Seal et al. (2012) is not supported by available clinical evidence and is unlikely to be true.
Assuming that spironolactone really did result in lesser breast development compared to the other antiandrogens, a better hypothesis for the mechanism would be that spironolactone doesn’t “stunt” breast development but rather simply inadequately opposes testosterone due to the known fact that it’s a relatively weak antiandrogen. This is applicable as androgens powerfully oppose the actions of estradiol in the breasts. In terms of the antimineralocorticoid activity of spironolactone, there is little indication that it might in some way be harmful for breast development.
A clinical 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 was originated by this transfeminine person. 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 glucocorticoid receptor and mineralocorticoid receptor agonist, and both of these receptors are involved in visceral fat accumulation with cortisol. The strong mineralocorticoid receptor blockade of spironolactone—and hence a presumable mixed profile of relatively weak glucocorticoid receptor agonism and strong mineralocorticoid receptor antagonism with spironolactone—appears to produce a very different result than one might expect if they assumed that cortisol only acted through the glucocorticoid receptor to mediate its effects on visceral fat (e.g., Mammi et al., 2016).
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: I intend to write a comprehensive article on this topic at some point, and so have been brief above, but see here for more on the issue of spironolactone and visceral fat for now.
Powers claims that spironolactone causes depression and fatigue. There is little clinical support for the notion that spironolactone worsens mood or causes depression (e.g., Wang et al., 1995; Basson & Prior, 1998; Otte et al., 2010; Wernze & Herdegen, 2014; Böhm et al., 2021). Some sources state that spironolactone may produce fatigue or lethargy as an effect secondary to lowered blood pressure however (e.g., Shaw, 2000). In any case, the incidence of this side effect appears to be very low (Layton et al., 2017 [Table]). Spironolactone even at high doses is generally described as well-tolerated in the literature (e.g., McMullen & Van Herle, 1993; Kim & Rosso, 2012; Layton et al., 2017; Roberts et al., 2020; Searle, Al-Niaimi, & Ali, 2020; Wang & Lipner, 2020; James, Jamerson, & Aguh, 2021).
With all of the preceding said about spironolactone, I agree with Powers that bicalutamide is advantageous to spironolactone in many ways and has significant promise for use in transfeminine hormone therapy (Aly W., 2020). It is much better than spironolactone as an antiandrogen in terms of both efficacy and tolerability. Spironolactone is a relatively weak androgen receptor antagonist and shows inconsistent effects on testosterone levels (Aly W., 2018; Aly W., 2020; Wiki). It also has strong off-target mineralocorticoid receptor antagonism that results in undesirable antimineralocorticoid side effects as well as risks such as hyperkalemia. Conversely, bicalutamide is far more potent as an antiandrogen in comparison and is highly selective as an androgen receptor antagonist. It is able to efficiently block even male-range levels of testosterone, and has essentially no side effects in people with estrogen. However, bicalutamide has a small risk of liver toxicity that can result in serious complications and even death. Spironolactone does not have this particular risk, and in relation to this, is considered to be an overall safer medication. Further research and assessment by the transgender medical community will be required to determine the roles of spironolactone versus bicalutamide in transfeminine hormone therapy. In any case, when it comes to spironolactone, this author just cares 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’ve discussed elsewhere however, there is no evidence that progesterone is involved in or required for complete breast development or feminization (see Aly W., 2019; Aly W., 2020). Moreover, women with CAIS, who have no progesterone, have excellent and full breast development and feminization, suggesting that progesterone is dispensable for these characteristics (Aly W., 2020). There is undeniably a role of progesterone in the internal lobuloalveolar development of the breasts, which is something that occurs mainly during pregnancy. However, this type of breast development is temporary and is largely or completely reversible. In relation to this, it’s unclear that progestogens will be able to improve the size and/or shape of the breasts in transfeminine people (Wierckx, Gooren, & T’Sjoen, 2014). Besides the uncertain role of progestogens in improving breast development, it’s also notable that premature introduction of progesterone in transfeminine people is unphysiological in terms of normal female puberty and might actually have an adverse influence on breast development (Aly W., 2019). However, this possibility is only theoretical at this time and remains to be evaluated and demonstrated in humans.
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 true. 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. Certain birth control pills, including birth control pills containing drospirenone as well as several other newer-generation progestins (e.g., cyproterone acetate, desogestrel, gestodene), have about 1.5- to 2-fold greater risk of venous blood clots than do levonorgestrel-containing birth control pills (Dragoman et al., 2018). That is the true finding.
It is thought that activation of the androgen receptor in the liver opposes estrogen-induced changes in production of coagulation factors, in turn reducing ethinylestradiol-mediated increases in coagulation. The main theory for the differences in rates of venous blood clots between birth control pills containing different progestins is that it is dependent on the relative androgenicity of the progestins (Wiegratz & Kuhl, 2006; Morimont et al., 2021). Levonorgestrel, the most androgenic progestin used in birth control pills, counteracts the liver-mediated increase in coagulation caused by the ethinylestradiol component of the pills. In contrast to levonorgestrel, other progestins are much less androgenic (e.g., desogestrel, gestodene) or are even antiandrogenic (e.g., drospirenone, cyproterone acetate), resulting in less or no counteraction of the procoagulatory effects of ethinylestradiol. Hence, it’s likely not that drospirenone is uniquely harmful, but rather it lacks androgenic effects of other agents that would otherwise reduce the detrimental effects of ethinylestradiol on coagulation. This has little relevance to transfeminine people, and in cisgender women, the optimal solution is not use more androgenic progestins over for instance drospirenone, but instead to move away from use of ethinylestradiol. This is something that is currently in progress (Stanczyk, Archer, & Bhavnani, 2013; Farris et al., 2017; Morimont et al., 2021).
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 however that progesterone may not fundamentally differ from progestins in terms of various risks and hence that this idea may be misguided. Moreover, researchers actually did try to use oral progesterone in birth control pills. But it was very weak in terms of progestogenic potency and they couldn’t achieve adequate inhibition of ovulation with it (Wiki). So progesterone was abandoned progesterone for oral birth control and progestins were developed instead. All of this is also not to mention the neurosteroid side effects of oral progesterone like sedation, especially at the very high doses that would be required for this form of 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.
Powers’s approach 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—estradiol with rectal progesterone—although much less convenient, is more physiological and possibly more 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 these risks.
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 trials. 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 progesterone receptor activation is responsible. Conversely, increased risk of coronary heart disease 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 the preceding, 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 progesterone receptor agonists, so either all progestins would have to be doing something additional to progesterone receptor agonism to produce the risks in question or progesterone would have to be doing something additional to partially cancel out its own progesterone receptor agonism so as to neutralize said risks. Both scenarios are technically possible but seem to 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 has been associated with minimally different risks relative to estrogen alone—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 significantly 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 of breast cancer with oral progesterone 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—which are standard progestogenic effects—even at very high doses (Wiki). The mechanisms underlying the atypicality of dydrogesterone are unknown. In any case, this progestin 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). In relation to this, the role of androgen replacement therapy in transfeminine people is unclear.
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 actually 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” or “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., progesterone receptor agonism).
- Powers at one point referred to the estrogen receptor as a “cell-surface” receptor. This may have just been a momentary slip up, but it’s incorrect. The estrogen receptor 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” estrogen receptors are actually associated with cell membranes as membrane estrogen receptors. Although not the dominant mode of estrogen action, these membrane-associated “nuclear” estrogen receptors have their own physiological effects as well.)
Use of correct terminology is of course important to avoid misunderstandings and confusion.
As I touched on in the introduction, I think that Powers’s efforts to help improve care in transgender hormone therapy are commendable. As mentioned before, certain approaches he employs—like high-dose parenteral estradiol, rectal progesterone, and bicalutamide—have significant value. 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 clinical blood work results, which I think are adequately objective measures (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 directly to transgender people, regardless of how inadequately supported many of said ideas may be. And due to his position of prestige and authority as a popular transgender health clinician, an alarming number of transgender people uncritically accept and believe such ideas, often with little or nothing in the way of questioning. I think that Powers needs to think a lot more about the influence he has among impressionable laypeople in our community and needs to be more careful about the things he says in his position.
Aside from blood work, Powers rarely if ever uses objective measurements of therapeutic changes in his clinical practice, largely relying instead on unreliable and unsubstantiated anecdotal observations. This is an approach that is riddled with pitfalls. He hasn’t had any of his findings or ideas published or peer-reviewed. Hence, none of his claims are currently subject to any sort of verification. He could easily be making cognitive and perceptual mistakes in his judgements and seeing apparent associations that would disappear upon objective quantification and statistical analysis. There are very good reasons for why things like formal research methods, statistics, evidence standards, peer review, and publication exist. For these reasons, great caution is warranted with Powers’s clinical anecdotes.
Powers’s current approach to research isn’t how it is normally done nor how it should be done. Research should be conducted first, then peer-reviewed and published, and only then should people learn about it—once there is 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 and responsible approach in the future. I would be pleased to see him employ objective measures of physical changes to substantiate his clinical observations and ideas. As an example, objective measures of breast development, like breast hemicircumference and breast–chest difference, are some possibilities that could easily be employed (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’d also be pleased to see Powers’s work be peer-reviewed. But until such changes, we should remain skeptical regarding his anecdotal claims.
See here for some later discussion on Powers and what he refers to as “WPATH”.