Endocrine Abstracts

Men with suppressed gonadotrophins, as induced by androgen-based contraceptive treatment, exhibit a 70% reduction in germ cell numbers (1). The mechanisms by which the germ cell populations are decreased are unknown. This study aimed to quantify the amount of germ cell apoptosis and proliferation and to identify the pathway(s) involved in gonadotrophin-induced germ cell loss in men. Testicular tissues from normal fertile men that received no treatment or testosterone (200 mg i.m. weekly) plus depot medroxyprogesterone acetate (300 mg i.m. once) for 2 or 6 weeks (n=5/10 per group) to suppress gonadotrophins and consequently spermatogenesis were used (1). Apoptosis and proliferation were identified by TUNEL (a DNA fragmentation marker) and PCNA (a cell cycle marker) labelling methods, respectively. Intrinsic and extrinsic apoptotic pathways were identified by co-localisation of TUNEL-labelled germ cells with the pathway-specific proteins: activated caspase (aCaspase) 9 and 8 by confocal microscopy. The proportion of cells labelled and co-labelled by each method was quantified using stereological techniques. By 2 and 6 weeks of gonadotrophin suppression, the proportion of TUNEL-labelled spermatogonia was increased to 354% and 268% of control (P<0.001), respectively. The proportion of TUNEL-labelled spermatocytes was increased (139% and 303% of control, respectively, not significant (NS)), with no TUNEL-labelled spermatids being observed. No difference in the number of PCNA-labelled cells was observed in gonadotrophin-suppressed men compared to control. By 2 and 6 weeks of gonadotrophin suppression, there was a trend that aCaspase 9 activity was increased to 130% of controls (NS), with no changes in aCaspase 8 activities. This study demonstrates for the first time that gonadotrophins act as survival factors for the spermatogonial (and possibly spermatocyte) population, possibly by regulating the intrinsic pathway of apoptosis. Understanding the mechanisms by which germ cells progress may provide important clues in infertile men where germ cells fail to progress due to hormonal pertubations.

(1) McLachlan et al. Journal of Clinical Endocrinology and Metabolism 2002 87: 546.