The 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 

What 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. 

If 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 proliferation. 
  
• 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 spironolactone.1

References:

1. Eplerenone (Inspra) product package insert.  Pfizer Inc., Ney York, NY.  April 2008.
2. Jackson 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. 2006:759-762.
3. 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 Med  1999;341:709-17.  
4. Pitt 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.  
5. Sasano 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.  
6. Kanhai 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.  
7. Burgess 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.  
8. Nicolis GL, Modlinger RS, Gabrilove JL.  A study of the histopathology of human gynecomastia.  J Clin Endocrinol Metab  1971;32:173-8.  
9. Narual HS, Carlson HE.  Gynecomastia.  Endocrinol Metab Clin North Am  2007;36:497-519.  
10. Karim A.  Spironolactone: disposition, metabolism, pharmacodynamics and bioavailability.  Drug Metab Rev  1978;8:151-88.  
11. Braunstein GD.  Aromatase and gynecomastia.  Endocr Relat Cancer  1999;6:315-24.  
12. Carlson 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.  
13. Ruan 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.
    

Eplerenone, Inspra, Spironolactone, Aldactone, Aldosterone Antagonist, Gynecomastia