Insights into male germ cell apoptosis due to depletion of gonadotropins caused by GnRH antagonists.
The role of pituitary gonadotropins in the regulation of spermatogenesis has been unequivocally demonstrated, although, the precise mechanism of this regulation is not clearly understood. Previous studies have shown that specific immunoneutralization of LH/testosterone caused apoptotic cell death of meiotic and post-meiotic germ cells while that of FSH resulted in similar death of meiotic cells. In the present study, the death process of germ cells has been characterized by depleting both FSH and testosterone by administering two different potent GnRH antagonists, Cetrorelix and Acyline to both rats and mice. Pro-survival factors like Bcl-2 and Bcl-x/l were unaltered in germ cells due to GnRH antagonist treatment, although a significant increase in several pro-apoptotic markers including Fas and Bax were evident at both protein and RNA levels. This culminated in cytochrome C release from mitochondria and eventually increase in the activity of caspase-8 and caspase-3. These data suggest that both extrinsic and intrinsic apoptotic death pathways are operative in the germ cells death following decrease in FSH and testosterone levels. Multiple injections of GnRH antagonist resulted in complete disappearance of germ cells except the spermatogonial cells and discontinuation of the treatment resulted in full recovery of spermatogenesis. In conclusion our present data suggest that the principal role of FSH and testosterone is to maintain spermatogenic homeostasis by inhibiting death signals for the germ cells.
Pareek
Tej K
TK
Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, Karnataka 560 012, India. tej.pareek@case.edu
Joshi
Ayesha R
AR
Sanyal
Amartya
A
Dighe
Rajan R
RR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism; D005640:Follicle Stimulating Hormone / Q000097:blood / Q000172:deficiency*; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D020836:Protein Structure, Quaternary; D051381:Rats; D017208:Rats, Wistar; D013094:Spermatozoa / Q000166:cytology*; D013737:Testis / Q000201:enzymology / Q000254:growth & development; D013739:Testosterone / Q000097:blood / Q000172:deficiency*; D051028:bcl-2-Associated X Protein / Q000737:chemistry
D015415:Biomarkers; D053418:Death Domain Receptor Signaling Adaptor Proteins; D051028:bcl-2-Associated X Protein; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D005640:Follicle Stimulating Hormone; D045304:Cytochromes c; D020169:Caspases; C062876:cetrorelix