A 62-year-old man with known coronary artery disease and ischemic left ventricular dysfunction presented with chest discomfort. His history was remarkable for New York Heart Association (NYHA) class IV congestive heart failure with depressed left ventricular ejection fraction. Physical examination revealed severe gynecomastia. The patient had been taking spironolactone (25 mg) daily for 8 years as part of his medication regimen for congestive heart failure. Spironolactone had been prescribed on the basis of RALES (Randomized Aldactone Evaluation Study), which reported spironolactone's benefits in reducing morbidity and mortality in patients with NYHA class III or IV heart failure.1
Gynecomastia is a well-described adverse effect of spironolactone and is related to dose and duration of treatment; overall prevalence is 10%.1 Spironolactone induces gynecomastia by decreasing testosterone production, increasing peripheral conversion of testosterone to estradiol, and displacing estradiol from sex hormone-binding globulin.1,2 Generally, discontinuation of treatment results in resolution of gynecomastia.
In 1999, RALES reported that spironolactone, in addition to standard therapy, decreases morbidity and death rates in patients with NYHA class III or IV heart failure. Gynecomastia or breast discomfort was reported as an adverse event in 10% of the men who participated in RALES.3 Other trials in which spironolactone was used have reported similar rates.4
Gynecomastia is defined as at least 2 cm of dense, subareolar tissue.2 It is seen in obese and elderly patients. Gynecomastia develops because of alterations in the ratio of free androgen to estrogen. Usual causes include enhanced peripheral aromatization of androgen to estrogen (obesity), displacement of estrogen from sex hormone-binding globulin, or decreased metabolism. Decreases in free androgen may occur as a result of increased sex hormone-binding globulin, increased metabolism, or impaired synthesis of androgen. Declining androgen synthesis is associated with the development of gynecomastia in elderly men.
TABLE.
Antihypertensive Medications Associated With Gynecomastia
Gynecomastia can be an adverse effect of medications. Many antihypertensive medications have been associated with the development of gynecomastia, but it is highest with spironolactone.1 Dosages higher than 150 mg/d have been associated with up to a 52% prevalence of the adverse effect. Generally, the effects are reversible after discontinuation of the drug.
Spironolactone induces gynecomastia by blocking androgen production, by blocking androgens from binding to their receptors, and by increasing both total and free estrogen levels.1,5 Production of testosterone is decreased by inhibiting 17α-hydroxylase and 17,20-desmolase, which are enzymes in the testosterone synthesis pathway. Estrogen levels are increased by enhancing the peripheral conversion of testosterone to estradiol and by displacing estradiol from sex hormone-binding globulin.
A selective aldosterone antagonist (eplerenone) has a lower incidence of gynecomastia, but the cost is higher.6
References
- 1.Mosenkis A, Townsend RR. Gynecomastia and antihypertensive therapy. J Clin Hypertens (Greenwich) 2004;6(8)469-470 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Prisant LM, Chin E. Gynecomastia and hypertension. J Clin Hypertens (Greenwich) 2005;7(4):245-248 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Pitt B, Zannad F, Remme WJ, et al. Randomized Aldactone Evaluation Study Investigators The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341(10):709-717 [DOI] [PubMed] [Google Scholar]
- 4.Chapman N, Dobson J, Wilson S, et al. Anglo-Scandinavian Cardiac Outcomes Trial Investigators Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension 2007;49(4):839-845 Epub 2007 Feb 19 [DOI] [PubMed] [Google Scholar]
- 5.Rose LI, Underwood RH, Newmark SR, Kisch ES, Williams GH. Pathophysiology of spironolactone-induced gynecomastia. Ann Intern Med. 1977;87(4):398-403 [DOI] [PubMed] [Google Scholar]
- 6.Pitt B, Remme W, Zannad F, et al. Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction [published correction appears in N Engl J Med. 2003;348(22):2271] N Engl J Med. 2003;348(14):1309-1321 Epub 2003 Mar 31 [DOI] [PubMed] [Google Scholar]