VOL. VI NO. VIII AUGUST 2004 THE JOURNAL OF CLINICAL HYPERTENSION 469

Gynecomastia is listed as a rare side effect of numerous antihypertensive medications (Table).

It occurs in <1% of persons who take these medica-tions and in most cases the incidence is no more common than that seen with placebo. However, one antihypertensive medication that is commonly associ-ated with gynecomastia is spironolactone.

Spironolactone-associated gynecomastia has been a recognized entity for more than 40 years. It has become more pertinent in the past 5 years with the widespread use of spironolactone for patients with congestive heart failure or resistant hypertension. Gynecomastia and/or breast pain was reported as an adverse event by 10% of men who received spironolactone at a dose of 25 mg/d in the Randomized Aldactone Evaluation Study (RALES).1 Spironolactone-associated gynecomas-tia is dose-dependent and has a reported incidence of up to 52% with the use of a dose of 150 mg/d. It is also related to duration of therapy, and is usually reversible after discontinuation of the drug.

There are several other endocrine side effects commonly reported with the use of spironolac-tone including impotence, decreased libido, and menstrual abnormalities. Gynecomastia and these other endocrine effects are the result of an altera-tion of the testosterone–estrogen ratio in favor of estrogen.2 Specifically, spironolactone blocks androgen production by inhibiting enzymes in the

testosterone synthetic pathway (i.e., 17α-hydroxy-lase and 17,20-desmolase), blocks testosterone and dihydrotestosterone from binding to their receptors, increases serum free estradiol by displacing estradiol from sex hormone binding globulin, and increases peripheral conversion of testosterone to estradiol.

To address this problem, a selective aldoste-rone antagonist, eplerenone, has been developed. Eplerenone does not cause gynecomastia even in patients who had previously developed this side effect while on spironolactone. The selectivity of eplerenone for the aldosterone receptor over other steroid receptors is thought to be the result of replacement of a 17α-thioacetyl group with a carbo-methoxy group.3 Consequently, in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS)4 the inci-dence of gynecomastia and other endocrine side effects in the treatment arm was the same as the incidence in the placebo arm. The principal find-ings of this study were a 15% relative risk reduc-tion (2.3% absolute risk reduction) of all-cause mortality and a 17% relative risk reduction (2.3% absolute risk reduction) of cardiovascular death with the use of eplerenone. These results are not as impressive as those reported with spironolactone in the RALES study, although there are important differences in the study designs. Eplerenone has not been compared head to head with spironolactone in any large clinical trial and it is considerably more expensive than spironolactone. Thus, the editorial accompanying the EPHESUS report recommended against using eplerenone (for the treatment of con-gestive heart failure in the proper clinical context) without first trying spironolactone.5

Gynecomastia is a common problem encountered during therapy with spironolactone. Despite the availability of eplerenone, a selective aldosterone

From the Hypertension Program, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PAAddress for correspondence:Raymond R. Townsend, MD, University of Pennsylvania, 201 White Building, 3600 Spruce Street, Philadelphia, PA 19104

C o m m o n Q u e s t i o n s a n d A n s w e r s i n t h e M a n a g e m e n t o f H y p e r t e n s i o nR a y m o n d R . T o w n s e n d , M D , S e c t i o n E d i t o r

www.lejacq.com ID: 3735

Gynecomastia and Antihypertensive Therapy

Ari Mosenkis, MD; Raymond R. Townsend, MD

The Journal of Clinical Hypertension (ISSN 1524-6175) is published monthly by Le Jacq Communications, Inc., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2004 by Le Jacq Communications, Inc., All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at showell@lejacq.com or 203.656.1711 x106.

THE JOURNAL OF CLINICAL HYPERTENSION VOL. VI NO. VIII AUGUST 2004470

antagonist that is not associated with endocrine side effects, spironolactone should still be the aldosterone antagonist of first choice for the treatment of heart failure or hypertension because it has well document-ed efficacy and is less costly. Nevertheless, if gyne-comastia or other troubling endocrine side effects develop with the use of spironolactone, eplerenone would be an appropriate substitute.

REFERENCES 1 Pitt B, Zannad F, Remme WJ, et al. The effect of spirono-

lactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341(10):709–717.

2 Rose LI, Underwood RH, Newmark SR, et al. Pathophysiology of spironolactone-induced gynecomastia. Ann Intern Med. 1977;87(4):398–403.

3 Moore TD, Nawarskas JJ, Anderson JR. Eplerenone: a selective aldosterone receptor antagonist for hypertension and heart failure. Heart Dis. 2003;5(5):354–363.

4 Pitt B, Remme W, Zannad F, et al. Eplerenone, a selec-tive aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348(14):1309–1321.

5 Jessup M. Aldosterone blockade and heart failure. N Engl J Med. 2003;348(14):1380–1382.

Table. Antihypertensive Medications Associated With GynecomastiaCOMMONLY ASSOCIATED Potassium sparing diuretics

SpironolactoneRARELY ASSOCIATEDCalcium channel blockers

NifedipineAmlodipineDiltiazemVerapamil

Angiotensin-converting enzyme inhibitorsCaptoprilEnalapril

Alpha receptor blockersDoxazosinPrazosin

Centrally acting agentsClonidine

Methyldopa

Reserpine

The Journal of Clinical Hypertension (ISSN 1524-6175) is published monthly by Le Jacq Communications, Inc., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2004 by Le Jacq Communications, Inc., All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at showell@lejacq.com or 203.656.1711 x106.