title: Prostate effect in dogs with the aldosterone receptor blocker eplerenone.
abstract: Eplerenone (Inspra) is an aldosterone receptor antagonist approved for the treatment of hypertension and heart failure after a myocardial infarction. In vitro receptor binding and transactivation studies showed eplerenone had high selectivity for the mineralocorticoid receptor over other steroid receptors (glucocorticoid, androgen, and progesterone). The most sensitive off-target effect of orally administered eplerenone preclinically was prostate atrophy in dogs. Dose-related prostate atrophy was observed at eplerenone dosages ≥15 mg/kg/day for 13 weeks or longer. The no observed adverse effect level (NOAEL) for the prostate effect in dogs was 5 mg/kg/day. The maximal effect was seen by 13 weeks and the atrophy was reversible even after 1 year of daily treatment. An additional study demonstrated dogs with eplerenone-induced prostate atrophy (confirmed by intrarectal ultrasound) had slightly decreased semen volume but no compound-related effects on libido, semen protein content, sperm motility, daily sperm production, or epididymal sperm transit time. Four possible mechanisms for prostate effect were investigated: (1) inhibition of testosterone synthesis and secretion; (2) inhibition of 5α-reductase, the enzyme within the prostate that converts testosterone into the more active growth factor dihydrotestosterone (DHT); (3) competitive antagonism of the androgen receptor; and (4) inhibition of 5α-reductase or competitive antagonism of the androgen receptor by aldosterone, which increased in dogs treated with eplerenone. Data from these studies supported blockade of androgen receptors at suprapharmacological concentrations of eplerenone. Another mineralocorticoid blocker, spironolactone, had greater antiandrogenic activity than eplerenone both in vivo and in vitro, and it has well known clinically significant antiandrogenic effects in humans, whereas eplerenone does not.
authors.affiliation: Takeda Global Research and Development, Deerfield, Illinois 60015, USA. stuart.levin@takeda.com
authors.forename: Stuart
authors.initials: S
authors.lastname: Levin
authors.forename: Ellen
authors.initials: E
authors.lastname: McMahon
authors.forename: Annette
authors.initials: A
authors.lastname: John-Baptiste
authors.forename: Rosonald R
authors.initials: RR
authors.lastname: Bell
mesh_terms: D000818:Animals; D001284:Atrophy / Q000139:chemically induced; D013196:Dihydrotestosterone / Q000378:metabolism; D004285:Dogs; D000077545:Eplerenone; D018120:Finasteride / Q000494:pharmacology; D006651:Histocytochemistry; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000378:metabolism / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D011467:Prostate / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D011944:Receptors, Androgen / Q000378:metabolism; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D013148:Spironolactone; D018120:Finasteride; D000077545:Eplerenone