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Questions And Answer

• Discovery

  This is a gonadotropic glycoprotein hormone secreted from the anterior pituitary. FSH stimulates follicular growth and estrogen production in the ovary and promotes spermatogenesis in the testis. In the 1960s, the purification and isolation of FSH were reported from the ovine, porcine, bovine, and human pituitaries. Human FSH was first fully purified in 1968. The aa sequence of the human FSH α-subunit and its identity with the luteinizing hormone (LH) α-subunit was demonstrated in 1974. The first aa sequence of the FSH β-subunit was also determined in 1974.;

• Structure

  FSH is a glycoprotein consisting of noncovalently linked glycoprotein hormone (GPH) α- and FSH β-subunits. The GPH α-subunit is common to LH, thyroid-stimulating hormone (TSH), and chorionic gonadotropin (CG). Both GPH α- and FSH β-subunits contain a cysteine-knot motif, which is critical for the heterodimer assembly and biological activity of FSH. The N- and O-linked oligosaccharide chains are important for the intracellular folding, secretion, metabolic clearance, and biological activity of FSH. Mr 25,000–41,000, pI 3.0–5.0. Multiple isoforms exist due to the microheterogeneity of oligosaccharide chains. Soluble in water, physiological saline solution, 50% alcohol, and 50% acetone; insoluble in alcohol, acetone, benzene, chloroform, and ether. Stable in 6 M urea; dissociated into two subunits in 1 M propionic acid.;

• Gene, mRNA, and precursor

  The human GPH α-subunit gene, CGA, location 6q12- q21, consists of four exons. Human GPH α-subunit mRNA has 397 b that encode a signal peptide of 24 aa residues and a mature protein of 92 aa residues. The human FSH β-subunit gene, FSHB, location 11p13, consists of three exons. Human FSH β-subunit mRNA has 506 b that encode a signal peptide of 19 aa residues and a mature protein of 110 aa residues. The GPH α- and FSH β-subunit genes are expressed in the basophilic gonadotropes in the anterior pituitary. In tetrapods, FSH and LH are coexpressed in gonadotropes, whereas they are produced in different cells in teleosts. The GPH α-subunit gene is also expressed in thyrotropes in the adenohypophysis and the placental trophoblast.
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• Synthesis and release

  The synthesis and release of FSH are regulated by gonadotropin-releasing hormone (GnRH); gonadotropin-inhibitory hormone (GnIH); gonadal proteins such as activin, inihibin, and follistatin; and the feedback effects of gonadal steroids.6, 7 In tetrapods, GnRH acts directly on gonadotropes and differentially regulates FSH and LH secretion through changes in the pattern of GnRH pulsatile secretion. GnIH inhibits FSH secretion in birds and mammals, whereas GnIH can stimulate and inhibit FSH secretion in fish depending on the species and reproductive status. Activin stimulates FSH secretion through binding to the activin receptor at the cell membrane of the gonadotropes, which is antagonized by the binding of inhibin and follistatin. FSH secretion is also regulated by gonadal steroids such as estradiol and progesterone. Gonadal steroids exert their effects at the level of the hypothalamus by changing GnRH secretion; and directly at the level of the gonadotropes, where they exert different effects, depending on the species and reproductive condition of the animals.;

• Receptors

  The receptor of FSH (FSHR) is a glycoprotein that belongs to a subclass of the rhodopsin/β-adrenergic subfamily of the membrane-bound GPCR superfamily. The human FSHR gene, FSHR, location 2p16.3, consists of 10 exons. The FSHR consists of 650–700 aa residues that contain a large N-terminal extracellular domain (~350 aa residues), seven transmembrane domains, and a C-terminal intracellular domain. The receptor mainly couples to the Gs protein, and FSH stimulates the production of cAMP in target cells.;

• Agonists and Antagonists

  Purified and recombinant human FSH, thiazolidinone compounds, cyclic and acyclic α- and β-aminocarboxamide derivatives, and biaryl derivatives are agonists. Antibodies to FSHR, aminoalkylamide derivatives, tetrahydroquinoline derivatives, 7-{4-[bis-(2-carbamoyl-ethyl)- amino]-6-chloro-(1,3,5)-triazin-2-ylamino)-4-hydroxy-3-(4- methoxy-phenylazo)-naphthalene}-2-sulfonic acid, and suramin (a nonselective FSHR-antagonist) are antagonists.;

• Clinical implications

  Hypergonadotropic ovarian dysgenesis is a disease characterized by a normal karyotype, highly elevated gonadotropins, and streaky gonads associated with primary amenorrhea. A mutation (Ala 189 Val) in the extracellular domain of FSHR is considered a probable cause of the disease. Functional studies revealed a lack of cAMP production by the mutated receptor upon FSH stimulation. FSH levels are useful in the investigation of menstrual irregularities, and in the diagnosis of pituitary disorders or diseases involving the ovaries or testes. Conditions with high FSH levels include premature menopause (i.e., premature ovarian failure), poor ovarian reserve, gonadal dysgenesis, Turner syndrome, Swyer syndrome, and Klinefelter syndrome. Conditions with low FSH levels include hypopituitarism, polycystic ovarian syndrome, Kallmann syndrome, Sheehan syndrome, and Chiari-Frommel syndrome.;

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