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.
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.
Description
Puregon was launched in Denmark, Germany and the UK for ovulation
induction in clomiphene-resistent anovulation and controlled ovarian
hyperstimulation. Transfected Chinese hamster ovary cells with plasmids containing
the genes encoding the α- and β-FSH subunits produced recFSH that was similar to
uroFSH. In both cases (follitropin α and β) no antibody formation was detected,
however, this form appeared to be more active than follitropin α in that there was a
25% greater pregnancy rate compared to uroFSH.
Description
Gonal-F was launched in Austria, Germany, Denmark, Ireland, Italy,
Norway, Sweden, Switzerland, France and the UK for the treatment of infertility. The
recombinant follicule stimulating hormone (recFSH) was produced by introducing the
genes for the α- and β-FSH subunits into the genome of Chinese hamster ovary cells.
The isolated recFSH was a glycosylated bioactive dimer that appeared to be identical
to urinary human FSH. Biochemically, the recFSH was equal to or slightly better to
the uroFSH. The ultra-high purity of recFSH makes it less prone to side effects from
contaminants in uroFSH and can be injectable.
Chemical Properties
Solid; soluble in water.
Originator
Genzyme (Switzerland)
Originator
Organon (Netherlands)
Uses
A major gonadotropin secreted by the adenohypophysis (PITUITARY GLAND, ANTERIOR). Follicle-stimulating hormone stimulates GAMETOGENESIS and the supporting cells such as the ovarian GRANULOSA CELLS, the testicular SERTOLI CELLS, and LEYDIG CELLS. FSH consi
Uses
Recombinant human FSH is used for the treatment of
infertility and to stimulate follicular development.
Recently, it has been well known that the majority of
gonadotroph adenomas are clinically silent/nonfunctioning and difficult to identify. They are poorly differentiated and produce and secrete hormones inefficiently.
These hormones include FSH β-, LH β-, and GPH
α-subunits.
Uses
Follicle stimulating hormone (FSH) from human pituitary has been used for-
- in vitro luteinization of Macaque granulosa cells
- luteal cell proliferation assay
- 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
Definition
A gonadotropic glycoprotein secreted by the anterior
pituitary gland. It regulates the metabolic activity of
the granulosa of the mammalian ovary; stimulates
maturation of ovarian follicles, and production of
estrogens. Spermatogenesis is partially under
brand name
Humegon (Organon); Pergonal (Serono).
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.
General Description
The α chain of FSHhas 89 amino acids and the β chain has 115 amino acids. The α chain is not active. FSH belongs to glycoprotein hormone family. It is secreted by the gonadotropic cells of pituitary gland.
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.]
Description
FSH Porcine is a glycoprotein produced from pituitaries of porcine. The FSH is purified by proprietary chromatographic techniques.
Background
Follicle stimulating hormone (FSH) is a hormone synthesised and secreted by gonadotropes in the anterior pituitary gland. FSH and LH act synergistically in reproduction: In women, in the ovary FSH stimulates the growth of immature Graafian follicles to maturation. As the follicle grows it releases inhibin, which shuts off the FSH production. In men, FSH enhances the production of androgen-binding protein by the Sertoli cells of the testes and is critical for spermatogenesis. In both males and females, FSH stimulates the maturation of germ cells. In females, FSH initiates follicular growth, specifically affecting granulosa cells. With the concomitant rise in inhibin B FSH levels then decline in the late follicular phase. This seems to be critical in selecting only the most advanced follicle to proceed to ovulation. At the end of the luteal phase, there is a slight rise in FSH that seems to be of importance to start the next ovulatory cycle. Like its partner, LH, FSH release at the pituitary gland is controlled by pulses of gonadotropin-releasing hormone (GnRH). Those pulses, in turn, are subject to the estrogen feed-back from the gonads.
