Actions of 5alpha-reductase inhibitors on the epididymis.
Testosterone is converted to the more biologically active androgen, dihydrotestosterone (DHT), by steroid 5alpha-reductase. Two isozymes of 5alpha-reductase, types 1 and 2, are abundantly expressed in the epididymis. DHT is the androgen found in the nuclei of epididymal cells and is essential for the maturation of spermatozoa. Thus, one approach to block androgen action in the epididymis is to inhibit DHT formation. Several compounds have been reported to inhibit either one or both forms of 5alpha-reductase in many tissues. The first commercially available inhibitor of 5alpha-reductase, finasteride, has a predominant effect on the type 2 isozyme, while more recently developed agents, such as dutasteride, PNU157706 and FK143, act as dual inhibitors. We found that the treatment of adult rats with such agents results in pronounced effects on the expression of genes essential to the formation of the optimal luminal microenvironment that is required for proper sperm maturation. Furthermore, drug treatment caused a significant decrease in the percentage of progressively motile and morphologically normal spermatozoa in the cauda epididymides. Mating females to treated males resulted in fewer successful pregnancies and a higher rate of pre-implantation loss. Thus, there may be a role for dual 5alpha-reductase inhibitors as potential components of a male contraceptive.
Departments of Pharmacology and Therapeutics and of Obstetrics and Gynecology, McGill University, Montréal, Qué., Canada. bernard.robaire@mcgill.ca
Bernard
B
Robaire
Natali A
NA
Henderson
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics / Q000378:metabolism; D058891:5-alpha Reductase Inhibitors; D000736:Androstenes / Q000494:pharmacology; D000818:Animals; D001378:Azasteroids / Q000494:pharmacology; D042944:Cholestenone 5 alpha-Reductase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D003272:Contraceptive Agents, Male / Q000494:pharmacology*; D013196:Dihydrotestosterone / Q000378:metabolism; D000068538:Dutasteride; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004822:Epididymis / Q000187:drug effects* / Q000201:enzymology; D005260:Female; D005306:Fertilization / Q000187:drug effects / Q000235:genetics; D018120:Finasteride / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D010654:Phenylbutyrates / Q000494:pharmacology; D051381:Rats; D013079:Sperm Maturation / Q000187:drug effects / Q000235:genetics; D013081:Sperm Motility / Q000187:drug effects / Q000235:genetics
C093354:4-(3-(3-(bis(4-isobutylphenyl)methylamino)benzoyl)-1H-indol-1-yl)butyric acid; D058891:5-alpha Reductase Inhibitors; D000736:Androstenes; D001378:Azasteroids; D003272:Contraceptive Agents, Male; D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; C112526:PNU 157706; D010654:Phenylbutyrates; D013196:Dihydrotestosterone; D018120:Finasteride; D042944:Cholestenone 5 alpha-Reductase; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D000068538:Dutasteride