Spironolactone

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Spironolactone
Skeletal formula for Spironolactone
Drug class: Antiandrogen
Dosage range: Oral: 100–300 mg/day[1]
Brand names: Aldactone, Spiractin, Verospiron, others
PubChem CID: 5833

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.[2][3][4][5][6][7][8][9][10][11] The first clinical study of spironolactone in transgender women was conducted in 1989,[3] although use had been reported by a gender dysphoria clinic in 1986.[2]

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 [12]
  • Concurrent use of lithium with potassium-sparing diuretics is not recommended, as they may provoke lithium toxicity by reducing renal clearance [13]
  • Spironolactone may increase the half-life of digoxin; dosage reduction or increased dosing intervals of digoxin may be necessary [14]
  • Aspirin has been shown to slightly reduce the natriuretic effect of spironolactone in healthy individuals [15]



References

  1. Endocrine_Society_Guidelines#Hormone Regimens
  2. 2.0 2.1 Prior, J. C., Vigna, Y. M., Watson, D., Diewold, P., & Robinow, O. (1986). Spironolactone in the presurgical therapy of male to female transsexuals: Philosophy and experience of the Vancouver Gender Dysphoria Clinic. Journal of Sex Information & Education Council of Canada, 1, 1-7.
  3. 3.0 3.1 Prior, J. C., Vigna, Y. M., & Watson, D. (1989). Spironolactone with physiological female steroids for presurgical therapy of male-to-female transsexualism. Archives of Sexual Behavior, 18(1), 49-57. Quote: "Antiandrogen therapy with spironolactone for male-to-female transsexualism has not been previously reported."
  4. Seal, L. J., Franklin, S., Richards, C., Shishkareva, A., Sinclaire, C., & Barrett, J. (2012). Predictive markers for mammoplasty and a comparison of side effect profiles in transwomen taking various hormonal regimens. The Journal of Clinical Endocrinology & Metabolism, 97(12), 4422-4428.
  5. Leinung, M. C. (2014). Variable Response to Oral Estradiol Therapy in Male to Female Transgender Patients. In Disorders of Sex Development and Transgender Medicine (pp. OR42-1). Endocrine Society. http://press.endocrine.org/doi/abs/10.1210/endo-meetings.2014.RE.2.OR42-1
  6. Leinung, M. C. (2014). Variable Response to Oral Estradiol Therapy in Male to Female Transgender Patients. In Disorders of Sex Development and Transgender Medicine (pp. OR42-1). Endocrine Society.
  7. Deutsch, M. B., Bhakri, V., & Kubicek, K. (2015). Effects of cross-sex hormone treatment on transgender women and men. Obstetrics and gynecology, 125(3), 605.
  8. Fung, R., Hellstern-Layefsky, M., Tastenhoye, C., Lega, I., & Steele, L. (2016). Differential effects of cyproterone acetate vs spironolactone on serum high-density lipoprotein and prolactin concentrations in the hormonal treatment of transgender women. The journal of sexual medicine, 13(11), 1765-1772.
  9. Fontanari, A. M. V., Costa, A. B., Aguiar, B., Tusset, C., Andreazza, T., Schneider, M., ... & Borba, A. O. (2016). Reduced serum concentrations of brain-derived neurotrophic factor (BDNF) in transsexual Brazilian men. Neuroscience letters, 630, 109-113.
  10. Liang, J. J., Jolly, D., Chan, K. J., & Safer, J. D. (2017). Testosterone levels achieved by medically treated transgender women in a United States endocrinology clinic cohort. Endocrine Practice.
  11. de Blok, C. J. M., Klaver, M., Wiepjes, C. M., Nota, N. M., Heijboer, A. C., Fisher, A. D., ... & den Heijer, M. (2017). Breast Development in Transwomen After One Year of Cross-sex Hormone Therapy: Results of A Prospective Multicenter Study. The Journal of Clinical Endocrinology & Metabolism.
  12. McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 1982
  13. Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 1121
  14. Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 1121
  15. McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 1982