two aldosterone antagonists on the market that are commonly used for the
treatment of hypertension (HTN) and/or heart failure (HF) due to left
ventricular systolic dysfunction are eplerenone (Inspra) and spironolactone
(Aldactone).1,2 In addition to these indications, spironolactone is
available generically, is less prone to drug interactions and is also used in
the management of primary aldosteronism, edema from cirrhosis, and prophylaxis
against hypokalemia.2 However, spironolactone is known to cause more
gynecomastia and/or breast pain in male patients than eplerenone. For
example, the RALES trial revealed that spironolactone caused gynecomastia and
breast pain in 10% of HF patients whereas only 0.5% of HF patients on
eplerenone in the EPHESUS trial.3,4 This low incidence of gynecomastia
with eplerenone is also consistent in patients with HTN where it was not found
to be different from placebo.1
regulates breast tissue proliferation in males that normally prevents the
formation of gynecomastia?
- In short, there is a balance between the inhibition of
breast epithelial cell growth by the presence of testosterone and the
activation of breast epithelial cell growth by estrogen.5-7 Any changes
in their regulatory influences can result in changes in breast tissue
proliferation and size.8 As such, anything that would inhibit the
concentration of free testosterone, reduce the presence of cytosolic androgen
receptors found in breast tissue or inhibit the binding of free testosterone to
available cytosolic androgen receptors can prevent the inhibitory influence on
breast tissue proliferation.9 The later occurs in patients taking
spironolactone, but is negligible with eplerenone.
both eplerenone and spironolactone are aldosterone antagonists, how then does
eplerenone cause less gynecomastia than spironolactone?
- Unlike eplerenone, spironolactone not only competitively inhibits aldosterone
from binding to the mineralocorticoid receptor, it is also known to inhibit
free testosterone from binding to androgen receptors in the cytoplasm of breast
cells (see figure below).2,10 It appears that the presence of a 9,11
epoxide group on eplerenone reduces its affinity for both the androgen and
progesterone receptors.2 This reduction in the formation of cytosolic
testosterone/androgen receptor complexes with eplerenone results in a loss of
the inhibition of gene transcription needed for breast tissue
proliferation. As a result of this inhibition, a greater degree of free
testosterone can then tightly bind to sex hormone binding globulin (SHBG), then
be converted via 17-oxosteroid reductase to androstenedione where it can
ultimately form estrone or be directly converted to estradiol via aromatase.9,11
Regardless of the pathway that the additional free testosterone now takes,
there is a shift in the balance towards estrogen induced breast tissue
- Furthermore, this result on breast tissue is also favored
by the presence of luteinizing hormone inhibition of androgen receptors in the
breast, as well as progesterone's stimulation of breast ductal morphogenesis.12,13 The
combination of these effects ultimately contributes to up to 10% of males
developing noticeable gynecomastia (breast enlargement and tenderness).
Due to this undesired side effect, adherence to spironolactone can be
compromised. It is important to note that a switch to eplerenone will
cost more money and requires the clinician to consider the patients kidney
function (eplerenone is contraindicated when the CrCl < 50 mL/min) and current
medications to avoid drug interactions that were not relevant with
- Eplerenone (Inspra) product package insert. Pfizer Inc., Ney York, NY. April 2008.
E. Drugs affecting renal and cardiovascular function. In: Goodman
& Gilman's The Pharmacological Basis of Therapeutics. 11ed.
Brunton LL, Lazo JS, Parker KL eds. McGraw-Hill. New York, NY.
- Pitt B, Zannad F, Remme WJ et al. The effect of
spironolactone on morbidity and mortality in patients with severe heart
failure. Randomized Aldactone Evaluation Study Investigators. N Engl J
B, Remme W, Zannad F et al. Eplerenone, a selective aldosterone
blocker, in patients with left ventricular dysfunction after myocardial
infarction. N Engl J Med 2003;348:1309-21.
H, Kimura M, Shizawa S et al. Aromatase and steroid receptors in
gynecomastia and male breast carcinoma: an immunohistochemical study. J
Clin Endocrinol Metab 1996;81:3063-7.
RC, Hage JJ, van Diest PJ et al. Short-term and long-term histologic
effects of castration and estrogen treatment on breast tissue of 14
male-to-female transsexuals in comparison with two chemically castrated
men. Am J Surg Pathol 2000;24:74-80.
HE, Shousha S. An immunohistochemical study of the long-term effects
of androgen administration on female-to-male transsexual breast: a
comparison with normal female breast and male breast showing
gynecomastia. J Pathol 1993;170:37-43.
GL, Modlinger RS, Gabrilove JL. A study of the histopathology of human
gynecomastia. J Clin Endocrinol Metab 1971;32:173-8.
- Narual HS, Carlson HE. Gynecomastia. Endocrinol Metab Clin North Am 2007;36:497-519.
- Karim A. Spironolactone: disposition, metabolism, pharmacodynamics and bioavailability. Drug Metab Rev 1978;8:151-88.
- Braunstein GD. Aromatase and gynecomastia. Endocr Relat Cancer 1999;6:315-24.
HE, Kane P, Lei ZM et al. Presence of luteinizing hormone/human
chorionic gonadotropin receptors in male breast tissues. J Clin
Endocrinol Metab 2004;89:4119-23.
W, Monaco ME, Kleinberg DL. Progesterone stimulates mammary gland
ductal morphogenesis by synergizing with and enhancing insulin-like
growth factor-I action. Endocrinology 2005;146:1170-8.