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Mechanisms of FSH synthesis: what we know, what we don't, and why you should care

2010; Elsevier BV; Volume: 93; Issue: 8 Linguagem: Inglês

10.1016/j.fertnstert.2010.03.034

1556-5653

Daniel J. Bernard, Jérôme Fortin, Ying Wang, Pankaj Lamba,

Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities

The pituitary gonadotropin hormones, FSH and LH, are key regulators of reproductive physiology. Though the two hormones are produced by the same cell type, often in response to the same endocrine and paracrine regulators, they sub-serve different biological functions and their synthesis and secretion are differentially regulated. This stems largely from differences in transcriptional, post-transcriptional, and post-translational regulation of their unique β subunits. That is, both hormones are dimeric glycoproteins and share a common α subunit. Their unique β subunits, however, derive from different genes encoding distinct proteins. Past and recent research indicates synthesis and release of the two hormones are subject to extensive and independent regulation. LH appears to be secreted predominantly via the regulated secretory pathway, whereas FSH release is largely constitutive. As such, investigations of FSH-β subunit synthesis may lend direct insight into mechanisms underlying patterns of secreted FSH, more so than investigations of the LHβ subunit. Here, we review recent investigations of transcriptional regulation of the FSH-β subunit gene from different mammalian species, including humans. The results reveal both conserved and species-specific regulatory mechanisms that might contribute to inter-species variation in FSH release. The pituitary gonadotropin hormones, FSH and LH, are key regulators of reproductive physiology. Though the two hormones are produced by the same cell type, often in response to the same endocrine and paracrine regulators, they sub-serve different biological functions and their synthesis and secretion are differentially regulated. This stems largely from differences in transcriptional, post-transcriptional, and post-translational regulation of their unique β subunits. That is, both hormones are dimeric glycoproteins and share a common α subunit. Their unique β subunits, however, derive from different genes encoding distinct proteins. Past and recent research indicates synthesis and release of the two hormones are subject to extensive and independent regulation. LH appears to be secreted predominantly via the regulated secretory pathway, whereas FSH release is largely constitutive. As such, investigations of FSH-β subunit synthesis may lend direct insight into mechanisms underlying patterns of secreted FSH, more so than investigations of the LHβ subunit. Here, we review recent investigations of transcriptional regulation of the FSH-β subunit gene from different mammalian species, including humans. The results reveal both conserved and species-specific regulatory mechanisms that might contribute to inter-species variation in FSH release. The gonadotropins FSH and LH are synthesized and secreted by gonadotrope cells of the anterior pituitary gland. Both hormones are noncovalently linked dimeric glycoproteins consisting of a common α-subunit (chorionic gonadotropin alpha [CGA]) and unique β-subunits (FSH-β and LH-β). The latter confer biologic specificity to the two ligands. FSH and LH play necessary and complementary roles in the control of mammalian reproduction. In female mammals, FSH stimulates ovarian follicle growth and maturation, as well as E2 synthesis by granulosa cells, whereas LH stimulates androgen production by theca cells and ovulation of the dominant follicle(s). The necessity for FSH in female reproduction is clearly demonstrated both clinically and in animal models. Women with loss-of-function mutations in the FSHB or FSH receptor (FSHR) genes present clinically with primary or secondary amenorrhea and associated arrest in follicle development at the preantral stage (see reviews [1Huhtaniemi I.T. Themmen A.P. Mutations in human gonadotropin and gonadotropin-receptor genes.Endocrine. 2005; 26: 207-217Crossref PubMed Scopus (45) Google Scholar, 2Themmen A.P.N. Huhtaniemi I.T. Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function.Endocr Rev. 2000; 21: 551-583Crossref PubMed Google Scholar, 3Themmen A.P. An update of the pathophysiology of human gonadotrophin subunit and receptor gene mutations and polymorphisms.Reproduction. 2005; 130: 263-274Crossref PubMed Scopus (36) Google Scholar]). Similar phenotypes are observed in Fshb- and Fshr-deficient (knockout) mice (4Kumar T.R. Wang Y. Lu N. Matzuk M.M. Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility.Nat Genet. 1997; 15: 201-204Crossref PubMed Scopus (679) Google Scholar, 5Danilovich N. Babu P.S. Xing W. Gerdes M. Krishnamurthy H. Sairam M.R. Estrogen deficiency, obesity, and skeletal abnormalities in follicle-stimulating hormone receptor knockout (FORKO) female mice.Endocrinology. 2000; 141: 4295-4308Crossref PubMed Google Scholar, 6Dierich A. Sairam M.R. Monaco L. Fimia G.M. Gansmuller A. LeMeur M. Sassone-Corsi P. Impairing follicle-stimulating hormone (FSH) signaling in vivo: targeted disruption of the FSH receptor leads to aberrant gametogenesis and hormonal imbalance.Proc Natl Acad Sci U S A. 1998; 95: 13612-13617Crossref PubMed Scopus (420) Google Scholar). In male mammals, LH stimulates androgen production by interstitial Leydig cells. Although FSH targets Sertoli cells in the testes to regulate spermatogenesis, its absolute necessity for reproduction has been a matter of some debate. Men homozygous for one particular inactivating mutation in the FSHR gene have variable extents of oligozoospermia, and two of those five men fathered children (one was infertile and two of unknown reproductive status) (7Tapanainen J.S. Aittomaki K. Min J. Vaskivuo T. Huhtaniemi I.T. Men homozygous for an inactivating mutation of the follicle-stimulating hormone (FSH) receptor gene present variable suppression of spermatogenesis and fertility.Nat Genet. 1997; 15: 205-206Crossref PubMed Scopus (301) Google Scholar). Similarly, male Fshr-deficient mice have reduced testis size and sperm counts but are fertile (4Kumar T.R. Wang Y. Lu N. Matzuk M.M. Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility.Nat Genet. 1997; 15: 201-204Crossref PubMed Scopus (679) Google Scholar). These data suggest that FSH plays a role in maintaining quantitatively normal spermatogenesis, but may not be fundamentally required for fertility in males. However, men with inactivating mutations in the FSHB subunit gene, who are unable to produce the dimeric ligand, are azoospermic (8Layman L.C. Porto A.L. Xie J. da Motta L.A. da Motta L.D. Weiser W. Sluss P.M. FSH β gene mutations in a female with partial breast development and a male sibling with normal puberty and azoospermia.J Clin Endocrinol Metab. 2002; 87: 3702-3707Crossref PubMed Scopus (50) Google Scholar, 9Phillip M. Arbelle J.E. Segev Y. Parvari R. Male hypogonadism due to a mutation in the gene for the β-subunit of follicle-stimulating hormone.N Engl J Med. 1998; 338: 1729-1732Crossref PubMed Scopus (140) Google Scholar, 10Berger K. Souza H. Brito V.N. d'Alva C.B. Mendonca B.B. Latronico A.C. Clinical and hormonal features of selective follicle-stimulating hormone (FSH) deficiency due to FSH β-subunit gene mutations in both sexes.Fertil Steril. 2005; 83: 466-470Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 11Lindstedt G. Nystrom E. Matthews C. Ernest I. Janson P.O. Chatterjee K. Follitropin (FSH) deficiency in an infertile male due to FSHβ gene mutation. A syndrome of normal puberty and virilization but underdeveloped testicles with azoospermia, low FSH but high lutropin and normal serum testosterone concentrations.Clin Chem Lab Med. 1998; 36: 663-665Crossref PubMed Scopus (95) Google Scholar). Other cases of idiopathic isolated FSH deficiency have also been reported and are similarly associated with azoospermia or oligoteratozoospermia and infertility (12Mantovani G. Borgato S. Beck-Peccoz P. Romoli R. Borretta G. Persani L. Isolated follicle-stimulating hormone (FSH) deficiency in a young man with normal virilization who did not have mutations in the FSHβ gene.Fertil Steril. 2003; 79: 434-436Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 13Giltay J.C. Deege M. Blankenstein R.A. Kastrop P.M. Wijmenga C. Lock T.T. Apparent primary follicle-stimulating hormone deficiency is a rare cause of treatable male infertility.Fertil Steril. 2004; 81: 693-696Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar). In contrast, male Fshb-deficient mice have similar phenotypes to Fshr knockout animals and are fertile (4Kumar T.R. Wang Y. Lu N. Matzuk M.M. Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility.Nat Genet. 1997; 15: 201-204Crossref PubMed Scopus (679) Google Scholar). At a minimum, these data suggest that FSH may be required for the initiation of spermatogenesis during development in humans, but not in rodents. FSH synthesis and secretion are regulated (both positively and negatively) by protein and steroidal factors from all levels of the hypothalamus-pituitary-gonadal (HPG) axis. Arguably, the most important stimulus for FSH is GnRH, a decapeptide secreted in pulsatile fashion from the hypothalamus into the pituitary portal vasculature. The necessity for GnRH in normal FSH regulation is clearly demonstrated in GnRH-deficient hypogonadal mice (hpg), which harbor a loss-of-function deletion mutation in the Gnhr1 gene (14Mason A.J. Hayflick J.S. Zoeller R.T. Young 3rd, W.S. Phillips H.S. Nikolics K. Seeburg P.H. A deletion truncating the gonadotropin-releasing hormone gene is responsible for hypogonadism in the hpg mouse.Science. 1986; 234: 1366-1371Crossref PubMed Scopus (0) Google Scholar). Mice homozygous for the mutation are hypogonadotropic and sexually immature (15Cattanach B.M. Iddon C.A. Charlton H.M. Chiappa S.A. Fink G. Gonadotrophin-releasing hormone deficiency in a mutant mouse with hypogonadism.Nature. 1977; 269: 338-340Crossref PubMed Scopus (228) Google Scholar). Although hypogonadotropic hypogonadism (HH) has similarly been reported in humans, emerging from mutations in a variety of genes, including the GnRH receptor (GNRHR), it was only recently that an inactivating GNRH1 mutation was described in siblings with HH (16Bouligand J. Ghervan C. Tello J.A. Brailly-Tabard S. Salenave S. Chanson P. et al.Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation.N Engl J Med. 2009; 360: 2742-2748Crossref PubMed Scopus (86) Google Scholar). There, a single base-pair insertion early in the GNRH1 coding sequence caused a frame-shift and consequently the absence of prepro-GNRH1 hormone production. Treatment of the affected individuals with pulsatile GnRH stimulated pulsatile LH secretion, indicating that, though required for gonadotropin secretion, GnRH is not required for gonadotrope development. Similar results are observed in hpg mice (17Charlton H.M. Halpin D.M. Iddon C. Rosie R. Levy G. McDowell I.F. et al.The effects of daily administration of single and multiple injections of gonadotropin-releasing hormone on pituitary and gonadal function in the hypogonadal (hpg) mouse.Endocrinology. 1983; 113: 535-544Crossref PubMed Google Scholar). GnRH is released in pulses, and the nature of these pulses (both amplitude and frequency) affects relative synthesis and secretion of FSH and LH. As reviewed previously (18Ferris H.A. Shupnik M.A. Mechanisms for pulsatile regulation of the gonadotropin subunit genes by GNRH1.Biol Reprod. 2006; 74: 993-998Crossref PubMed Scopus (49) Google Scholar, 19Marshall J.C. Dalkin A.C. Haisenleder D.J. Griffin M.L. Kelch R.P. GnRH pulses—the regulators of human reproduction.Trans Am Clin Climatol Assoc. 1993; 104: 31-46PubMed Google Scholar), rapid pulses (e.g., every 30 minutes) tend to favor LH release, whereas slower pulses (e.g., every 2–4 hours) preferentially stimulate FSH. Changes in pulse frequency might explain situations in which LH and FSH are differentially secreted (e.g., at the luteal-follicular phase transition of the menstrual cycle). Interestingly, FSH may not depend on pulsatile GnRH to the extent required for LH, at least not in rodents. For example, once-daily injections of GnRH are sufficient to stimulate dramatic increases in pituitary and plasma FSH, but not LH, in hpg mice (17Charlton H.M. Halpin D.M. Iddon C. Rosie R. Levy G. McDowell I.F. et al.The effects of daily administration of single and multiple injections of gonadotropin-releasing hormone on pituitary and gonadal function in the hypogonadal (hpg) mouse.Endocrinology. 1983; 113: 535-544Crossref PubMed Google Scholar). In addition, continuous GnRH also stimulates FSH (but not LH) secretion, while decreasing pituitary content of both gonadotropins, in hpg mice (20Gibson M.J. Kasowski H. Dobrjansky A. Continuous gonadotropin-releasing hormone infusion stimulates dramatic gonadal development in hypogonadal female mice.Biol Reprod. 1994; 50: 680-685Crossref PubMed Google Scholar). In humans and other primates, pulsatile GnRH appears to be necessary for both FSH and LH secretion (21Belchetz P.E. Plant T.M. Nakai Y. Keogh E.J. Knobil E. Hypophysial responses to continuous and intermittent delivery of hypopthalamic gonadotropin-releasing hormone.Science. 1978; 202: 631-633Crossref PubMed Google Scholar, 22Southworth M.B. Matsumoto A.M. Gross K.M. Soules M.R. Bremner W.J. The importance of signal pattern in the transmission of endocrine information: pituitary gonadotropin responses to continuous and pulsatile gonadotropin-releasing hormone.J Clin Endocrinol Metab. 1991; 72: 1286-1289Crossref PubMed Google Scholar). The bases for these interspecies differences are not yet known, but in the section “How do hormones turn FSH synthesis on (and off)? GnRH regulation of Fshb,” we discuss our current understanding of molecular mechanisms through which GnRH might regulate expression of the Fshb/FSHB gene in several species, including humans. Although changes in GnRH pulse dynamics may explain some differential regulation of FSH and LH, other members of the HPG axis also make important contributions. The activins, inhibins, and follistatins were all discovered based on their abilities to regulate FSH, but not LH, secretion from rat primary pituitary cultures (23Vale W. Rivier C. Hsueh A. Campen C. Meunier H. Bicsak T. et al.Chemical and biological characterization of the inhibin family of protein hormones.Recent Prog Horm Res. 1988; 44: 1-34PubMed Google Scholar, 24Ying S.Y. Inhibins, activins, and follistatins: gonadal proteins modulating the secretion of follicle-stimulating hormone.Endocr Rev. 1988; 9: 267-293Crossref PubMed Google Scholar, 25Bilezikjian L.M. Blount A.L. Leal A.M. Donaldson C.J. Fischer W.H. Vale W.W. Autocrine/paracrine regulation of pituitary function by activin, inhibin and follistatin.Mol Cell Endocrinol. 2004; 225: 29-36Crossref PubMed Scopus (67) Google Scholar). In vivo studies in rats and other species confirmed the stimulatory effect of activins and inhibitory actions of inhibins and follistatins on FSH release. From the basic scientist's perspective, the activins are arguably the most interesting members of this trinity of FSH-selective regulatory molecules. As described in greater detail in the section “How do hormones turn FSH synthesis on (and off)? Activin regulation of Fshb,” they stimulate intracellular signaling that culminates in enhanced expression of the Fshb subunit and subsequent dimeric hormone secretion. Current data suggest that inhibins and follistatins produce their effects on FSH by antagonizing activins' actions rather than by actively initiating signaling events. Inhibins, which are structurally related to activins, are secreted by testicular Sertoli cells and ovarian granulosa cells and act in endocrine fashion to suppress FSH synthesis and secretion. They bind to activin receptors on gonadotropes, but do not promote the assembly of active signaling complexes. Instead, through competitive antagonism, they prevent activins from producing their stimulatory effects. A coreceptor, betaglycan (also known as the transforming growth factor β [TGF-β] type III receptor [TGFBR3]), increases inhibin affinity for activin receptors, thereby making it a very potent antagonist (26Gray P.C. Bilezikjian L.M. Vale W. Antagonism of activin by inhibin and inhibin receptors: a functional role for βglycan.Mol Cell Endocrinol. 2002; 188: 254-260Crossref PubMed Google Scholar, 27Lewis K.A. Gray P.C. Blount A.L. MacConell L.A. Wiater E. Bilezikjian L.M. Vale W. β-Glycan binds inhibin and can mediate functional antagonism of activin signalling.Nature. 2000; 404: 411-414Crossref PubMed Scopus (344) Google Scholar). Follistatins, which are ubiquitously expressed (including in gonadotropes), are structurally distinct from activins and inhibins, but bind to activins with high affinity, preventing receptor binding (28Esch F.S. Shimasaki S. Mercado M. Cooksey K. Ling N. Ying S. et al.Structural characterization of follistatin: a novel follicle-stimulating hormone release-inhibiting polypeptide from the gonad.Mol Endocrinol. 1987; 1: 849-855Crossref PubMed Google Scholar, 29Ying S.Y. Becker A. Swanson G. Tan P. Ling N. Esch F. et al.Follistatin specifically inhibits pituitary follicle stimulating hormone release in vitro.Biochem Biophys Res Commun. 1987; 149: 133-139Crossref PubMed Google Scholar, 30Thompson T.B. Lerch T.F. Cook R.W. Woodruff T.K. Jardetzky T.S. The structure of the follistatin:activin complex reveals antagonism of both type I and type II receptor binding.Dev Cell. 2005; 9: 535-543Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). Follistatins also promote internalization and degradation of activins (31Cash J.N. Rejon C.A. McPherron A.C. Bernard D.J. Thompson T.B. The structure of myostatin:follistatin 288: insights into receptor utilization and heparin binding.EMBO J. 2009; 28: 2662-2676Crossref PubMed Scopus (24) Google Scholar, 32Hashimoto O. Nakamura T. Shoji H. Shimasaki S. Hayashi Y. Sugino H. A novel role of follistatin, an activin-binding protein, in the inhibition of activin action in rat pituitary cells. Endocytotic degradation of activin and its acceleration by follistatin associated with cell-surface heparan sulfate.J Biol Chem. 1997; 272: 13835-13842Crossref PubMed Scopus (119) Google Scholar). The net result is less bioavailable activins and therefore a loss of positive drive on FSH biosynthesis. In light of these actions of inhibins and follistatins, we will focus on mechanisms of activin signaling in gonadotropes for the purposes of the present review. Multiple forms of the activins have been described, but from the perspective of reproductive biology, activins A, B, and AB appear to be most relevant (33Lau A.L. Kumar T.R. Nishimori K. Bonadio J. Matzuk M.M. Activin βC and βE genes are not essential for mouse liver growth, differentiation, and regeneration.Mol Cell Biol. 2000; 20: 6127-6137Crossref PubMed Scopus (81) Google Scholar, 34Matzuk M.M. Kumar T.R. Shou W. Coerver K.A. Lau A.L. Behringer R.R. Finegold M.J. Transgenic models to study the roles of inhibins and activins in reproduction, oncogenesis, and development.Recent Prog Horm Res. 1996; 51 (discussion 155–127): 123-154PubMed Google Scholar). The proteins are members of the TGF-β superfamily and, as such, are disulfide-linked dimeric proteins. Activin/inhibin βA (INHBA) and βB (INHBB) are distinct genes whose protein products homo- or heterodimerize to form activins A, B, or AB. Historically, most studies have relied on activin A because this was the activin subtype first made recombinantly in quantities sufficient for experimentation (35Schwall R.H. Nikolics K. Szonyi E. Gorman C. Mason A.J. Recombinant expression and characterization of human activin A.Mol Endocrinol. 1988; 2: 1237-1242Crossref PubMed Google Scholar). Interestingly, however, activin B may be the more relevant form with respect to FSH regulation. Although the proteins were first purified from ovarian follicular fluid and presumed to act in endocrine fashion on the pituitary, subsequent studies suggested that their effects are more likely to be autocrine or paracrine (36Welt C.K. Crowley Jr., W.F. Activin: an endocrine or paracrine agent?.Eur J Endocrinol. 1998; 139: 469-471Crossref PubMed Google Scholar). Rat gonadotropes as well as immortalized murine gonadotropes (LβT2 cells; see section “What enables gonadotrope cells to uniquely synthesize the FSH-β subunit? LβT2 cells: the long-awaited players”) make activin B, but not activin A, and immunoneutralization studies in rat and ovine primary culture implicate activin B as the relevant intrapituitary ligand for FSH synthesis (37Baratta M. West L.A. Turzillo A.M. Nett T.M. Activin modulates differential effects of estradiol on synthesis and secretion of follicle-stimulating hormone in ovine pituitary cells.Biol Reprod. 2001; 64: 714-719Crossref PubMed Google Scholar, 38Corrigan A.Z. Bilezikjian L.M. Carroll R.S. Bald L.N. Schmelzer C.H. Fendly B.M. et al.Evidence for an autocrine role of activin B within rat anterior pituitary cultures.Endocrinology. 1991; 128: 1682-1684Crossref PubMed Google Scholar, 39Roberts V. Meunier H. 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Gardner H.A. Lee K.F. Jaenisch R. Activin/inhibin β B subunit gene disruption leads to defects in eyelid development and female reproduction.Genes Dev. 1994; 8: 414-427Crossref PubMed Google Scholar). This may, however, reflect compensation by another ligand, such as activin A, because deletion of the activin receptor Acvr2 in mice leads to dramatic declines in FSH production and release, with no apparent effect on LH (43Matzuk M.M. Kumar T.R. Bradley A. Different phenotypes for mice deficient in either activins or activin receptor type II.Nature. 1995; 374: 356-360Crossref PubMed Google Scholar, 44Kumar T.R. Agno J. Janovick J.A. Conn P.M. Matzuk M.M. Regulation of FSHβ and GnRH receptor gene expression in activin receptor II knockout male mice.Mol Cell Endocrinol. 2003; 212: 19-27Crossref PubMed Scopus (17) Google Scholar). Just as hpg mice underscore the essential role for GnRH in gonadotropin production, so to do the Acvr2-null mice emphasize the absolute necessity for activin or activin-like signaling in normal FSH synthesis and secretion, at least in rodents. In rodents, the current model posits that gonadotrope-derived activin B stimulates FSH synthesis and secretion via regulation of Fshb transcription (see section “How do hormones turn FSH synthesis on (and off)? Activin regulation of Fshb” for more details). Gonadally derived inhibins (inhibins A and B) act in endocrine fashion to suppress FSH production via competitive binding to activin receptors on gonadotropes, blocking the actions of locally derived activins. Although follistatins can be found in circulation, the majority are bound to activins, casting doubt on an endocrine role for the protein (45McConnell D.S. Wang Q. Sluss P.M. Bolf N. Khoury R.H. Schneyer A.L. et al.A two-site chemiluminescent assay for activin-free follistatin reveals that most follistatin circulating in men and normal cycling women is in an activin-bound state.J Clin Endocrinol Metab. 1998; 83: 851-858Crossref PubMed Scopus (54) Google Scholar). Likewise, circulating activin A is predominantly bound to follistatins and other serum proteins, suggesting that the interplay between follistatins and activins in target tissues is likely to reflect autocrine/paracrine actions of the proteins (46Muttukrishna S. Fowler P.A. George L. Groome N.P. Knight P.G. Changes in peripheral serum levels of total activin A during the human menstrual cycle and pregnancy.J Clin Endocrinol Metab. 1996; 81: 3328-3334Crossref PubMed Scopus (143) Google Scholar). Indeed, there is good evidence to suggest that intrapituitary follistatins antagonize pituitary-derived activin stimulation of FSH production in rodents (47Besecke L.M. Guendner M.J. Sluss P.A. Polak A.G. Woodruff T.K. Jameson J.L. Bauer-Dantoin A.C. Weiss J. Pituitary follistatin regulates activin-mediated production of follicle-stimulating hormone during the rat estrous cycle.Endocrinology. 1997; 138: 2841-2848Crossref PubMed Scopus (52) Google Scholar). A role for the activin-inhibin-follistatin system in regulating FSH in humans has been more difficult to establish (48Lahlou N. Chabbert-Buffet N. Christin-Maitre S. Le Nestour E. Roger M. Bouchard P. Main inhibitor of follicle stimulating hormone in the luteal-follicular transition: inhibin A, oestradiol, or inhibin B?.Hum Reprod. 1999; 14: 1190-1193Crossref PubMed Scopus (51) Google Scholar), although mounting evidence strongly implicates activins as positive regulators of FSH in our species. As in rodents, activin B is expressed in human gonadotropes (49Uccella S. La Rosa S. Genasetti A. Capella C. Localization of inhibin/activin subunits in normal pituitary and in pituitary adenomas.Pituitary. 2000; 3: 131-139Crossref PubMed Scopus (17) Google Scholar). Activin A stimulates FSH secretion and/or FSHB mRNA levels in fetal human pituitary cultures as well as in some pituitary adenomas (50Alexander J.M. Jameson J.L. Bikkal H.A. Schwall R.H. Klibanski A. The effects of activin on follicle-stimulating hormone secretion and biosynthesis in human glycoprotein hormone-producing pituitary adenomas.J Clin Endocrinol Metab. 1991; 72: 1261-1267Crossref PubMed Google Scholar, 51Takano K. Yamashita N. Kojima I. Kitaoka M. Teramoto A. Ogata E. Effects of activin A and somatostatin on intact FSH secretion and intracellular Ca2+ concentration in human FSH-secreting pituitary adenoma cells.Biochem Biophys Res Commun. 1992; 182: 1408-1415Crossref PubMed Google Scholar, 52Blumenfeld Z. Ritter M. Inhibin, activin, and follistatin in human fetal pituitary and gonadal physiology.Ann N Y Acad Sci. 2001; 943: 34-48Crossref PubMed Google Scholar). In perimenopausal women, increases in serum FSH are associated with decreased levels of inhibin B (53MacNaughton J. Banah M. McCloud P. Hee J. Burger H. Age related changes in follicle stimulating hormone, luteinizing hormone, oestradiol and immunoreactive inhibin in women of reproductive age.Clin Endocrinol (Oxf). 1992; 36: 339-345Crossref PubMed Google Scholar, 54Reame N.E. Wyman T.L. Phillips D.J. de Kretser D.M. Padmanabhan V. Net increase in stimulatory input resulting from a decrease in inhibin B and an increase in activin A may contribute in part to the rise in follicular phase follicle-stimulating hormone of aging cycling women.J Clin Endocrinol Metab. 1998; 83: 3302-3307Crossref PubMed Scopus (96) Google Scholar, 55Klein N.A. Illingworth P.J. Groome N.P. McNeilly A.S. Battaglia D.E. Soules M.R. Decreased inhibin B secretion is associated with the monotropic FSH rise in older, ovulatory women: a study of serum and follicular fluid levels of dimeric inhibin A and B in spontaneous menstrual cycles.J Clin Endocrinol Metab. 1996; 81: 2742-2745Crossref PubMed Scopus (278) Google Scholar). The idea here, of course, is that in the face of reduced endocrine inhibins, pituitary activins are less inhibited in their signaling in gonadotropes. Along these lines, a soluble form of the activin type II receptor (ACVR2), which binds and bioneutralizes activins, inhibits FSH release in postmenopausal women (56Borgstein N.G. Yang Y. Condon C.H. Haltom E. Sherman M.L. ACE-011, a soluble activin receptor type IIA IgG-Fc fusion protein, decreases follicle stimulating hormone and increases bone-specific alkaline phosphatase, a marker of bone formation, in postmenopausal healthy women.Cancer Res. 2009; 69: 1160Crossref Google Scholar). These and other observations (57Welt C.K. Hall J.E. Adams J.M. Taylor A.E. Relationship of estradiol and inhibin to the follicle-stimulating hormone variability in hypergonadotropic hypogonadism or premature ovarian failure.J Clin Endocrinol Metab. 2005; 90: 826-830Crossref PubMed Scopus (27) Google Scholar, 58McLachlan R.I. Dahl K.D. Bremner W.J. Schwall R. Schmelzer C.H. Mason A.J. Steiner R.A. Recombinant human activin-A stimulates basal FSH and GnRH-stimulated FSH and LH release in the adult male macaque, Macaca fascicularis.Endocrinology. 1989; 125: 2787-2789Crossref PubMed Google Scholar, 59Stouffer R.L. Dahl K.D. Hess D.L. Woodruff T.K. Mather J.P. Molskness T.A. Systemic and intraluteal infusion of inhibin A or activin A in rhesus monkeys during the luteal phase of the menstrual cycle.Biol Reprod. 1994; 50: 888-895Crossref PubMed Google Scholar, 60Stouffer R.L. Woodruff T.K. Dahl K.D. Hess D.L. Mather J.P. Molskness T.A. Human recombinant activin-A alters pituitary luteinizing hormone and follicle-stimulating hormone secretion, follicular development, and steroidogenesis, during the menstrual cycle in rhesus monkeys.J Clin Endocrinol Metab. 1993; 77: 241-248Crossref PubMed Scopus (36) Google Scholar) strongly implicate a role for activins in human FSH synthesis and secretion. In the section “How do hormones turn FSH synthesis on (and off