Gonadotrophins regulate germ cell survival, not proliferation, in normal adult men
1 Prince Henry's Institute, Clayton, Level 4, 43-51 Kanooka Grove, Victoria 3168, Australia 2 Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria 3168, Australia 3 Department of Anatomy and Cell Biology, Monash University, Clayton, Victoria 3000, Australia
4 Correspondence address. Tel: +61-3-9594-7913; Fax: +61-3-9594-7909; E-mail: sarah.meachem{at}princehenrys.org
BACKGROUND: Gonadotrophins support spermatogenesis via poorly understood mechanisms. We aimed to determine the effect of FSH/LH suppression in regulating germ cell apoptosis and proliferation in normal fertile men.
METHODS: Testicular tissues were obtained after gonadotrophin suppression induced by testosterone alone or combined with depot medroxyprogesterone acetate for 2 or 6 weeks and an untreated group of men (referred to as ‘normal men’) served as controls (n = 5 or 10 men per group). Apoptosis and proliferation were identified by terminal deoxynucleotidyl transferase-mediated dUDP nick-end labelling (TUNEL) and proliferating cell nuclear antigen (PCNA) labelling methods, respectively. Intrinsic and extrinsic apoptotic pathways were identified by immunohistochemistry using the pathway-specific proteins: activated caspase (aCaspase) 9 and 8 and quantified using stereological techniques.
RESULTS: By 2 and 6 weeks, the proportion of TUNEL-labelled spermatogonia increased to 354% and 268% respectively, compared with normal men (P < 0.001), with increased caspase 9 [223 and 166% compared with normal men (P < 0.001)], but no increase in caspase 8, immunoreactivity. At 6 weeks, the proportions of TUNEL-labelled spermatocytes and round spermatids tended to increase (303 and 180% compared with normal men, NS), as did caspase 9 (199 and 147% compared with normal men, NS) and caspase 8 immunoreactivities (286 and 243% compared with normal men, NS and P = 0.06), respectively. The proportion of TUNEL-labelled elongating/elongated spermatids tended to increase (144 and 138% compared with normal men, NS) at 2 and 6 weeks, respectively, with no change in either caspase immunoreactivities. Even though the number of PCNA-labelled cells did not change with gonadotrophin suppression, the balance between proliferation and apoptosis was lower in spermatogonia (P = 0.01) and spermatocytes (P = 0.3) between treated and untreated normal men.
CONCLUSIONS: We demonstrated that gonadotrophins act as spermatogonial survival factors via the regulation of intrinsic apoptotic pathway, whereas having no effect of cellular proliferation in normal men.
Key words: spermatogonia/caspase/apoptosis/intrinsic pathway/extrinsic pathway
Submitted on August 27, 2007; resubmitted on October 12, 2007; accepted on October 23, 2007.
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