Spironolactone

Spironolactone is a steroidal antiandrogen used in feminizing hormone regimens. It is the most commonly used antiandrogen for feminizing HRT in the United States, due to the FDA finding the hepatotoxic effects of [cyproterone] too risky as of current time (despite this, it is the most popular outside of the United States).

Transgender studies
Spironolactone has been assessed in a number of clinical studies for transgender women. The first clinical study of spironolactone in transgender women was conducted in 1989, although use had been reported by a gender dysphoria clinic in 1986.

Pharmacology
Spironolactone is a antagonist of the mineralocorticoid receptor with high affinity and an antagonist of the androgen receptor also with high but lower affinity. As such, it is an antimineralocorticoid and an antiandrogen. The drug is a mixed agonist/antagonist of the estrogen receptor with not entirely clear affinity. Hence, it may have some mixed estrogenic and antiestrogenic or selective estrogen receptor modulator-like activity. Spironolactone is an agonist of the progesterone receptor and an antagonist of the glucocorticoid receptor, but with very low affinity that is unlikely to be clinically relevant. It is a weak inhibitor of a variety of enzymes involved in steroid hormone production including 17α-hydroxylase, 17,20-lyase, 11β-hydroxylase, 21-hydroxylase, aldosterone synthase (18-hydroxylase), and cholesterol side-chain cleavage enzyme, as well as 17β-hydroxysteroid dehydrogenase 2.

Although spironolactone has a short plasma [half-life], tts major metabolites include 7α-thiomethylspironolactone (7α-TMS), 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and canrenone (7α-desthioacetyl-δ6-spironolactone). These metabolites have much longer elimination half-lives of 13.8 hours, 15.0 hours, and 16.5 hours, respectively. In addition, they are biologically active similarly to spironolactone, including acting as antagonists of the mineralocorticoid and androgen receptors. As such, spironolactone is a prodrug and its metabolites are responsible for its therapeutic effects.

Effiacy
Despite some controversy relating to the efficacy of spironolactone from outdated sources, a November 2017 study with a specific focus on testosterone suppression using spironolactone revealed positive results on its usage as an anti-androgen. In the study spanning three years from baseline onwards with usage of spironolactone in a 100-200mg oral dosage range (variable based on BMI), the levels declined from a median 385 ng/dl from initial visit to 130ng/dl by 12 months.

The conclusion was that the efficacy of spironolactone was that regardless of estrogen consumption, spironolactone was capable of suppressing testosterone levels to a cis female range in transgender women. Estrogens inclusion did appear to increase the efficacy, though the two are recommended in conjunction for transgender HRT treatments.

Though less potent in dosage and rate of action in contrast to [cyproterone] (which reduces a similar level to below 130ng/dl in half the time), it is safer in regards to liver toxicity and long term side effects.

Breast development
In a recent survey, transgender patients prescribed spironolactone were more likely to ask for breast augmentation than patents prescribed cyproterone acetate.