Estrogen-Induced Developmental Disorders of the Rat Penis Involve Both Estrogen Receptor (ESR)- and Androgen Receptor (AR)-Mediated Pathways

• Published in: Biology of reproduction Vol. 81; no. 3; pp. 507 - 516
• Main Authors: Goyal, H.O, Braden, T.D, Williams, C.S, Williams, J.W
• Format: Journal Article
• Language: English
• Published: United States Society for the Study of Reproduction, Inc 01.09.2009; Society for the Study of Reproduction
• Subjects: Aging - blood; Aging - drug effects; Aging - physiology; Androgen Receptor Antagonists; Androgens; Animals; Animals, Newborn; Disorders of Sex Development - blood; Disorders of Sex Development - chemically induced; Estrogens - adverse effects; Female; Hormone Antagonists - pharmacology; Male; Organ Size - genetics; Penile Diseases - blood; Penile Diseases - chemically induced; Penile Diseases - congenital; Penis - abnormalities; Penis - drug effects; Penis - growth & development; Penis - metabolism; Rats; Rats, Sprague-Dawley; Receptors, Androgen - metabolism; Receptors, Androgen - physiology; Receptors, Estrogen - antagonists & inhibitors; Receptors, Estrogen - metabolism; Receptors, Estrogen - physiology; Sexual Maturation - drug effects; Signal Transduction - drug effects; Testosterone - blood
• ISSN: 0006-3363; 1529-7268
• DOI: 10.1095/biolreprod.108.071951

This study tested the hypothesis that the estrogen receptor (ESR) pathway, androgen receptor (AR) pathway, or both mediate estrogen-induced developmental penile disorders. Rat pups received diethylstilbestrol (DES), with or without the ESR antagonist ICI 182,780 (ICI) or the AR agonist dihydrotestosterone (DHT) or testosterone (T), from Postnatal Days 1 to 6. Testicular T concentration, penile morphology and morphometry, and/or fertility was determined at age 7, 28, or 150 days. DES treatment alone caused 90% reduction in the neonatal intratesticular T surge; this reduction was prevented by ICI coadministration, but not by DHT or T coadministration. Unlike the T surge, coadministration of ICI and coadministration of DHT or T mitigated penile deformities and loss of fertility. Generally, ICI, DHT, or T treatment alone did not alter penile morphology; however, fertility was 20% that of controls in ICI-treated rats vs. 70%-90% in DHT- or T-treated rats. The lower fertility in the rats treated with ICI alone could be due to altered sexual behavior, as these males did not deposit vaginal plugs. In conclusion, observations that both an ESR antagonist and AR agonists prevent penile deformities and infertility suggest that both pathways are involved in estrogen-induced penile disorders. Observations that coadministration of ICI, but not DHT or T, prevents the DES-induced reduction in the neonatal T surge suggest that, although ICI exerts its mitigating effect both at the level of Leydig cells and penile stromal cells, DHT and T do so only at the level of stromal cells.