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Usage

Uses

Follicle stimulating hormone is used in various applications across different industries, including:
1. Used in Biomedical Research:
FSH is used as a research tool for in vitro luteinization of Macaque granulosa cells, luteal cell proliferation assays, culturing of preantral follicle cells obtained from mice, in vitro maturation of immature cumulus-oocyte complexes (COCs) obtained from mice, and culture of RAW264.7 cell line.
2. Used in Infertility Treatment:
Recombinant human FSH is used as a therapeutic agent for the treatment of infertility and to stimulate follicular development. It is produced by introducing the genes for the αand β-FSH subunits into the genome of Chinese hamster ovary cells, resulting in a glycosylated bioactive dimer that appears to be identical to urinary human FSH.
3. Used in Ovulation Induction:
FSH is used as an ovulation induction agent in clomiphene-resistant anovulation and controlled ovarian hyperstimulation. Transfected Chinese hamster ovary cells with plasmids containing the genes encoding the αand β-FSH subunits produce recombinant FSH that is similar to urinary FSH.
4. Used in Pharmaceutical Industry:
Gonal-F and Purge are examples of recombinant follicle-stimulating hormone (recFSH) products launched in various countries for the treatment of infertility and ovulation induction. These products offer ultra-high purity and reduced side effects compared to urinary-derived FSH.
5. Used in Drug Development:
Agonists and antagonists of FSH, such as purified and recombinant human FSH, thiazolidinone compounds, cyclic and acyclic αand β-aminocarboxamide derivatives, biaryl derivatives, antibodies to FSHR, aminoalkylamide derivatives, tetrahydroquinoline derivatives, and suramin, are used in the development of new drugs targeting FSH receptors for various therapeutic applications.
Chemical Properties:
FSH is a solid that is soluble in water.

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.

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.

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.

Originator

Genzyme (Switzerland)

Biological Functions

Follitropins are hormonal products that consist entirely of FSH and are used to stimulate ovarian follicle growth in women who do not have primary ovarian failure. In the absence of an adequate endogenous LH surge, however, hCG must be given following the use of follitropins to stimulate ovulation.

Biochem/physiol Actions

FSH (follicle stimulating hormone) in involved in the growth of ovarian follicles and steroidogenesis of ovaries. FSHR (follicle stimulating hormone receptor) interacts with FSH in the ovaries, and determines the responsiveness to this hormone. Depressed levels of FSHR result in poor responsiveness and influence folliculogenesis. In Caucasian population, certain polymorphisms in FSHR gene are more commonly found in patients with polycystic ovary syndrome (PCOS). In male fetus and neonates, it facilitates the proliferation of Sertoli cells. In pubescent males, it stimulates spermatogonia to undergo mitosis.

Clinical Use

The gonadotropin follicle-stimulating hormones (FSH), follitropin alfa (Gonal-F) and follitropin beta (Follistim), are produced in the anterior lobe of the pituitary gland. FSH can function in two ways. On the one hand, it causes increased spermatogenesis in men. On the other hand, in concert with estrogen and luteinizing hormone (LH), it stimulates follicular growth and development in women. Consequently, FSH may be useful in the treatment of infertility. FSH is a member of a superfamily of proteins, all structurally related, which includes LH, chorionic gonadotropin, and thyroid-stimulating hormone (TSH).

Purification Methods

FSH is purified by Sephadex G100 gel filtration followed by carboxymethyl-cellulose with NH4OAc pH 5.5. The latter separates luteinising hormone from FSH. Its solubility in H2O is 0.5%. It has an isoelectric point of 4.5. A solution of 1mg in saline (100mL) can be kept at 60o for 0.5hour. Activity is retained in a solution at pH 7-8 for 0.5hour at 75o. The activity of a 50% aqueous EtOH solution is destroyed at 60o in 15minutes. [Bloomfield et al. Biochim Biophys Acta 533 371 1978, Hartree Biochem J 100 754 1966, Pierce & Parsons Ann Rev Biochem 50 465 1981.]