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Male Gynecomastia
Bridgett A. Haynes, MD,* and Farouk Mookadam, MBBChB, FRCPC†
*Department of Internal Medicine and †Division of Cardiovascular Diseases,
Mayo Clinic Arizona, Scottsdale

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 Asso-
ciation (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 spirono­
lactone and is related to dose and duration of treatment; overall
prevalence is 10%.1 Spironolactone induces gynecomastia by
decreasing testosterone production, increasing peripheral con-
version 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 spironolac-
tone 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 aromatiza-
tion 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 associ-
ated with the development of gynecomastia in elderly men.
TABLE. Antihypertensive Medications Associated
With Gynecomastia
Potassium-sparing diuretics
Spironolactone
Calcium channel blockers
Nifedipine
Amlodipine
Diltiazem
Verapamil
Angiotensin-converting enzyme inhibitors
Captopril
Enalapril
a-Receptor blockers
Doxazosin
Prazosin
Centrally acting agents
Clonidine
Methyldopa
Reserpine
Gynecomastia can be an adverse effect of medications. Many
antihypertensive medications have been associated with the
development of gynecomastia, but it is highest with spironolac-
tone.1 Dosages higher than 150 mg/d have been associated with
up to a 52% prevalence of the adverse effect. Generally, the ef-
fects are reversible after discontinuation of the drug.
Spironolactone induces gynecomastia by blocking an-
drogen 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
1. Mosenkis A, Townsend RR. Gynecomastia and antihypertensive therapy. J
Clin Hypertens (Greenwich). 2004;6(8)469-470.
2. Prisant LM, Chin E. Gynecomastia and hypertension. J Clin Hypertens
(Greenwich). 2005;7(4):245-248.
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.
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.
5. Rose LI, Underwood RH, Newmark SR, Kisch ES, Williams GH.
Pathophysiology of spironolactone-induced gynecomastia. Ann Intern Med.
1977;87(4):398-403.
6. Pitt B, Remme W, Zannad F, et al; Eplerenone Post-Acute Myocardial Infarc-
tion 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.
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