Spironolactone can be ineffective as an antiandrogen for many trans women

For trans women and transfeminine people who choose medical transition, one of the most common treatments is the use of hormonal medications to reduce testosterone levels and raise estrogen levels. By moving testosterone and estrogen levels into the normal female range, cross-sex hormone therapy diminishes masculine features and produces the development of feminine features.

However, one of the medications most commonly used to block testosterone for trans women in the United States may be one of the less effective medications for this purpose. A growing body of evidence suggests that spironolactone does not usefully lower testosterone into the female range for many trans women.

The beneficial effects of hormone therapy for trans women include physical feminization and relief of gender dysphoria, as well as a reduction in depressive, anxious, and dissociative symptoms, lower stress levels, and improvement in body image and quality of life. But for this treatment to be most effective, testosterone levels need to be suppressed and maintained at low levels.

What level is low enough? Laboratory reference ranges for normal testosterone levels in premenopausal cis women have been listed as 10 to 55 (Jain et al., 2019) or 10 to 75 nanograms per deciliter (Leinung et al., 2018). The Endocrine Society’s clinical practice guidelines for trans people recommend that trans women’s testosterone should be kept below 50 nanograms per deciliter (Hembree et al., 2017), whereas another study (Leinung et al., 2018) defined testosterone suppression in trans women as being achieved by levels below 100 nanograms per deciliter.

So we know the target – how do we get there? Taking estradiol alone does not do enough to suppress testosterone levels in trans women who haven’t had their testes removed. In the United States, by far the most commonly used testosterone blocker for trans women who are past puberty is spironolactone, a diuretic and blood pressure-lowering medication that has antiandrogenic effects. Most adult trans women in the country who haven’t had surgery will take this medication as a part of HRT.

But the actual efficacy of spironolactone in suppressing testosterone levels into the female range is questionable, with a high variability in testosterone even between trans women who take the same dosage of spironolactone. In recent years, multiple studies have found that many trans women don’t achieve this degree of suppression using only spironolactone as an antiandrogen, and in comparison, other antiandrogens have been shown to be far more effective in this population.

Liang et al. (2018) reviewed the testosterone levels of 98 trans women taking spironolactone and oral estradiol, measured at several clinic visits over the course of three and a half years of treatment. The authors calculated each woman’s average testosterone levels starting at one year of treatment up to three and a half years, and based on this measure, divided this population into quartiles (fourths). The first quartile, representing those with the most complete suppression of testosterone, was found to have levels “declining steadily from the initial visit before levelling out and remaining consistently around 10 ng/dL”. The second quartile showed a similar pattern of consistent suppression, but not to the same degree, achieving steady testosterone levels of “under 100 ng/dL”.

However, the last quartile apparently showed little response to spironolactone at all, with “mean testosterone levels that fluctuated at high levels without a discernable pattern of decline”. Referencing the Endocrine Society’s recommendation that trans women’s testosterone levels be suppressed to below 50 ng/dL, the authors stated that while “patients from the highest suppressing quartile could reliably achieve this level on average, the other three quartiles would unlikely be able to achieve this level.” Additionally, in this group of trans women, the dosage of spironolactone “did not correspond with differences in achieved testosterone suppression”. Under the conditions of this study – the use of spironolactone and oral estradiol commonly prescribed to trans women in the United States – only a quarter of trans women had their testosterone suppressed to female levels, another quarter experienced no reliable or consistent suppression of testosterone at all, and simply increasing the dose of spironolactone may not make a difference in trans women’s testosterone levels as a group. Instead, there was clear and substantial inter-individual variation in testosterone suppression achieved by spironolactone.

Angus et al. (2019) examined the testosterone levels of 80 trans women patients who were taking estradiol with either spironolactone or cyproterone acetate (CPA), an antiandrogen and synthetic progestin widely used abroad but unavailable in the United States. Those who were taking spironolactone achieved a median testosterone level of 57.7 ng/dL (2.0 nmol/L), but with substantial variation: 50% of the trans women on spironolactone had testosterone levels between 26 ng/dL and 271.1 ng/dL, potentially far exceeding the normal female range. The authors stated that only 40% of trans women on spironolactone were able to suppress their testosterone below 57.7 ng/dL. In comparison, the group taking CPA had a median testosterone level of 23.1 ng/dL (0.8 nmol/L), with 50% of these women having levels between 17.3 and 34.6 ng/dL. And while only 40% of the group taking spironolactone had levels below 57.7 ng/dL, 90% of those taking CPA had suppressed their testosterone below this threshold.

Leinung, Feustel, & Joseph (2019) examined the lab results of 166 trans women patients seen at one clinic from 2007 to 2016, and found that the presence or absence of spironolactone as part of their regimen (some took only estradiol with no spironolactone, while others took estradiol with the antiandrogen finasteride instead) “had no statistically significant effect on testosterone”. Notably, the authors point out that in one of the earliest studies (Prior et al., 1989) supporting the use of spironolactone to lower trans women’s testosterone levels, all of these women were also taking the synthetic progestin and antiandrogen medroxyprogesterone acetate (MPA), either daily or for two out of every four weeks. They observe: “This is the article cited in support of spironolactone suppressing testosterone, when it supports just as well the use of medroxyprogesterone.”

Jain, Kwan, & Forcier (2019) analyzed the hormone levels of 92 trans women being seen at the same clinic across an average span of 3.4 years, who received either spironolactone or spironolactone with the addition of MPA. Again, it was found that spironolactone alone did not suppress testosterone into the female range: those taking only spironolactone had an average level of 215 ng/dL. In comparison, those receiving spironolactone plus MPA achieved an average testosterone level of 79 ng/dL.

So, if spironolactone doesn’t reliably reduce testosterone levels to the female range for many trans women, what are the alternatives? Despite its apparent efficacy, CPA is unapproved in the United States due to concerns over a small risk of liver toxicity. MPA is an inexpensive generic medication that’s available in the U.S., so adding this medication may be of benefit to those trans women who aren’t reaching female levels of testosterone on spironolactone alone. There are also long-acting GnRH agonists such as leuprolide, triptorelin, goserelin, and histrelin, as well as GnRH antagonists such as degarelix, which effectively stop the body from producing any sex hormones. Unfortunately, these are currently only available as injections or implants that can cost thousands of dollars a month, and they aren’t often covered by insurance. Bicalutamide, a nonsteroidal antiandrogen with feminizing effects, has received a passing mention as a possible medication for trans women in various publications, and it was previously used as both a puberty blocker and a feminizing agent in a group of adolescent trans girls. However, it’s not in widespread clinical use in trans women by any measure, and it carries a small risk of liver toxicity and lung toxicity.

Trans women outside of the United States have a wider range of options available for antiandrogens used as part of their HRT regimen, but even within the United States, there are still other medications that are similarly safe, affordable, and more effective at suppressing testosterone than spironolactone alone. It’s recommended that trans people have their blood drawn at least yearly both to monitor hormone levels and to detect any potentially harmful effects. With wider awareness of the findings of these recent studies, trans women and their providers can be better equipped to manage their treatment for the most effective results. And as usual, the disclaimer: I’m not a doctor – I just read what they publish.

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