Effects of PNU157706, a dual 5alpha-reductase inhibitor, on rat epididymal sperm maturation and fertility.
Sperm entering the epididymis gain progressive motility and fertilizing ability in a process termed maturation. The functional dependence of the epididymis on dihydrotestosterone (DHT) is well established, yet few studies have examined the consequences on the epididymis of inhibiting DHT formation. We have shown that inhibition of both isoforms of 5alpha-reductase (types 1 and 2), the enzyme that converts testosterone to DHT, has pronounced effects on epididymal gene expression. In the present study, we investigate whether inhibiting 5alpha-reductase has consequences on epididymal sperm maturation. Rats were treated with vehicle or 10 mg/kg/day PNU157706, a dual-type inhibitor, for 28 days. Fertility and several key facets of sperm maturation were analyzed. Changes in sperm motility were assessed by computer-assisted sperm analysis (CASA). Changes in sperm morphology were assessed by CASA and electron microscopy. The motility of spermatozoa from the cauda epididymidis of treated animals showed a significant decrease in both the percentage of motile and progressively motile sperm as well as altered motion parameters. The morphology of cauda epididymal spermatozoa was also adversely affected by the treatment; the most prominent effect was a markedly elevated proportion of sperm that retained their cytoplasmic droplet. Matings with treated males resulted in fewer successful pregnancies and a higher rate of preimplantation loss. Progeny outcome was unaffected. The compromised sperm motility and morphology likely contribute to the subfertility of inhibitor-treated rats. Our results indicate a role for dual 5alpha-reductase inhibitors in further studies of epididymal physiology and as a potential component of a male contraceptive.
Henderson
Natali Anne
NA
Department of Pharmacology and Therapeutics, McGill University, Montréal, Quebec, Canada.
Robaire
Bernard
B
D058891:5-alpha Reductase Inhibitors; D000736:Androstenes / Q000494:pharmacology*; D000818:Animals; D000988:Antispermatogenic Agents; D003272:Contraceptive Agents, Male; D010064:Embryo Implantation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004822:Epididymis / Q000187:drug effects*; D005260:Female; D005298:Fertility / Q000187:drug effects*; D008297:Male; D008854:Microscopy, Electron; D011247:Pregnancy; D011256:Pregnancy Outcome; D051381:Rats; D017207:Rats, Sprague-Dawley; D013079:Sperm Maturation / Q000187:drug effects*; D013081:Sperm Motility / Q000187:drug effects; D013094:Spermatozoa / Q000187:drug effects / Q000648:ultrastructure
D058891:5-alpha Reductase Inhibitors; D000736:Androstenes; D000988:Antispermatogenic Agents; D003272:Contraceptive Agents, Male; D004791:Enzyme Inhibitors; C112526:PNU 157706