Insights into male germ cell apoptosis due to depletion of gonadotropins caused by GnRH antagonists

Abstract

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.

Apoptotic sperm biomarkers and the correlation between conventional sperm parameters and clinical characteristics

“…Indeed, it has been shown that both extrinsic and intrinsic apoptotic death pathways are operative in the germ cells following the decrease in FSH and testosterone levels. Therefore, FSH and testosterone maintain spermatogenic homoeostasis by inhibiting death signals for the germ cells (Pareek, Joshi, Sanyal, & Dighe, 2007;Shaha, 2008).…”

Male germ cell apoptosis: regulation and biology

“…During seminiferous tubule maturation, testosterone and the synergistic action of FSH with oestradiol support germ cell survival while oestradiol alone has an inhibitory, pro-apoptotic effect. It has been shown that both extrinsic and intrinsic apoptotic death pathways are operative in the germ cells following decrease in FSH and testosterone levels; therefore, FSH and testosterone maintain spermatogenic homeostasis by inhibiting death signals for the germ cells (Pareek et al 2007). Excess testosterone can cause death, for example, after injection of testosterone undecanoate, the expression of Fas/FasL in testis increase correlatively in a time-dependent manner, reaching a maximum level on day 30 (Zhou et al 2001).…”

Photoperiod-gonadotropin mismatches induced by treatment with acyline or FSH in Siberian hamsters: impacts on ovarian structure and function

“…after w7.5 weeks of treatment). The 50 mg acyline dose has been shown to effectively suppress FSH in female P. sungorus ) and alternate-day dosing maintains low FSH levels for at least 48 h (Pareek et al 2007). Further, although acyline treatment suppresses gonadotropin levels, the secretion of other pituitary hormones that are known to vary based on photoperiod, such as prolactin and melatonin, is unaffected, and many aspects of the LD phenotype (e.g.…”