Prostate effect in dogs with the aldosterone receptor blocker eplerenone

Area of Science:

• Pharmacology
• Endocrinology
• Toxicology

Background:

• Eplerenone is an aldosterone receptor antagonist used for hypertension and heart failure.
• Eplerenone exhibits high selectivity for the mineralocorticoid receptor over other steroid receptors.
• Preclinical studies identified prostate atrophy in dogs as a sensitive off-target effect.

Purpose of the Study:

• To investigate the mechanism and reversibility of eplerenone-induced prostate atrophy in dogs.
• To compare the antiandrogenic activity of eplerenone with spironolactone.

Main Methods:

• Oral administration of eplerenone to dogs at various dosages and durations.
• Assessment of prostate morphology, semen parameters, and reproductive organ function.
• Investigation of potential mechanisms including steroidogenesis inhibition, 5α-reductase activity, and androgen receptor antagonism.

Main Results:

• Dose-dependent prostate atrophy observed at eplerenone dosages ≥15 mg/kg/day for ≥13 weeks.
• No observed adverse effect level (NOAEL) for prostate effect was 5 mg/kg/day.
• Prostate atrophy was reversible even after one year of treatment; minimal impact on semen volume without affecting libido or sperm parameters.
• Mechanistic studies suggested androgen receptor blockade at suprapharmacological concentrations.
• Eplerenone demonstrated significantly less in vivo and in vitro antiandrogenic activity compared to spironolactone.

Conclusions:

• Eplerenone-induced prostate atrophy in dogs is a reversible, off-target effect mediated by suprapharmacological androgen receptor blockade.
• Eplerenone possesses minimal antiandrogenic activity compared to spironolactone, suggesting a lower risk of clinical antiandrogenic effects in humans.