Why Eplerenone Causes Less Gynecomastia Than Spironolactone

Eplerenone (Inspra) and spironolactone (Aldactone) are two aldosterone antagonists commonly used for the treatment of hypertension (HTN) and heart failure (HF) due to left ventricular systolic dysfunction. Spironolactone is also available generically and is used to manage primary aldosteronism, edema from cirrhosis, and prophylaxis against hypokalemia. However, spironolactone is known to cause more gynecomastia and breast pain in male patients than eplerenone. This article aims to explore the reasons behind this difference in side effects.

Breast Tissue Proliferation in Males

Gynecomastia presents as palpable subareolar tissue and should be differentiated from pseudogynecomastia (lipomastia), a generalized fat accumulation in male breasts.

In males, breast tissue proliferation is regulated by a balance between the inhibition of breast epithelial cell growth by testosterone and the activation of breast epithelial cell growth by estrogen. Any changes in their regulatory influences can result in changes in breast tissue proliferation and size. Factors that could affect this balance include inhibiting free testosterone concentration, reducing cytosolic androgen receptors found in breast tissue, or inhibiting free testosterone binding to available cytosolic androgen receptors. The latter occurs in patients taking spironolactone but is negligible with eplerenone.

Eplerenone's Reduced Affinity for Androgen and Progesterone Receptors

Eplerenone and spironolactone are aldosterone antagonists, but their effects on gynecomastia differ due to their molecular structures. Spironolactone inhibits aldosterone binding to the mineralocorticoid receptor and free testosterone binding to androgen receptors in the cytoplasm of breast cells. In contrast, an epoxide group on eplerenone reduces its affinity for both the androgen and progesterone receptors. 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.

Shift in the Balance Towards Estrogen-Induced Breast Tissue Proliferation

As a result of this inhibition, a greater degree of free testosterone can tightly bind to sex hormone-binding globulin (SHBG), be converted via 17-oxosteroid reductase to androstenedione, ultimately form estrone, or be directly converted to estradiol via aromatase. Regardless of the pathway the additional free testosterone now takes, there is a shift in the balance toward estrogen-induced breast tissue proliferation.

Luteinizing hormone inhibition of androgen receptors in the breast and progesterone's stimulation of breast ductal morphogenesis also contribute to this result. The combination of these effects ultimately contributes to up to 10% of males developing noticeable gynecomastia (breast enlargement and tenderness) when using spironolactone.

Adherence and Considerations for Switching to Eplerenone

Due to the undesired side effect of gynecomastia, adherence to spironolactone can be compromised. A switch to eplerenone may be considered; however, it will cost more money and requires the clinician to consider the patient's kidney function (eplerenone is contraindicated when the CrCl < 50 mL/min) and current medications to avoid drug interactions that were not relevant with spironolactone.


Eplerenone causes less gynecomastia than spironolactone due to its reduced affinity for androgen and progesterone receptors, resulting from an epoxide group on its molecular structure. This difference in affinity allows eplerenone to have a lesser impact on the balance between testosterone and estrogen, ultimately leading to a lower risk of gynecomastia in male patients. In addition, the hormonal factors, such as luteinizing hormone inhibition of androgen receptors and progesterone's stimulation of breast ductal morphogenesis, further contribute to the increased risk of gynecomastia with spironolactone.

While eplerenone may provide an alternative treatment option for patients experiencing gynecomastia with spironolactone, it is essential for healthcare providers to carefully assess the patient's kidney function and potential drug interactions before switching medications. Moreover, the increased cost of eplerenone should be considered when determining the most appropriate treatment plan.


Narual HS, Carlson HE. Gynecomastia. Endocrinol Metab Clin North Am  2007;36:497-519. 

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