There are both similarities and differences in how FSH secretion is regulated when compared to LH. The synthesis and secretion of LH as well as FSH is stimulated by GnRH and suppressed by gonadal steroid hormones through GnRH suppression. However, two paracrine factors, pituitary activin and follistatin, and testicular inhibin-B selectively regulate FSH secretion by regulating FSH-P gene expression (67). Because of these unique control mechanisms for FSH, LH and FSH secretion are sometimes dissociated.
Activin, a member of the TGF-P family of growth factors, stimulates FSH-P mRNA transcription and prolongs FSH-P mRNA half-life (68-70). Activin is a dimeric peptide composed of two similar subunits that were designated as P-subunits because the identification of activin followed the cloning of inhibin, an a-P heterodimer. There are at least four forms the P subunit: PA, PB, PC, and PD. The pituitary expresses PB, and activin-B (PbPb) is the predominate form in the pituitary, whereas most other tissues produce activin-A. Activin functions in neural and mesodermal morphogenesis, wound healing, vascular remodeling, and inflammation, as well as in reproduction (71-74).
In the process of activin signaling (see Fig. 6), a series of events, including the activation of intracellular messengers, is involved. Initially, the activin ligand binds to a specific type II receptor subunit, either ActRII or IIB (75-77). Subsequent to ligand binding, the type II subunit pairs with a type I receptor subunit (either ActRI or IB) and forms a heteromeric complex at the cell surface (78-80). It is believed that the serine/threonine kinase of the type II subunit is responsible for phosphorylation of the type I subunit, thereby initiating postreceptor signaling/phosphorylation (see 81 for review). Although several potential postreceptor targets have been proposed, the best characterized family involved in activin signaling includes the mothers against dpp-related (Smad) proteins (see 81-83 for reviews).
The initial family member, MAD, was identified in Drosophila and was downstream to the BMP receptor (also a member of the TGF-P family) (84). Thereafter, the mammalian Smads were identified (85-92). In relation to the activin response system, Smad-2 and Smad-3 are primarily involved, partnering with Smad-4 (also known as DPC4) to convey the postreceptor signal to the nucleus (85-89). The Smad-2 gene product, when overexpressed in Xenopus ectodermal explants, induces mesodermal differentiation similar to activin (85,90). Yet, both Smad-2 and Smad-3 associate with activin receptors (and TGF-P receptors for the Smad-3), whereby after activin/activin receptor binding, they undergo phosphorylation and then translocation from cytoplasm to nucleus (81,87,89,91).
Activin actions may use the signaling Smads in a tissue-specific fashion. In the rat ovary, Smad-2 mRNA and protein expression are significantly higher and may vary with follicular development when compared with Smad-3 mRNA, which was expressed at a low, constant level (92). A nuclear target for Smad-2 is likely in mammals in light of data obtained in Xenopus, where Smad-2 is involved in the activin-mediated activation of the MIX.2 gene via binding to FAST-1 (a winged-helix DNA-binding protein now known as FoxH1) (93). In addition, a second forkhead domain protein, FAST2, may play a role in the transduction of activin signals to the nucleus (94). Smad-2 expression is also likely to be under physiologic regulation, with protein content increasing in granulosa cells during follicular development and Smad-2 protein and mRNA concentrations increasing with TGF-P treatment (95).
As noted previously, Smad-2 mediated actions likely involve association with Smad-4 and the formation of hetero-oligomers (86). Smad-4 is essential for activin signaling, because transfection of a constitutively active Smad-4 construct alone can induce activin-like effects, whereas cellular expression of Smad-2 alone does not confer responsiveness (86). Furthermore, the Smad-2/3 binding to Smad-4 may represent an additional regulatory site in light of data suggesting the presence of "inhibitory" Smads. Smad-6 and -7 do not contain a C-terminal region required for phosphorylation and, therefore, their activation is not regulated by kinases (89,96). Data regarding physiologic regulation of the inhibitory Smads' gene or protein expression are currently lacking, but TGF-P can rapidly (30-60 min) induce Smad-7 mRNA expression in COS cells (97). Therefore, alteration in Smad-7 (or Smad-6) could represent an important mechanism in modulating activin action.
Activin actions are antagonized by follistatin that binds to and neutralizes the bioac-tivity of activin, as well as by inhibin that competes with activin for binding to the activin receptor (98). Inhibin is an antagonist of activin because it fails to initiate intracellular SMAD signaling. Betaglycan, a membrane proteoglycan, functions as an accessory receptor binding protein for inhibin, as well as for TGF-P, and functions in inhibin suppression of activin signaling (99). Follistatin is structurally unrelated to activin and inhibin but, like activin, is found in all tissues examined. In the rat pituitary gland, follistatin is upregulated by activin, GnRH, and pituitary adenylate cyclase-acti-vating polypeptide (PACAP) and is suppressed by testosterone and by follistatin, no doubt through binding to activin. In primate pituitary cultures, on the other hand, GnRH is ineffective, and testosterone, as well as activin, increases follistatin expression (100). Pituitary follistatin influences the FSH and LH response to castration. Follistatin expression increases after orchidectomy in adult male rats (101), and there is a reciprocal relationship over time between follistatin and FSH-P gene expression, implying that follistatin attenuates the FSH castration response in that species. In male primates, including man, by contrast, the follistatin mRNA level is unaffected by bilateral orchidectomy and FSH-P mRNA increases approx 50-fold (55). Thus, follistatin functions as a brake on FSH production in male rodents but not in primates.
Inhibin is produced by Sertoli cells and by fetal Leydig cells and plays a fundamental role in the selective regulation of FSH (102). Inhibin may also be an intragonadal regulator, but that function of inhibin is less well understood. The term inhibin was first applied in 1932 (103) to the aqueous extract of bull testis that prevented the development of castration cells within the anterior pituitary and was distinguished from androitin, which was present in the ether extract and stimulated prostate growth, and is now known as testosterone.
Inhibin is a heterodimer of an a-subunit and one of two P-subunits, PA and PB. Of these, only the PB subunit is expressed by the testis, and, therefore, testicular inhibin is inhibin B. The inhibin a-subunit gene is upregulated by FSH, whereas the factors regulating the PB subunit gene are not well understood. The level of inhibin/activin PB mRNA in the rat testis is unaffected by hypophysectomy or by FSH treatment (103 a). Transcription factors of the GATA-binding protein family regulate both the inhibin P-and the a-subunit promoters (104). Control of inhibin PB by a germ cell factor is suggested by the decline in plasma inhibin-B levels, but not inhibin-a subunit levels, that follow destruction of germ cells by cancer chemotherapy (105).
Because inhibin suppresses FSH secretion (106), plasma inhibin-B and FSH concentrations are inversely related in normal men and are more strongly correlated inversely when values from men with primary testicular failure are included in the analysis (107). The relationship between circulating inhibin-B and FSH in normal men differs from that between serum LH and testosterone, which is bidirectional. Consequently, there is no correlation between circulating LH and testosterone among normal men. The different relationships between plasma LH with testosterone compared to FSH with inhibin-B levels was clearly demonstrated in experiments conducted by Ramaswamy et al. (108). These investigators removed one testis from adult male rhesus monkeys, after which the plasma levels of both testosterone and inhibin B decreased. However, the decline in testosterone was brief and was restored to normal by a rise in LH, whereas inhibin-B levels remained at approx 50% of baseline values for up to 6 wk, even though FSH levels rose. Similarly, Anawalt et al. (107) found that large FSH doses were required to increase circulating inhibin B levels in normal men. Thus, LH and testosterone form a classical feed-forward/feedback loop in adults, whereas inhibin-B controls FSH but is less dependent on FSH stimulation. Inhibin-B levels increase during the neonatal phase of development and again at puberty. Although plasma LH and FSH levels rise at these developmental stages, the number of Sertoli cells also increases. Furthermore, studies in adult monkeys showed a strong positive correlation between circulating inhibin-B levels and Sertoli cell number (109).
Thus, circulating inhibin-B reflects the number and function of Sertoli cells and is less dependent on FSH stimulation.
FSH activates a G protein-associated seven-transmembrane Sertoli cell receptor (110). The activated receptor stimulates adenylate cyclase and increases intracellular cAMP levels. Numerous Sertoli cell genes are activated by cAMP, most often through cAMP-dependent PKA, with subsequent phosphorylation of the CREB transcription factor. The role of FSH in spermatogenesis is, however, a matter of controversy (see Chapter 6). The classical view was that FSH stimulates spermatogenesis and that LH stimulated testosterone production. However, spermatogenesis is qualitatively maintained by testosterone alone in hypophysectomized rats or in rats immunized against GnRH. More recently, men with an inactivating mutation of the FSH-R gene were identified in Finland. The testes of the five homozygous men were reduced in size and the sperm count and or motility was reduced, but two men were fertile (111). Moreover, an FSH-P-deficient mouse was developed, and was likewise fertile (112), implying that FSH is not essential for male fertility. On the other hand, spermatogenesis is not quantitatively normal in these models, and FSH acts synergistically with testosterone in rodents or with hCG in men, implying a role for FSH receptor activation in spermatogenesis. Species differences in the progression of undifferentiated spermato-gonia and in the production of FSH independent of GnRH, may explain why FSH is less important in rodents than in primates.
Activin, inhibin, and follistatin may also act locally in the testes to regulate reproductive function. Activin receptor gene expression has been detected in Sertoli cells, primary spermatocytes and round spermatids, and radiolabeled activin-A binding has been demonstrated in the latter cell types (113-115). Both proposed inhibin receptors, betaglycan and InhBP/p120, are present in rat Ledig cells (99,116), and betaglycan is expressed in germ cells (117). In general, activin treatment reduces hCG-driven Ley-dig cell production of androgens (118), whereas inhibin action can prevent activin effects (118) and stimulates testosterone release in some (119), but not all (120), studies. In terms of actions on gamete production, activin and inhibin have opposing actions with activin-stimulating (121) and inhibin-reducing (122,123) spermatogene-sis. Thus, the balance of activin and inhibin (and potentially follistatin), directly in the testes, may affect both endocrine signals via altered testosterone production, as well as gamete maturation.
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