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A Review of Studies on Spironolactone and Testosterone Levels in Cisgender Men and Transfeminine People

By Aly W. | First published December 19, 2018 | Last modified January 21, 2021

Notice: This page was originally posted as a thread on Reddit and has not yet been properly or fully revised since being moved to Transfeminine Science.

Abstract / TL;DR

Spironolactone is an antiandrogen used in transfeminine hormone therapy which is especially employed in the United States. It is widely considered to act as an androgen receptor antagonist and as an androgen synthesis inhibitor, both blocking the actions of testosterone and lowering testosterone levels in transfeminine people. A literature search was conducted to review studies assessing the influence of spironolactone on testosterone levels in cisgender men and transfeminine people. The results of these studies were mixed, but in most studies spironolactone showed no apparent influence on testosterone levels. These findings suggest that spironolactone has inconsistent and limited effects on testosterone levels in people with testes. Moreover, these data as well as studies of estradiol alone indicate that estradiol is mainly responsible for lowered testosterone levels when the combination of estradiol and spironolactone is used as a hormone therapy regimen in transfeminine people. Besides testosterone suppression, spironolactone also acts as a direct antagonist of the androgen receptor and this importantly contributes to its antiandrogenic efficacy as well. However, studies in cisgender women suggest that spironolactone is a relatively weak androgen receptor antagonist and is likely best-suited for blocking relatively low testosterone levels. Taken together, the antiandrogenic effectiveness of spironolactone in transfeminine people appears to be limited. Other antiandrogens may be more effective in transfeminine people and may be considered instead or as alternatives to spironolactone in those in whom testosterone levels with estradiol plus spironolactone remain inadequately suppressed.

Introduction

Spironolactone, also known by its major brand name Aldactone, is an antiandrogen which is commonly used in transfeminine hormone therapy. It is used in combination with estrogen in transfeminine people to help control the effects of testosterone. Spironolactone is used in transfeminine hormone therapy particularly in the United States, where another antiandrogen, cyproterone acetate (CPA; brand name Androcur), is unavailable. Conversely, CPA is the main antiandrogen used in transfeminine people in most of the rest of the world. Another type of medication, gonadotropin-releasing hormone agonists (GnRH agonists), are the major antiandrogens used in certain places like the United Kingdom and as of recently the Netherlands. The combination of estradiol with CPA or a GnRH agonist in transfeminine people consistently suppresses testosterone levels into the normal range for cisgender women. Hence, both CPA and GnRH agonists are very effective antiandrogens in transfeminine people.

Spironolactone acts as an androgen receptor antagonist but is also known to function as an androgen synthesis inhibitor. A widespread notion in the transgender community as well as in the transgender health community and medical literature is that spironolactone decreases testosterone levels and that this is a major part of how it works as an antiandrogen. In reality however, the evidence to support this notion is limited and the available data from studies are conflicting. The purpose of this article is to review the available studies on spironolactone and testosterone levels in people assigned male at birth (i.e., cisgender men and transfeminine people) and to discuss whether and to what extent spironolactone lowers testosterone levels. In addition, the role of androgen receptor blockade in the antiandrogenic effectiveness of spironolactone in transfeminine people is briefly reviewed.

Spironolactone and Testosterone Levels

Literature Review Results

A literature search was performed to identify studies assessing the influence of spironolactone on levels of testosterone and other relevant hormones in cisgender men and transfeminine people. A work-in-progress companion document with a table of these studies can be found here. The literature search identified many mostly small and low-quality but notable studies conducted in the 1970s and 1980s which assessed the influence of spironolactone on sex hormone levels in cisgender men (sources in doc). In addition, a retrospective chart review by Dr. Jerilynn Prior and colleagues in the mid-to-late 1980s was the first study to assess spironolactone as an antiandrogen for therapeutic use in transfeminine people and described the impact of spironolactone on testosterone levels in transfeminine people (Prior et al., 1986; Prior, Vigna, & Watson, 1989). Decades later, additional studies were conducted which assessed spironolactone and testosterone levels in transfeminine people (Leinung, 2014; Cheung et al., 2018; Leinung et al., 2018; Liang et al., 2018; Angus et al., 2019; Jain, Kwan, & Forcier, 2019).

A total of 26 studies were identified in the literature. A few additional studies with the related medications canrenone or potassium canrenoate were also catalogued but were excluded. The results of the identified studies in terms of the influence of spironolactone on testosterone are mixed. In 15 of 26 studies (58%), there was no change in testosterone levels; in 6 of 26 studies (23%), testosterone levels were decreased; in 1 of 26 studies (4%), testosterone levels were increased; and in 4 of 26 studies (15%), no conclusions could be drawn (not reported, confounding, or other methodological issues). Most of the studies were small, but some of the more recent studies in transfeminine people were larger.

In many of the studies that found no change in testosterone levels with spironolactone, this was the case even when very high doses of spironolactone were used for prolonged periods of time. For example, one notable study of 400 mg/day spironolactone for 6 months in a small group of young men found no change in gonadotropin, testosterone, or estradiol levels (Caminos-Torres, Ma, & Snyder, 1977). This was likewise the case in a couple of more recent and relatively large studies that specifically assessed spironolactone in combination with estradiol in transfeminine people (Leinung, 2014; Leinung et al., 2018 [Graph]). However, another more recent study contradicted these two studies in that it found lower testosterone levels with the combination of spironolactone and estradiol than with estradiol alone (with reportedly no significant differences between the two groups in terms of estradiol dose or levels) (Cheung et al., 2018; Angus et al., 2019). Nonetheless, testosterone levels were still suppressed much less with estradiol plus spironolactone than with estradiol plus CPA in this study (Angus et al., 2019 [Graph]). In a couple of other recent studies of estradiol plus spironolactone in transfeminine people, there was no control group without spironolactone and hence the influence of spironolactone on testosterone levels could not be assessed (Liang et al., 2018; Jain, Kwan, & Forcier, 2019). In any case, testosterone levels on average were not suppressed into the normal cisgender female range and thus the findings of these studies are still of interest (Liang et al., 2018; Jain, Kwan, & Forcier, 2019). The reason for the discrepant results among studies in terms of spironolactone and influence on testosterone levels is unclear.

The fact that in the available studies testosterone levels have usually been unchanged with spironolactone but have sometimes been decreased and have almost never been increased suggests that spironolactone may be a clinically significant testosterone synthesis inhibitor but that it is only a weakly effective one with highly inconsistent and variable effects on testosterone levels. This is also supported by findings that estradiol plus spironolactone usually does not reduce testosterone levels into the normal cisgender female range in transfeminine people, with testosterone levels often remaining well above this range. In any case, the conflicting findings in terms of spironolactone and testosterone levels warrant more research with better study designs, particularly randomized controlled trials.

A Bit of History

The use of spironolactone in transfeminine hormone therapy and the notion that it decreases testosterone levels in transfeminine people originated from publications in the mid-to-late 1980s by Dr. Jerilynn Prior and colleagues (Prior et al., 1986; Prior, Vigna, & Watson, 1989). In the study, transfeminine people, who were either on high-dose estrogen therapy with inadequate testosterone suppression or were pre-hormone therapy, were put on physiological-dose estrogen therapy in combination with 200 to 600 mg/day spironolactone and 10 mg/day cyclic or continuous oral medroxyprogesterone acetate (Prior et al., 1986; Prior, Vigna, & Watson, 1989). The authors reported that despite the lower estrogen dosage, testosterone levels significantly decreased, from 169 ng/dL to 87 ng/dL (–49%) in those who had already been on hormone therapy and to 49 ng/dL in those who had not previously been on hormone therapy (Prior et al., 1986; Prior, Vigna, & Watson, 1989).

Prior and her colleagues interpreted their results as demonstrating that spironolactone decreased testosterone levels (Prior et al., 1986; Prior, Vigna, & Watson, 1989). However, there is an important confounding factor present which is likely to preclude this conclusion from being valid. Medroxyprogesterone acetate (MPA), which was used concomitantly in the study, is a progestogen, and progestogens are antigonadotropins which are able to lower testosterone levels themselves analogously to estrogen (Aly W., 2018; Aly W., 2019). Indeed, studies of MPA have shown it to dose-dependently lower testosterone levels in cisgender men (Wiki). Moreover, MPA has frequently been used in transfeminine people for such purposes, and a recent study showed that the same dosage of MPA used by Prior and colleagues decreased testosterone levels by a considerable degree when added to estradiol and spironolactone therapy (Jain, Kwan, & Forcier, 2019; Aly W., 2019). It is possible that MPA was responsible for the lower testosterone levels observed in the study rather than spironolactone, a point which has since been raised in the literature by other researchers who failed to replicate Prior’s findings on spironolactone and decreased testosterone levels in transfeminine people (Leinung et al., 2018). Interestingly, Prior and colleagues concluded that spironolactone was responsible for the decreased testosterone levels observed in their study even though they themselves mentioned in their papers that MPA was included to help suppress testosterone levels (Prior et al., 1986; Prior, Vigna, & Watson, 1989).

It is also notable that Prior’s papers and their methodology and results were presented in ways that were very confusing and unclear. This might have obscured the potential role of MPA in the reported decreases in testosterone levels and the fact that spironolactone may not have been causative of the changes. The findings of Prior and colleagues were of course in contradiction with the many small studies conducted in the 1970s and 1980s which overall found no influence of spironolactone on testosterone levels in cisgender men but which Prior and her colleagues made no mention of.

Surprisingly, no other studies after that of Prior appear to have assessed the influence of spironolactone on testosterone levels in transfeminine people until the mid-2010s, roughly 25 years later. These studies showed mixed findings, with two studies finding no influence of spironolactone on testosterone levels (Leinung, 2014; Leinung et al., 2018) but one study reporting lower testosterone levels with estradiol plus spironolactone than with estradiol alone although with nonetheless incomplete testosterone suppression and much less decrease than with estradiol plus CPA (Cheung et al., 2018; Angus et al., 2019).

Comparison With Other Antiandrogenic Approaches

Estrogens like estradiol and progestogens like CPA and MPA dose-dependently suppress testosterone levels and will essentially always substantially suppress testosterone levels provided that adequate doses are used (Aly W., 2018; Wiki; Graphs). With high levels of estradiol alone, gonadal testosterone suppression will be suppressed completely and testosterone levels will be reduced to the normal cisgender female range (Aly W., 2018; Wiki; Graphs). The marked suppression of testosterone levels with sufficient doses of estrogens and progestogens is in notable contrast to spironolactone. Many people don’t realize the ability of estradiol to suppress testosterone and many mistakenly assume that it is the antiandrogen—which is often spironolactone—that is mostly or fully responsible for the decrease in testosterone levels seen with estradiol plus an antiandrogen in transfeminine people. It is certainly true that antiandrogens like CPA and GnRH agonists play an important role in testosterone suppression in transfeminine people. However, as evidenced by the present article on studies of testosterone suppression with spironolactone, this is not necessarily the case. It is notably also not the case with certain other antiandrogens besides spironolactone, like the androgen receptor antagonist bicalutamide.

Spironolactone and Androgen Receptor Antagonism

Although spironolactone doesn’t appear to be very effective for decreasing testosterone levels based on the findings of the present article and literature review, it is a competitive antagonist of the androgen receptor in addition to being a weak androgen synthesis inhibitor and hence also directly blocks androgens from mediating their biological effects in the body. This is likely to be its main mechanism of action as an antiandrogen and may account for most or all of its therapeutic antiandrogenic efficacy. In accordance, spironolactone has been reported to be effective in studies of spironolactone for the treatment of androgen-dependent conditions like acne and hirsutism in cisgender women despite not affecting testosterone levels in many of these studies (Aly W., 2020). Spironolactone has also been reported to be effective in the treatment of gonadotropin-independent precocious puberty in boys in spite of apparently not decreasing testosterone levels in these individuals as well (Holland, 1991). Lastly, androgen receptor antagonism of spironolactone is suggested by the dose-dependent breast pain and gynecomastia (male breast development) that occur with it in cisgender men despite its lack of clear dose-related influence on testosterone levels (Wiki). These side effects are attributable to disinhibition of estrogenic action in the breasts due to androgen receptor blockade with retained estradiol levels (Wiki).

Although spironolactone is clearly effective as androgen receptor antagonist, it is a relatively weak androgen receptor blocker at typical doses used in cisgender women and transfeminine people (Wiki):

Spironolactone has been found to have effectiveness in the treatment of hirsutism in women at a dosage of as low as 50 mg/day. The effectiveness of spironolactone in the treatment of hirsutism in women has been found to be near-significantly greater at a dosage of 100 mg/day relative to a dosage of 200 mg/day (19% ± 8% and 30% ± 3% reduction in hair shaft diameter, respectively; p = 0.07). Levels of free testosterone were unchanged, suggesting that the antiandrogenic efficacy of spironolactone was due exclusively to direct AR blockade. In addition, other studies have found that 100 mg/day spironolactone is significantly or near-significantly inferior to 500 mg/day flutamide in improving symptoms of acne and hirsutism. One study compared placebo and dosages of spironolactone of 50, 100, 150, and 200 mg/day in the treatment of acne in women and observed progressive increases in response rates up to the 200 mg/day dosage. These findings suggest that the antiandrogenic effectiveness of spironolactone is not maximal below a dosage of 200 mg/day, and are in accordance with the typical dosage range of spironolactone of 50 to 200 mg/day in women.

Put another way, spironolactone at typical doses seems best suited for handling female-range levels of testosterone rather than the higher levels that often persist in transfeminine people. Accordingly, animal studies have found that CPA, flutamide, and bicalutamide are all far more effective androgen receptor antagonists than spironolactone (Bonne & Ranaud, 1974; Hecker, Hasan, & Neumann, 1980; Sivelle, Underwood, & Jelly, 1982; Snyder, Winneker, & Batzold, 1989 [Table]; Yamasaki et al., 2004 [Graph]).

Due to its relatively weak strength as an androgen receptor antagonist and its limited effectiveness in lowering testosterone levels, spironolactone is likely a less effective antiandrogen than other options used in transfeminine people. These alternatives include CPA, other progestogens (e.g., non-oral progesterone, MPA), GnRH agonists (and antagonists), bicalutamide, and high-dose estradiol monotherapy. These approaches may be used in transfeminine people instead of spironolactone or may be considered when testosterone suppression is inadequate with estradiol plus spironolactone.