A Review of Studies on Spironolactone and Testosterone Suppression in Cisgender Men, Cisgender Women, and Transfeminine People

By Aly | First published December 19, 2018 | Last modified April 5, 2024

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, cisgender women, 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. 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 for hormone therapy 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 antiandrogenic approaches 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 reduce 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 Europe and most of the rest of the world. Another type of medication, gonadotropin-releasing hormone (GnRH) agonists, are the major antiandrogens used in certain places like the United Kingdom. The combination of estradiol with CPA or a GnRH agonist in transfeminine people consistently suppresses testosterone levels into the normal female range (<50 ng/dL or <1.8 nmol/L) (Aly, 2018; Aly, 2019). 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. As an example, spironolactone has been shown in preclinical research to inhibit several enzymes involved in gonadal and adrenal androgen production, including CYP17A1 (17α-hydroxylase/17,20-lyase) among others, and to substantially decrease concentrations of androgens in these studies (Loriaux et al., 1976; Callan, 1988; McMullen & Van Herle, 1993). However, the steroid synthesis inhibition of spironolactone appears to only occur at very high doses and concentrations of spironolactone (Loriaux et al., 1976; McMullen & Van Herle, 1993). For example, spironolactone is used at 10- to 20-fold smaller doses by body weight in humans than in animal studies that have demonstrated substantial steroid synthesis inhibition with the agent (McMullen & Van Herle, 1993).

A widespread notion in the transgender community, as well as in the transgender health community and in the medical literature, is that spironolactone decreases testosterone levels and that this is a major part of how it works as an antiandrogen in transfeminine people. In actuality however, the clinical evidence to support this notion appears to be limited, and available data from studies appear to be highly conflicting. The purpose of this article is to review the available clinical studies on spironolactone and testosterone levels in cisgender men, cisgender women, and transfeminine people in order to help elucidate whether and to what extent spironolactone lowers testosterone levels in humans. In addition, the role of androgen receptor blockade in the antiandrogenic effects of spironolactone is briefly reviewed.

Spironolactone and Testosterone Levels

A literature search was performed to identify studies assessing the influence of spironolactone on levels of testosterone as well as other relevant sex hormones in cisgender men and transfeminine people. Other sex hormones besides testosterone included dihydrotestosterone (DHT), androstenedione (A4), estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin, among others. Search engines included PubMed/MEDLINE and Google Scholar and relevant keywords were employed (e.g., “spironolactone”, “aldactone”, “testosterone”). Both observational studies (e.g., retrospective and prospective cohort and case–control studies) as well as randomized controlled trials (RCTs) where available were included. Studies are discussed separately based on whether they used spironolactone alone in cisgender men, spironolactone in cisgender women, spironolactone alone in transfeminine people, or spironolactone combined with estrogen in transfeminine people.

Spironolactone Alone in Cisgender Males

A total of 22 studies of spironolactone and sex hormone levels in cisgender males were identified (Table 1). These studies assessed pre-treatment versus post-treatment hormone levels with spironolactone, hormone levels with spironolactone versus a comparator group, or both. Within the identified studies, testosterone levels were not significantly changed in 12 of 22 studies (55%), decreased in 4 of 22 (18%) studies, increased in 1 of 22 (4.5%) studies, and mixed or unknown (e.g. divergences in changes of total versus free testosterone levels or didn’t actually report testosterone levels) in 4 of 22 (18%) studies. Most of the studies were very small (fewer than 10 people), with several exceptions. The studies were of highly variable lengths, with some being several days and others lasting for weeks or months. Few of the studies were RCTs. Most of the studies were very old, with a majority published in the 1970s and the rest published in the 1980s and 1990s. In relation to the preceding, the quality of data was limited.

Table 1: Studies of sex hormone levels with spironolactone alone in cisgender males:

Abbreviations: T = testosterone; E2 = estradiol; E1 = estrone; E3 = estriol; E = estrogen(s); P4 = progesterone; 17α-OHP = 17α-hydroxyprogesterone; A4 = androstenedione; EC = etiocholanolone; DHT = dihydrotestosterone; DHEA = dehydroepiandrosterone; DHEA-S = dehydroepiandrosterone sulfate; 17-KS = 17-ketosteroids; LH = luteinizing hormone; FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; PRL = prolactin; TRH = thyrotropin-releasing hormone; FAI = free androgen index; SHBG = sex hormone-binding globulin; BPH = benign prostatic hyperplasia; RCT = randomized controlled trial.

A few additional studies with the spironolactone-related drugs canrenone or potassium canrenoate (a prodrug of canrenone) (e.g., Soldactona) were also identified (Dymling, Nilsson, & Hökfelt, 1972; Dymling & Hökfelt, 1973; Erbler, 1974; Corvol et al., 1976; Dymling, 1978). These studies are notable as canrenone is a known active metabolite of spironolactone and as the studies consistently found decreased androgen levels with drugs delivering canrenone. In any case, the studies are excluded from the present review as they did not actually employ spironolactone.

Although the quality of these studies is limited, the findings of the studies, which are mixed but are overall more suggestive against spironolactone reducing testosterone levels than it doing so, are in notable contrast to similar studies of CPA and testosterone suppression in cisgender men that were published in the 1970s and 1980s. These studies consistently found that CPA suppressed testosterone levels by 40 to 70% on average (Aly, 2019). Subsequently, the findings were replicated in several more modern studies of CPA in cisgender men and transfeminine people, which likewise found that the drug given alone consistently suppressed testosterone levels by about 45 to 65% on average (Aly, 2019).

Spironolactone in Cisgender Women

Spironolactone has a long history of use in cisgender women in the treatment of androgen-dependent skin and hair conditions like acne, hirsutism, scalp hair loss, and hyperandrogenism (due to e.g. polycystic ovary syndrome (PCOS)). It has been used at similar doses for androgen-dependent conditions in cisgender women as it has in transfeminine people (e.g., 50–200 mg/day most typically). There are many dozens of studies of spironolactone as an antiandrogen in cisgender women (e.g., PubMed). Instead of attempting to individually review all of these studies, the present article will discuss the findings of several papers that have themselves reviewed substantial numbers of these studies and have summarized available findings on testosterone levels with spironolactone.

Callan (1988) reviewed the literature on spironolactone for treatment of acne and hirsutism in cisgender women and found that some clinical studies reported decreased levels of testosterone and/or other androgens with spironolactone (4 studies cited) whereas other studies reported no change in androgen levels (4 studies cited). The author cited several studies to support the claim that androgen receptor antagonism with spironolactone is more clinically important than any influence it has on androgen production (5 studies cited). For instance, clinical benefits against acne and hirsutism occurred with spironolactone both before androgen levels decrease as well as when androgen levels do not decrease.

McMullen & Van Herle (1993) reviewed 19 studies of spironolactone for treatment of androgen-dependent conditions in cisgender women, with a majority of these studies reporting long-term hormone levels. Most of the studies were open-label and uncontrolled, with only five studies having a control group and only two studies being double-blind placebo-controlled trials. Changes in hormone levels across studies were very heterogenous, with the majority of changes not reaching statistical significance. Only 1 of 7 (14%) studies found a decrease in DHEA-S levels. The review concluded that a clinically significant change in adrenal androgen levels with spironolactone in cisgender women was not supported. Conversely, testosterone levels were decreased with spironolactone in 13 of 16 (81%) of studies. However, in the only two RCTs, there were no differences in testosterone levels with spironolactone versus in the placebo control groups. As such, the review concluded that the decreased testosterone levels with spironolactone in cisgender women reported in many of the non-RCT studies may not actually be a real phenomenon. As with Callan (1988), the review noted that the major mechanism of action of spironolactone as an antiandrogen is likely to be androgen receptor blockade.

Bradstreet et al. (2007) cited and discussed a Cochrane review of spironolactone for treatment of acne and/or hirsutism in cisgender women (Farquhar et al., 2003). Cochrane reviews are rigorous high-quality systematic reviews of all of the available RCTs for a given medical intervention. The Cochrane review identified 19 RCTs, with 9 included in the review, 8 excluded due to methodological issues (e.g., with randomization), and two others which were described as “awaiting assessment” (Farquhar et al., 2003). Bradstreet and colleagues noted per the Cochrane review that spironolactone at a dosage of 100 mg/day had little influence on levels of DHEA, DHEA-S, or testosterone in the trials evaluated and said that this is because its mechanism of action as an antiandrogen is androgen receptor antagonism (Bradstreet et al., 2007). The Cochrane review itself did not discuss changes in androgen or testosterone levels with spironolactone in aggregate. An update of the Cochrane review was published in 2009, but with no new studies found and with the findings unchanged (Brown et al., 2009).

Layton et al. (2017) was a hybrid systematic review of spironolactone for acne in cisgender women. In a table discussing the mechanism of action of spironolactone and other antiandrogens for acne, the authors stated that “Data from over 50 articles reporting effects [of spironolactone] on serum androgens are equivocal” (i.e., ambiguous, uncertain, questionable) (Layton et al., 2017). The review further noted that inhibition of androgen synthesis by spironolactone in humans may be unlikely at therapeutic doses and may occur instead only at supraphysiological doses (with Menard et al. (1979) cited in support of these claims, presumably related to the very high doses required) (Layton et al., 2017).

Rozner et al. (2019) reviewed clinical studies of the endocrine effects of spironolactone in cisgender women to assess whether it is safe to use in women with past or present breast cancer receiving endocrine therapy. The review included 18 studies with 465 women (mostly having androgen-dependent conditions) assessing the influence of spironolactone on sex hormone levels. The assessed studies included retrospective cohort studies, case–control studies, and RCTs. Of the included studies, 10 (56%) studies (with 179 women) found no change in testosterone levels with spironolactone, 8 (44%) studies (with 253 women) found a decrease, and 1 (6%) study (with 33 women) found an increase in free but not total testosterone levels. Changes in levels of DHEA-S, androstenedione, and estrogen were also assessed and findings were similar, with no changes observed in majorities of studies for these hormones. The review concluded that there is no significant change in levels of androgens, estrogen, or gonadotropins with spironolactone in cisgender women.

Almalki et al. (2020) conducted a systematic review and network meta-analysis of RCTs on the comparative efficacy of several types of medications (statins, metformin, spironolactone, and combined birth control pills) on reducing testosterone levels in cisgender women specifically with PCOS. Nine RCTs including 613 women were included for all of the medications. The meta-analysis concluded that the statin atorvastatin was more effective than the other included medications in reducing testosterone levels. Only two of the included RCTs employed spironolactone, one of which was with spironolactone alone (n=34) versus metformin (n=35) (Ganie et al., 2004) and the other of which was with spironolactone plus metformin (n=62) versus spironolactone alone (n=51) versus metformin alone (n=56) (Ganie et al., 2013). Both of the included trials found that spironolactone alone significantly decreased testosterone levels in pre-treatment versus post-treatment comparisons (Ganie et al., 2004; Ganie et al., 2013). No trials of spironolactone versus placebo controls were included.

Taken together, the available studies of spironolactone and testosterone levels in cisgender women with androgen-dependent conditions are highly inconsistent and mixed, but with numerous studies finding no significant changes in testosterone levels. The reasons for the findings being so mixed are unclear, but may relate to study methodology and quality. Findings in this population seem particularly notable as regulation of the hypothalamic–pituitary–gonadal (HPG) axis by androgens in women is minimal to negligible, in turn making it such that androgen receptor antagonists will have little effect of upregulating gonadal sex hormone production as they can in cisgender men and transfeminine people. As a result, there is less homeostatic interference that could influence findings in evaluating the steroid synthesis inhibition of spironolactone in this sex, and hence these studies may provide a clearer picture of steroid synthesis inhibition as a possible clinical effect of spironolactone. However, as the findings are still so mixed, the results seem inconclusive. In any case, only a limited effect at best seems clear.

Spironolactone Alone in Transfeminine People

Only one study of spironolactone alone (without estrogen) and sex hormone levels in transfeminine people was identified (Table 2). It was conducted by Louis Gooren and colleagues of the Dutch Center of Expertise on Gender Dysphoria (CEGD) at the Vrije Universiteit Medical Center (VUMC) in Amsterdam, Netherlands in the 1980s. The study compared levels of testosterone, DHT, estradiol, LH, FSH, and prolactin before and after treatment with 200 mg/day spironolactone for 6 weeks in 6 young pre-hormone-therapy transfeminine people. It found slightly but significantly increased testosterone levels, increased prolactin levels, and no change in levels of estradiol, DHT, LH, or FSH.

Table 2: Studies of sex hormone levels with spironolactone alone in transfeminine people:

Abbreviations: T = testosterone; E2 = estradiol; DHT = dihydrotestosterone; LH = luteinizing hormone; FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; PRL = prolactin; TRH = thyrotropin-releasing hormone.

The fact that this study was done by the CEGD is notable as this institute is among the most prolific research centers on transgender hormone therapy in the world (Bakker, 2021), and, while they evaluated spironolactone as well as nilutamide as antiandrogens in studies in transfeminine people in the 1980s and 1990s (Wiki), the group ultimately settled on using only CPA instead. This was probably related to the lack of testosterone suppression with spironolactone and pure androgen receptor antagonists like nilutamide, as the researchers have touched on in other publications (e.g., Gooren, 1999).

Estrogen Plus Spironolactone in Transfeminine People

Eleven studies of the combination of estrogen and spironolactone and sex hormone levels in transfeminine people were identified (Table 3). The first study was conducted by Jerilynn Prior and colleagues in Canada in the 1980s. Subsequent studies were conducted over 25 years later by groups in the United States, Australia, Israel, and Thailand. All of the studies were retrospective chart reviews or prospective non-randomized studies, with the exception of a single RCT.

Table 3: Studies of testosterone levels with estrogen plus spironolactone in transfeminine people:

Abbreviations: E = estrogen; E2 = estradiol; EV = estradiol valerate; CEEs = conjugated [equine] estrogens; CPA = cyproterone acetate; MPA = medroxyprogesterone acetate; GnRH = gonadotropin-releasing hormone; T = testosterone; DHEA-S = dehydroepiandrosterone sulfate; LH = luteinizing hormone; FSH = follicle-stimulating hormone; PRL = prolactin.

The data on the testosterone levels with estrogen plus spironolactone in transfeminine people from the 11 studies in the table can be roughly summarized. Some studies reported mean testosterone levels and some reported median testosterone levels, so these cases must be considered separately. In terms of reported mean testosterone levels across studies (4 studies), the median value of these study averages would be about 171 ng/dL and the range of study averages would be about 95 to 215 ng/dL. In terms of reported median testosterone levels across studies (7 studies), the median value of these study medians would be about 55 ng/dL and the range of study medians would be about 11 to 468 ng/dL. One study had to be excluded due to concomitant use of the progestogen medroxyprogesterone acetate (MPA) in all individuals (Prior, Vigna, & Watson, 1989; Prior et al., 1986). Insights from the preceding results include large variability in testosterone levels across studies and mean testosterone levels being much higher than median testosterone levels. Limitations of the preceding values include lack of equivalent estrogen and spironolactone dosages and levels across studies, lack of equivalent durations of hormone therapy across studies, lack of equivalent testosterone blood-testing methodologies across studies, lack of equivalent transfeminine patient samples, and, in the case of the study median testosterone values, two of the studies notably having almost all but not all individuals on spironolactone (80 and 94% rather than 100%). These limitations likely underlie the large variability in reported values across studies. In any case, these results suggest that estrogen plus spironolactone results in variably inadequate testosterone suppression in most transfeminine people, which is in notable major contrast to testosterone suppression with estrogen plus CPA or a GnRH agonist in transfeminine people.

Individual findings of the studies include inadequate testosterone suppression with estradiol plus spironolactone in most transfeminine people (Leinung et al., 2018; Liang et al., 2018; Jain, Kwan, & Forcier, 2019; Sofer et al., 2020; Burinkul et al., 2021), no difference in testosterone suppression with spironolactone versus without spironolactone (Leinung et al., 2018), lack of notable influence of spironolactone dosage on testosterone suppression (Liang et al., 2018; SoRelle et al., 2019), and inferior testosterone suppression with estradiol plus spironolactone compared to estradiol plus CPA or a GnRH agonist in transfeminine people (Angus et al., 2019; Sofer et al., 2020; Burinkul et al., 2021). Conversely, some studies have found adequate or near-adequate testosterone suppression with estradiol plus spironolactone in most or almost all transfeminine people (Deutsch, Bhakri, & Kubicek, 2015; Angus et al., 2019; SoRelle et al., 2019; Cirrincione et al., 2021; Pappas et al., 2021), and some studies have found indications of greater testosterone suppression with spironolactone versus without spironolactone (Angus et al., 2019; Cirrincione et al., 2021). On the other hand, some studies using estradiol alone without any antiandrogen at physiological estradiol levels (<200 pg/mL) have reported adequate testosterone suppression similarly to the preceding estradiol plus spironolactone studies (Reardon et al., 2013; Spratt et al., 2014; Cirrincione et al., 2021). One study was confounded by the concomitant use of MPA, which is known to suppress testosterone levels on its own, and hence reliable conclusions cannot not be drawn from this study (Prior, Vigna, & Watson, 1989; Prior et al., 1986). Indeed, it is notable that this study found lower mean testosterone levels with estrogen and spironolactone than any other study did. A couple of studies found that testosterone levels progressively decline with time (particularly over the first 12 months) with estradiol plus spironolactone in most transfeminine people (Liang et al., 2018; Sofer et al., 2020). Whether the decreases in testosterone levels with time were more related to estradiol or to spironolactone is unclear, though estradiol seems more likely (e.g., Wiki).

Taken together, the findings of available studies on estradiol plus spironolactone and testosterone suppression in transfeminine people are highly variable and mixed, although overall more studies support spironolactone having poor or no testosterone-suppressing effectiveness. The reasons underlying the differences in findings on testosterone suppression between studies are unclear, but contributing factors may include varying estradiol doses, routes, and levels, durations of hormone therapy, differing laboratory assays of testosterone levels, and other differences in study methodologies, as well as limitations in study and evidence quality. In any case, the conflicting nature of the findings is in major contrast to the almost invariably strong to maximal testosterone suppression in studies of estradiol plus CPA and estradiol plus GnRH agonists in transfeminine people.

Spironolactone, Androgen Receptor Antagonism, and Clinical Antiandrogenic Effectiveness

The clinical antiandrogenic effectiveness of spironolactone in cisgender women with androgen-dependent skin and hair conditions, like acne, hirsutism, and scalp hair loss, is well-established (Brown et al., 2009; van Zuuren & Fedorowicz, 2016; Layton et al., 2017; Barrionuevo et al., 2018; James, Jamerson, & Aguh, 2022; Wang et al., 2023). Conversely, the clinical antiandrogenic efficacy of spironolactone in transfeminine people has been very limitedly assessed to date and is largely unknown (Angus et al., 2021). Spironolactone does not appear to be very effective for decreasing testosterone levels in either cisgender women or transfeminine people based on the findings of the present review. However, spironolactone is a competitive antagonist of the androgen receptor in addition to its actions a weak androgen synthesis inhibitor, and hence it also directly blocks androgens from mediating their effects in the body (Loriaux et al., 1976; McMullen & Van Herle, 1993). Based on studies in populations besides transfeminine people, for instance cisgender women (discussed above) and cisgender boys with gonadotropin-independent precocious puberty (e.g., Holland, 1991), in which spironolactone has not decreased testosterone levels but has nonetheless been effective as an antiandrogen, the androgen receptor blockade of spironolactone is likely to be its main mechanism of action as an antiandrogen and may account for most or all of its therapeutic antiandrogenic effectiveness.

However, while spironolactone is clearly effective as an androgen receptor antagonist, it appears to be a relatively weak androgen receptor blocker at typical doses used in cisgender women and transfeminine people. Numerous publications in the literature describe spironolactone as being only a weak androgen receptor antagonist (Wiki; Wiki). In relation to this, animal studies have found that spironolactone is a far less potent androgen receptor antagonist than other antiandrogens like CPA, flutamide, and bicalutamide (Bonne & Raynaud, 1974; Hecker, Hasan, & Neumann, 1980; Sivelle, Underwood, & Jelly, 1982; Weissmann et al., 1985; Labrie et al., 1987; Snyder, Winneker, & Batzold, 1989 [Table]; Yamasaki et al., 2004 [Graph]). Moreover, in cisgender women, the population in which spironolactone is most widely used as an antiandrogen, testosterone levels are relatively low, on average about 20-fold lower than in cisgender men (around 30 ng/dL on average compared to about 600 ng/dL on average, respectively) (Aly, 2018). However, many cisgender women with androgen-dependent conditions have PCOS, which is associated with limitedly elevated testosterone levels (e.g., perhaps around 60 ng/dL on average) (Aly, 2018). The typical therapeutic dose range of spironolactone in cisgender women with androgen-dependent conditions is 50 to 200 mg/day, in which its effectiveness may be assumed to be dose-dependent, and this is roughly the same general dosage range used in transfeminine people (though up to 300–400 mg/day may be used and are allowed for by guidelines) (Aly, 2018; Aly, 2020).

A relatively small amount of dose-ranging data on spironolactone in cisgender women with androgen-dependent conditions exists, but in any case substantiates its dose-dependent effectiveness across its clinically used dose range (partially reviewed in Hammerstein (1990) and Shaw (1996)). One study compared spironolactone at doses of 50 to 200 mg/day with placebo for treatment of acne in cisgender women and reported progressive increases in effectiveness with spironolactone up to the 200 mg/day dosage (Goodfellow et al., 1984). Similarly, another study found that progressively increasing the dosage of spironolactone from 100 mg/day, to 150 mg/day, and up to 200 mg/day, resulted in increased effectiveness in the treatment of acne in cisgender women (Charny, Choi, & James, 2017). Spironolactone has been reported to be effective in the treatment of hirsutism in cisgender women at a dosage of as low as 50 mg/day (Diamanti-Kandarakis, Tolis, & Duleba, 1995). However, even a dosage of 100 mg/day did not appear to be maximally effective for hirsutism in a study that compared different doses of spironolactone; effectiveness was near-significantly greater at a dosage of 100 mg/day relative to a dosage of 200 mg/day (19% ± 8% and 30% ± 3% (mean ± SEM) reduction in hair shaft diameter, respectively; p = 0.07) (Lobo et al., 1985). Levels of free testosterone in this study were unchanged, suggesting that the effects of spironolactone was purely due to androgen receptor blockade. Finally, a 2022 systematic review of spironolactone for treatment of androgen-related scalp hair loss in cisgender women reported that the drug was “largely ineffective” at doses of less than 100 mg/day, whereas doses of 100 to 200 mg/day were effective (James, Jamerson, & Aguh, 2022).

Aside from dose-ranging studies, the antiandrogenic efficacy of spironolactone can be evaluated by comparing it to more potent antiandrogenic regimens. A study found that spironolactone 100 mg/day was significantly inferior to flutamide, a substantially more potent androgen receptor antagonist, in improving androgen-dependent skin and hair symptoms in cisgender women (Cusan et al., 1994). However, in other studies, there were no significant differences between spironolactone 100 mg/day and flutamide for hirsutism (Erenus et al., 1994; Moghetti et al., 2000; Inal, Yildirim, & Taner, 2005; Karakurt et al., 2008). Spironolactone and flutamide were variably taken together with an ethinylestradiol-containing combined birth control pill in these studies, which is likely to have limited detection of differences in effectiveness. This is because these birth control pills considerably suppress total and free testosterone levels and hence have substantial antiandrogenic effects themselves (Zimmerman et al., 2014; Amiri et al., 2018). In a biochemical study, spironolactone 100 mg/day was numerically inferior to flutamide in reducing levels of prostate-specific antigen (PSA) in cisgender women (Negri et al., 2000). This is notable as PSA is a systemic biomarker of androgen action (Negri et al., 2000). However, the study had small sample sizes, and the differences between groups were not statistically significant (Negri et al., 2000). A case report of a cisgender woman with female pattern hair loss and normal androgen levels found that treatment with spironolactone 200 mg/day for 5 years failed to improve or halt progression of her hair loss, in spite of almost complete loss of secondary sexual hair, but switching to flutamide resulted in a considerable improvement in hair loss after 12 months (Yazdabadi & Sinclair, 2011 [Figure]). Besides comparison with flutamide, a study found that spironolactone 100 mg/day was inferior to spironolactone 100 mg/day plus finasteride, a 5α-reductase inhibitor and hence functional antiandrogen, for hirsutism in cisgender women (–36.6% vs. –51.3% in scores; p < 0.005) (Unlühizarci et al., 2002; Keleştimur et al., 2004).

The preceding findings suggest that the clinical antiandrogenic effectiveness of spironolactone in cisgender women is not maximal at a dosage of below at least 200 mg/day despite the relatively low testosterone levels in these individuals. Put another way, spironolactone at typical doses seems best-suited for blocking female-range levels of testosterone. As many transfeminine people do not achieve female-range testosterone levels with estradiol plus spironolactone therapy, and in fact often have testosterone levels well above the normal female range or even in the male range, spironolactone may not be fully effective as an antiandrogen at the typical doses used in transfeminine hormone therapy. Higher doses of spironolactone, like 300 to 400 mg/day, may be to some degree more effective.

Summary, Discussion, and Conclusions

Numerous studies have assessed the influence of spironolactone on testosterone levels in cisgender men, cisgender women, and transfeminine people. Although the quality of these studies has often been limited, the studies have revealed highly inconsistent influences of spironolactone on testosterone levels in these populations, with many studies finding no changes, some studies finding decreases, and a small number of studies finding increases. The findings of studies of spironolactone and testosterone levels are in notable contrast to those of studies with estrogens, progestogens like CPA, and GnRH agonists, which consistently show substantial decreases in testosterone levels. This has been the case even in studies of similarly low quality to those of some of the included spironolactone studies (e.g., many of those in cisgender men). The fact that in the available studies testosterone levels with spironolactone have usually been unchanged, but have sometimes been decreased and have rarely been decreased, seems to suggest that spironolactone may be a clinically significant inhibitor of steroid hormone synthesis, but that it is only a weakly efficacious one, and that its effects may be variable depending on the individual and other clinical circumstances. In any case, the conflicting findings warrant more research with higher-quality study designs, particularly RCTs that have with spironolactone versus without comparison groups.

The notion that spironolactone decreases testosterone levels in transfeminine people, and the use of spironolactone in transfeminine hormone therapy in general, appear to have originated from the papers on spironolactone in transfeminine people published by Dr. Jerilynn Prior and colleagues in the 1980s (Prior, Vigna, & Watson, 1989; Prior et al., 1986). In their study, transfeminine people who were either already on high-dose estrogen therapy with inadequate testosterone suppression or had not yet started hormone therapy were put on physiological-dose estrogen therapy in combination with 200 to 600 mg/day spironolactone. Cyclic or continuous administration of the progestogen MPA at an oral dose of 10 mg/day was also given to all of the individuals. The authors reported that despite the lower estrogen dosage, testosterone levels 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 were pre-hormone therapy. Prior and her colleagues concluded that spironolactone helps to decrease testosterone levels in transfeminine people and that it can be used as a safer alternative to high doses of estrogen for this purpose.

However, the concomitant use of MPA in the study is a major confounding factor in terms of their results. This is because MPA is a progestogen, and progestogens, like estrogens, are antigonadotropins which are able to robustly suppress testosterone levels on their own (Aly, 2018; Aly, 2019). Indeed, MPA alone has been shown to dose-dependently lower testosterone levels in cisgender men (Wiki), and at a dosage of 10 mg/day, has been shown to considerably suppress testosterone levels in transfeminine people when added to estradiol and spironolactone therapy (Jain, Kwan, & Forcier, 2019). Hence, MPA may have been, and likely was, responsible for the decreases in testosterone levels seen in the study, rather than spironolactone. This point was also notably raised by other researchers, who were unable to replicate Prior and colleagues’ results on spironolactone and testosterone levels in transfeminine people (Leinung et al., 2018). Strangely, Prior and colleagues concluded that spironolactone was responsible for the decreased testosterone levels in their study even though they noted in their papers that MPA was also given to help suppress testosterone levels (as well as to help improve breast development). The work of Prior and colleagues likely resulted in the prominent and long-standing, but poorly supported, notion that spironolactone decreases testosterone levels in transfeminine people. Subsequent studies assessing the hypothesis that spironolactone decreases testosterone levels in transfeminine people were not published until 25 years after Prior and colleagues’ studies, with several of these studies, though not all of them, failing to replicate the earlier findings of Prior and colleagues.

Many people do not realize the capacity of estradiol to substantially and even completely 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 and antiandrogen therapy 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 review of studies of testosterone suppression with spironolactone, it is not necessarily always the case that the antiandrogen plays a major role—or potentially even any role—in reducing testosterone levels. This is notably also not the case with certain other antiandrogens besides spironolactone, for instance pure androgen receptor antagonists like bicalutamide, which likewise do not decrease testosterone levels but instead can actually increase them (Aly, 2019; Wiki). Clinicians and transfeminine people attributing observations of testosterone decreases to spironolactone rather than to estradiol with estradiol and spironolactone therapy may also have played a role in the perception that spironolactone considerably decreases testosterone levels in transfeminine people.

Due to its relatively weak strength as an androgen receptor antagonist and its limited efficacy in lowering testosterone levels, spironolactone is likely to be a limitedly effective antiandrogen in transfeminine people. Additionally, spironolactone is likely to be less effective than other antiandrogenic approaches used in transfeminine hormone therapy which either more robustly block androgens or more substantially reduce testosterone levels, for instance CPA, other progestogens (e.g., MPA, non-oral progesterone), GnRH agonists (and antagonists), bicalutamide, and high-dose parenteral estradiol monotherapy. These approaches can be used in transfeminine people instead of or in addition to spironolactone, or could be considered when testosterone suppression is inadequate with estradiol and spironolactone.

More studies are needed to evaluate the influence of spironolactone on testosterone levels, especially RCTs that compare estradiol alone versus estradiol plus spironolactone in transfeminine people. More research is also needed to clarify why some studies find highly inadequate testosterone suppression with estradiol alone or estradiol plus spironolactone while other studies find excellent or satisfactory testosterone suppression with these regimens. In any case, available data overall suggest that spironolactone does not consistently suppress testosterone levels, and that estradiol plus spironolactone produces inadequate testosterone suppression in many transfeminine people. Moreover, available data suggest that spironolactone is a relatively weak androgen receptor antagonist at the typical clinical doses used in cisgender women and transfeminine people, and is able to block only relatively low or female-range testosterone levels. Hence, spironolactone may not be fully effective in blocking the testosterone it fails to suppress, and may be particularly unsuitable for transfeminine people with testosterone levels that are well above the normal female range. In any case, more research is similarly needed to assess the androgen receptor antagonism and clinical antiandrogenic effectiveness of spironolactone.

Updates

Update 1: Spironolactone for Adult Female Acne (SAFA) Trial

A large new phase 3 RCT, the Spironolactone for Adult Female Acne (SAFA) trial, was published in May 2023 and assessed the effectiveness of spironolactone in the treatment of acne in cisgender women:

• Santer, M., Lawrence, M., Renz, S., Eminton, Z., Stuart, B., Sach, T. H., Pyne, S., Ridd, M. J., Francis, N., Soulsby, I., Thomas, K., Permyakova, N., Little, P., Muller, I., Nuttall, J., Griffiths, G., Thomas, K. S., & Layton, A. M. (2023). Effectiveness of spironolactone for women with acne vulgaris (SAFA) in England and Wales: pragmatic, multicentre, phase 3, double blind, randomised controlled trial. BMJ, 381, e074349. [DOI:10.1136/bmj-2022-074349]

The trial included a total of 342 women, including 176 treated with spironolactone and 166 in the placebo control group. The dose of spironolactone employed was 50 mg/day for the first 6 weeks and then 100 mg/day thereafter. The trial was 24 weeks (5.5 months) in duration. Women who might become pregnant were required to use a hormonal or barrier method of contraception.

Spironolactone significantly outperformed placebo in terms of improvement in mean Acne-QoL symptom scores (higher is better). Significant improvement was apparent within 12 weeks of treatment (+45% in scores with spironolactone, +38% with placebo) and was highest at 24 weeks (+61% in scores with spironolactone, +35% with placebo). There was no difference in the rates of women who reported improvement in acne scores at 12 weeks (72% with spironolactone, 68% with placebo), but there was a significant difference at 24 weeks (82% with spironolactone, 63% with placebo). In terms of the Investigator’s Global Assessment (IGA), treatment success at 12 weeks was 19% with spironolactone and 6% with placebo. Rates of hormonal contraceptive use in the spironolactone and placebo groups were not reported. Testosterone levels were also not reported. A small subset of the women had PCOS (15% in the spironolactone group, 23% in the placebo group).

Adverse effects occurred only slightly more often with spironolactone than with placebo (64% vs. 51%, p = 0.01). The only side effect that occurred significantly more often with spironolactone than with placebo was headache (20% vs. 12%; p = 0.02). However, a few other side effects trended towards occurring significantly more frequently with spironolactone than with placebo: “other” (17% vs. 11%; p = 0.06), dizziness/vertigo/lightheadness (19% vs. 12%; p = 0.07), vomiting/being sick (2% vs. 1%; p = 0.16), and polyuria (urinary frequency) (31% vs. 25%; p = 0.18). Rates of other potentially relevant side effects, like abdominal pain, breast enlargement, breast tenderness, drowsiness/sleepiness, fatigue/tiredness, menstrual irregularity, and reduced libido, were all not different between spironolactone and placebo. There were no serious adverse reactions in the trial. Rates of compliance were similar between the spironolactone and placebo groups, suggesting that spironolactone was well-tolerated.

This trial is the largest and most rigorous RCT of spironolactone in the treatment of androgen-dependent skin and hair conditions in cisgender women that has been conducted to date. Although spironolactone was found to be effective in this study and was about twice as effective as placebo in terms of Acne-QoL symptom scores and three times as effective as placebo in terms of IGA treatment success rates, the effectiveness of spironolactone was seemingly less than in previous clinical studies of spironolactone for acne. This may be related to the relatively low doses of spironolactone used in this study (50–100 mg/day), to the more rigorous and less-risk-of-bias design of the study (large phase 3 RCT), to a possibly too-short treatment duration (24 weeks/5.5 months), and to concomitant hormonal contraceptive use possibly blunting the degree of potential improvement. The latter is relevant as hormonal contraceptives containing ethinylestradiol provide a considerable improvement in acne via functional antiandrogenic effects all on their own. A final possibility however is that spironolactone is simply a less effective antiandrogen even in cisgender women than has been previously thought. On the other hand, similarly to findings in previous clinical studies, spironolactone was well-tolerated and produced few side effects.

Update 2: New Spironolactone and Testosterone Suppression Studies

The following new studies have additionally assessed and found inadequate testosterone suppression in transfeminine people treated with estradiol and spironolactone:

• Angus, L. M., Leemaqz, S., Zajac, J. D., & Cheung, A. S. (November 2023). A randomised controlled trial of spironolactone versus cyproterone in trans people commencing estradiol. AusPATH 2023 Symposium. [URL] [PDF] [Trans Health Research Blog Post]
• Angus, L. M., Leemaqz, S. Y., Zajac, J. D., & Cheung, A. S. (November 2023). The effect of cyproterone and spironolactone on breast development in transgender women: a randomised controlled trial. ESA/SRB/ENSA 2023 ASM 26-29 November, Brisbane, 54–55 (abstract no. 132). [URL] [PDF] [Full Abstract Book] [Trans Health Research Blog Post]
• Miro, E., Rizzone, K., Ho, T., Mark, B., Sullivan, E., & Cushman, D. (2024). 2024 AMSSM Research Podium Presentations: Testosterone Levels Among Transgender Women on Gender-affirming Hormone Therapy. Clinical Journal of Sports Medicine, 34(2), 152–152. [DOI:10.1097/JSM.0000000000001212]
• Yang, W., Hong, T., Chang, X., Han, M., Gao, H., Pan, B., Zhao, Z., & Liu, Y. (2024). The efficacy of and user satisfaction with different antiandrogens in Chinese transgender women. International Journal of Transgender Health, advance online publication. [DOI:10.1080/26895269.2024.2323514]

Angus et al. (2023) and Yang et al. (2024) compared estradiol plus spironolactone to estradiol plus CPA and are described in-depth in a section of a different article located here. Yang et al. (2024) found that in addition to spironolactone resulting in much less testosterone suppression than CPA, it was also less effective than CPA as an antiandrogen on multiple clinical measures of demasculinization.

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