Role of FSH in the regulation of spermatogenesis: clinical aspects

IntroductionUnder normal conditions male reproduction in mammalsrequires four distinct components which have to interact in aconcerted fashion with female reproductive functions toguarantee successful procreation:•sperm as the actual carrier of genetic information and as thefertilizing agent;•semen as the transport medium for sperm;•organs to transfer semen into the female genital tract;•male sexual behaviour.In addition to genetic, neuronal and vascular integrity hormonesare essential for the regular function of the four components. Inparticular, the endocrine feedback-mechanism involvinghypothalamus, pituitary and testis is responsible for eachcomponent and their coordinated interplay. One hypothalamichormone, GnRH, is responsible for the release of twogonadotrophins, FSH and LH, and the exact role of the twogonadotrophins in male reproduction remains an enigma ofandrological research.Through mediation by speciﬁc receptors both gonadotro-phins act on the testis: LH on Leydig cells and FSH on Sertolicells, and it is unclear why the single hypothalamic signal istranslated into a dual pituitary signal controlling malereproductive functions. The early concept of regulation oftesticular function surmised that LH stimulates testosteroneproduction and FSH controls spermatogenesis (Greep, 1937). However, so far only one mammalian animal model could bediscovered where such a clear separation of the two functionsmay occur, i.e. the Djungarian hamster. In this seasonal breederFSH can induce full spermatogenesis and viable sperm(function 1 above) while testosterone appears to be requiredonly for functions 2–4 (Lerchl et al., 1993; Niklowitz et al.,1997). In most other mammals, in particular, in nonhuman andhuman primates the roles played by the two gonadotrophins inthe regulation of male reproductive functions appear to be muchmore closely interwoven. However, recent ﬁndings in geneti-cally manipulated mice have suggested that FSH may not berequired for spermatogenesis (e.g. Kumar et al., 1997; Dierichet al., 1998). Although extrapolating data from small laboratoryrodents to the humans has its limitations, these ﬁndings haveleft many clinicians in a quandary concerning the role of FSH inhuman spermatogenesis and its implications for diagnosis andtreatment of male hypogonadism and infertility.The purpose of this brief review is to summarize the currentknowledge about the role of FSH as distinct from that of LH andtestosterone in human male reproduction. Experimentalevidence from nonhuman primates as the most relevantanimal model is used to substantiate ﬁndings in humans.Since initiation of spermatogenesis may have differenthormonal requirements than maintenance of the process, thetwo situations are considered separately. Moreover, a distinc-tion between qualitatively and quantitatively normal sperma-togenesis will be drawn. The evidence cited for a role of FSHalone or LH/testosterone alone or for synergism of the twogonadotrophins is summarized in Tables 1 and 2.Role of FSH in the initiation of spermatogenesisPatients with hypogonadotrophic hypogonadism represent avaluable experimental model to study the role of gonado-trophins in spermatogenesis. Patients with secondaryhypogonadism due either to idiopathic hypogonadotrophichypogonadism (IHH) and Kallmann’s syndrome or to hypo-pituitarism can be effectively treated with pulsatile GnRH or acombination of both gonadotrophins in order to inducespermatogenesis and achieve fertility (Whitcomb & Crowley,1990; Burgues et al., 1997; Bu¨chter et al., 1998). Under thesetreatments sperm appear in the ejaculate and sperm concentra-tions increase progressively. However, sperm concentrationsreach normal values in only few patients, although this is notnecessary for the induction of pregnancy, and the time requiredto achieve a pregnancy can be quite variable (Bu¨chter et al.,1998). Under clinical conditions it appears that both gonadotro-phins, either stimulated by GnRH or given directly, are requiredto achieve fertility in such patients while FSH alone or incombination with low-dose testosterone is not able to inducefertility (Schaison et al., 1993). This failure of FSH treatmentto induce spermatogenesis in hypogonadotrophic patientscontrasts with the observation of the fertile eunuch syndrome,