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 acetate 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.

Contraindications

 * Spironolactone can reduce vascular responsiveness to norepinephrine and regional or general anesthesia should be used with caution in patients receiving spironolactone


 * Concurrent use of lithium with potassium-sparing diuretics is not recommended, as they may provoke lithium toxicity by reducing renal clearance


 * Spironolactone may increase the half-life of digoxin; dosage reduction or increased dosing intervals of digoxin may be necessary


 * Aspirin has been shown to slightly reduce the natriuretic effect of spironolactone in healthy individuals