Folliclestimulating hormone FSH and spermatogenesis

5.6.1 FSH receptor and sites of FSH action

Remarkably, the expression of the FSH receptor appears to be restricted to Sertoli cells only. Previous reports on spermatogonial expression of FSH receptor have not been confirmed to date. In all likelihood, FSH also acts on spermatogenesis indirectly via a single somatic cell type. Testicular FSH receptor expression in the ratis highest in stages XII-II (Heckertand Griswold 2002; Rannikko etal. 1996),e.g. when A-type spermatogonia develop further, first spermatocytes appear and when the second meiotic division is being completed. In the human testis, FSH receptor expression could not be clearly associated with a particular spermatogenic stage(s) but was unequivocally confined to Sertoli cells (Bockers et al. 1994; Vannier et al.

1996). Alternative splicing generates several FSH receptor transcripts and several FSH isoforms circulate but the relevance of this to spermatogenesis is not yet clear (Simoni et al. 2002; Ulloa-Aguirre et al. 2003). Despite substantial investigational efforts it has remained a mystery why FSH receptor expression is so cell-specific.

5.6.2 FSH dependence of spermatogenesis

Observations that testosterone alone in some studies could quantitatively maintain or reinitiate spermatogenesis in the adult rat model prompted the question of whether there is a need for FSH in spermatogenesis (Zirkin et al. 1994). This question received support by reports that spermatogenesis continued at least in qualitatively normal manner and fertility was retained in FSH-^-subunit deficient mice (Kumar etal. 1997). On the other hand, spermatogenesis and spermatid maturation are affected in FSH-receptor deficient mice (Krishnamurthy et al. 2000a; 2000b). Stereological analysis in these mice yielded a clear-cut reduction of numbers of Sertoi cells and germ cells (Wreford etal. 2001). Conversely, immunization against FSH or its receptor interfered with spermatogenesis in the rat (Graf et al.

1997) and inhibition ofboth FSH and LH induced a more pronounced inhibition of spermatogenesis than inhibition of LH alone (McLachlan et al. 2002a; 2002b). To date, a role for FSH in immature and adult rat spermatogenesis is unequivocally established (El Shennawy etal. 1998). How critical FSH is for spermatogenesis has also been clearly demonstrated in primate studies. Patients with selective inactivating mutations ofthe FSH-^-subunit exhibit hypogonadism and can be azoospermic (Lindstedt etal. 1998; Phillip etal. 1998). Immunization studies against FSH in rhesus monkeys and in bonnet monkey provoked marked testicular involution and even infertility (Moudgal et al. 1997a; 1997b; Nieschlag et al. 1999). In a hypophysec-tomized man bearing an activating mutation of the FSH receptor, spermatogenesis was sustained (Gromoll etal. 1996).

In the GnRH antagonist-treated nonhuman primate model, human FSH was able to qualitatively maintain and restore spermatogenesis (Weinbauer etal. 1991). Several studies also suggest that FSH maybe influence the quality of sperm, i.e. chromatin condensation, in primate testis (Moudgal and Sairam 1998). Several clinical studies in volunteers for endocrine male contraception also point to a particular FSH dependence of human spermatogenesis (see Chapter 23). In general, incomplete suppression of FSH secretion prevented the achievement of azoospermia.

Unlike for LH, there seems to be a need to further increase the sensitivity of FSH assays in order to be able to assess whether FSH has been completely suppressed or not in clinical studies (Robertson etal. 2001). Corroborating findings for a essential role of FSH were also obtained in similar studies in cynomolgus monkeys (Narula et al. 2002; Weinbauer et al. 2001b). In the latter study, an escape of FSH but not bioactive LH secretion during testosterone-induced suppression was followed promptly by an increase of inhibin B levels, testis size and sperm number. In the former study, levels of bioactive FSH correlated with the induction of oligozoosper-mia and azoospermia.

Whether FSH alone can initiate complete spermatogenesis during pubertal development is not entirely clear. FSH unequivocally stimulated testicular cell numbers in the species studied. In the rhesus monkey, administration ofhuman FSH preparations clearly increased spermatogonial and Sertoli cell numbers, and the development of some spermatocytes (Arslan etal. 1993; Ramaswamy etal. 1998; Schlatt et al. 1995). However, data on treating animals throughout a prolonged period of several weeks or months with species-specific FSH are lacking owing to insufficient amounts of appropriate preparations. In mice overexpressing either human FSH (Haywood etal. 2003) or human FSH receptor (Haywood etal. 2002) the spermato-genic process was initiated including the formation of postmeiotic cells and some degree of spermatid elongation. However, the complete spermatogenic process was not initiated.

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