| glycoprotein hormones, alpha polypeptide | |||||||
|---|---|---|---|---|---|---|---|
 FSH (α-FSH (green), β-FSH (orange)) with receptors (blue) | |||||||
| Identifiers | |||||||
| Symbol | CGA | ||||||
| NCBI gene | 1081 | ||||||
| HGNC | 1885 | ||||||
| OMIM | 118850 | ||||||
| RefSeq | NM_000735 | ||||||
| UniProt | P01215 | ||||||
| Other data | |||||||
| Locus | Chr. 6q14-q21 | ||||||
| |||||||
| Follicle-stimulating hormone, beta polypeptide | |||||||
|---|---|---|---|---|---|---|---|
 Follicle-stimulating hormone | |||||||
| Identifiers | |||||||
| Symbol | FSHB | ||||||
| NCBI gene | 2488 | ||||||
| HGNC | 3964 | ||||||
| OMIM | 136530 | ||||||
| RefSeq | NM_000510 | ||||||
| UniProt | P01225 | ||||||
| Other data | |||||||
| Locus | Chr. 11p13 | ||||||
| |||||||
Follicle-stimulating hormone (FSH) is agonadotropin, aglycoproteinpolypeptide hormone.[1] FSH is synthesized and secreted by thegonadotropic cells of theanterior pituitary gland[2] and regulates the development, growth,pubertal maturation, and reproductive processes of the body. FSH andluteinizing hormone (LH) work together in thereproductive system.[3]
FSH is a 35.5 kDaglycoproteinheterodimer, consisting of twopolypeptide units, alpha and beta. Its structure is similar to those ofluteinizing hormone (LH),thyroid-stimulating hormone (TSH), andhuman chorionic gonadotropin (hCG). Thealpha subunits of the glycoproteins LH, FSH, TSH, and hCG are identical and consist of 96amino acids, while the beta subunits vary.[4][5] Both subunits are required for biological activity. FSH has a beta subunit of 111 amino acids (FSH β), which confers its specific biologic action, and is responsible for interaction with thefollicle-stimulating hormone receptor.[6] The sugar portion of the hormone is covalently bonded toasparagine, and is composed ofN-acetylgalactosamine,mannose,N-acetylglucosamine,galactose, andsialic acid.
In humans, the gene for thealpha subunit is located at cytogenetic location 6q14.3.[7] It is expressed in two cell types, most notably the basophils of the anterior pituitary. The gene for the FSH beta subunit is located on chromosome 11p13, and is expressed in gonadotropes of the pituitary cells, controlled byGnRH, inhibited byinhibin, and enhanced byactivin.[8]
FSH regulates the development, growth, pubertal maturation and reproductive processes of the human body.[9]
Control of FSH release from the pituitary gland is unknown. Low frequencygonadotropin-releasing hormone (GnRH) pulses increase FSH mRNA levels in the rat,[10] but is not directly correlated with an increase in circulating FSH.[11] GnRH has been shown to play an important role in the secretion of FSH, with hypothalamic-pituitary disconnection leading to a cessation of FSH. GnRH administration leads to a return of FSH secretion. FSH is subject to oestrogen feed-back from the gonads via the hypothalamic pituitary gonadal axis.
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FSH stimulates the growth and recruitment of immatureovarian follicles in theovary. In early (small) antral follicles, FSH is the major survival factor that rescues the small antral follicles (2–5 mm in diameter for humans) fromapoptosis (programmed death of the somatic cells of the follicle and oocyte). In the luteal-folliclephase transition period the serum levels of progesterone and estrogen (primarily estradiol) decrease and no longer suppress the release of FSH, consequently FSH peaks at about day three (day one is the first day of menstrual flow). The cohort of small antral follicles is normally sufficient in number to produce enoughInhibin B to lower FSH serum levels.[citation needed]
In addition, there is evidence thatgonadotropin surge-attenuating factor produced by small follicles during the first half of the follicle phase also exerts a negative feedback on pulsatileluteinizing hormone (LH) secretion amplitude, thus allowing a more favorable environment for follicle growth and preventing premature luteinization.[13]
As a woman nears perimenopause, the number of small antral follicles recruited in each cycle diminishes and consequently insufficient Inhibin B is produced to fully lower FSH and the serum level of FSH begins to rise. Eventually, the FSH level becomes so high thatdownregulation of FSH receptors occurs and by postmenopause any remaining small secondary follicles no longer have FSH nor LH receptors.[14]
When the follicle matures and reaches 8–10 mm in diameter it starts to secrete significant amounts ofestradiol. Normally in humans only one follicle becomes dominant and survives to grow to 18–30 mm in size and ovulate, the remaining follicles in the cohort undergoatresia. The sharp increase in estradiol production by the dominant follicle (possibly along with a decrease ingonadotrophin surge-attenuating factor) cause a positive effect on the hypothalamus and pituitary and rapidGnRH pulses occur and anLH surge results.
The increase in serumestradiol levels causes a decrease in FSH production by inhibitingGnRH production in the hypothalamus.[15]
The decrease in serum FSH level causes the smaller follicles in the current cohort to undergo atresia as they lack sufficient sensitivity to FSH to survive. Occasionally two follicles reach the 10 mm stage at the same time by chance and as both are equally sensitive to FSH both survive and grow in the low FSH environment and thus two ovulations can occur in one cycle possibly leading to non-identical (dizygotic) twins.[citation needed]
FSH stimulates primaryspermatocytes to undergo the first division ofmeiosis, to form secondary spermatocytes.[citation needed]
FSH enhances the production ofandrogen-binding protein by theSertoli cells of thetestes by binding toFSH receptors on theirbasolateral membranes,[16] and is critical for the initiation ofspermatogenesis.
Follicle-stimulating hormone is typically measured in the earlyfollicular phase of the menstrual cycle, typically day three to five, counted from last menstruation. At this time, the levels of estradiol (E2) and progesterone are at the lowest point of themenstrual cycle. FSH levels in this time is often calledbasal FSH levels, to distinguish from the increased levels when approaching ovulation.[17]
FSH is measured ininternational units (IU). For Human Urinary FSH, one IU is defined as the amount of FSH that has an activity corresponding to 0.11388 mg of pure Human Urinary FSH.[18] For recombinant FSH, one IU corresponds to approximately 0.065 to 0.075 μg of a "fill-by-mass" product.[19]The mean values for women beforeovulation are around (3.8-8.8) IU/L. After ovulation these levels drop to between (1.8-5.1) IU/L. At the mid of themenstrual cycle it reaches its highest value, between (4.5-22.5) IU/L. Duringmenopause, the values goes up even more, between (16.74-113.59) IU/L.For men, the mean values are around (1.5-12.4) IU/L.[20]
FSH levels are normally low duringchildhood and, in females, high aftermenopause.
The most common reason for high serum FSH concentration is in a female who is undergoing or has recently undergonemenopause. High levels of FSH indicate that the normal restricting feedback from the gonad is absent, leading to an unrestricted pituitary FSH production. FSH may contribute to postmenopausal osteoporosis and cardiovascular disease.[21]
If high FSH levels occur during the reproductive years, it is abnormal. Conditions with high FSH levels include:
Most of these conditions are associated with subfertility or infertility. Therefore, high FSH levels are an indication of subfertility or infertility.
Diminished secretion of FSH can result in failure of gonadal function (hypogonadism). This condition is typically manifested in males as failure in production of normal numbers of sperm. In females, cessation of reproductive cycles is commonly observed.[citation needed]Conditions with very low FSH secretions are:
Isolated FSH deficiency due to mutations in the gene for β-subunit of FSH is rare with 13 cases reported in the literature up to 2019.[24]
FSH is used commonly in infertility therapy, mainly forovarian hyperstimulation as part ofIVF. In some cases, it is used inovulation induction for reversal ofanovulation as well.
FSH is available mixed with LH activity in variousmenotropins including more purified forms of urinarygonadotropins such asMenopur, as well as without LH activity as recombinant FSH (Gonapure, Gonal F, Follistim, Follitropin alpha).
Elevated FSH receptor levels have been detected in the endothelia of tumor vasculature in a very wide range of solid tumors. FSH binding is thought to upregulate neovascularization via at least two mechanisms – one in theVEGF pathway, and the other VEGF independent – related to the development of umbilical vasculature when physiological. This presents possible use of FSH and FSH-receptor antagonists as an anti-tumor angiogenesis therapy (cf.avastin for current anti-VEGF approaches).[25]
