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Follicle-stimulating hormone (FSH) is a gonadotropin, a
glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
polypeptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A p ...
hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and luteinizing hormone (LH) work together in the reproductive system.


Structure

FSH is a 35.5 kDa
glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
heterodimer In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...
, consisting of two
polypeptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A p ...
units, alpha and beta. Its structure is similar to those of luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and human chorionic gonadotropin (hCG). The alpha subunits of the glycoproteins LH, FSH, TSH, and hCG are identical and consist of 96
amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
, while the beta subunits vary. 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 the
follicle-stimulating hormone receptor The follicle-stimulating hormone receptor or FSH receptor (FSHR) is a transmembrane receptor that interacts with the follicle-stimulating hormone (FSH) and represents a G protein-coupled receptor (GPCR). Its activation is necessary for the hormo ...
. The sugar portion of the hormone is covalently bonded to asparagine, and is composed of N-acetylgalactosamine, mannose,
N-acetylglucosamine ''N''-Acetylglucosamine (GlcNAc) is an amide derivative of the monosaccharide glucose. It is a secondary amide between glucosamine and acetic acid. It is significant in several biological systems. It is part of a biopolymer in the bacterial ...
, galactose, and
sialic acid Sialic acids are a class of alpha-keto acid sugars with a nine-carbon backbone. The term "sialic acid" (from the Greek for saliva, - ''síalon'') was first introduced by Swedish biochemist Gunnar Blix in 1952. The most common member of this gr ...
.


Genes

In humans, the gene for the alpha subunit is located at cytogenetic location 6q14.3. 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 by GnRH, inhibited by inhibin, and enhanced by
activin Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Identified in 1986, activin enhances FSH biosynthesis and secretion, and participates in the regulation of the menstrual ...
.


Activity/functions

FSH regulates the development, growth, pubertal maturation and reproductive processes of the human body. * In both ''males'' and ''females'', FSH stimulates the maturation of primordial germ cells. * In ''males'', FSH induces Sertoli cells to secrete androgen-binding proteins (ABPs), regulated by inhibin's
negative feedback Negative feedback (or balancing feedback) occurs when some function (Mathematics), function of the output of a system, process, or mechanism is feedback, fed back in a manner that tends to reduce the fluctuations in the output, whether caused by ...
mechanism on the
anterior pituitary A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis or pars anterior) is the glandular, anterior lobe that together with the posterior lobe (posterior pituitary, or the neurohypophysis) makes up the p ...
. Specifically, activation of Sertoli cells by FSH sustains spermatogenesis and stimulates inhibin B secretion. * 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. Control of FSH release from the pituitary gland is unknown. Low frequency gonadotropin-releasing hormone (GnRH) pulses increase FSH mRNA levels in the rat, but is not directly correlated with an increase in circulating FSH. 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.


Effects in females

FSH stimulates the growth and recruitment of immature ovarian follicles in the
ovary The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. ...
. In early (small) antral follicles, FSH is the major survival factor that rescues the small antral follicles (2–5 mm in diameter for humans) from
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes incl ...
(programmed death of the somatic cells of the follicle and oocyte). In the luteal-follicle phase 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 enough Inhibin B to lower FSH serum levels. In addition, there is evidence that
gonadotropin surge-attenuating factor Gonadotropin surge-attenuating factor (GnSAF) is a nonsteroidal ovarian hormone produced by the granulosa cells of small antral ovarian follicles in females. GnSAF is involved in regulating the secretion of luteinizing hormone (LH) from the anteri ...
produced by small follicles during the first half of the follicle phase also exerts a negative feedback on pulsatile luteinizing hormone (LH) secretion amplitude, thus allowing a more favorable environment for follicle growth and preventing premature luteinization. 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 that downregulation of FSH receptors occurs and by postmenopause any remaining small secondary follicles no longer have FSH nor LH receptors. When the follicle matures and reaches 8–10 mm in diameter it starts to secrete significant amounts of estradiol. 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 undergo atresia. The sharp increase in estradiol production by the dominant follicle (possibly along with a decrease in gonadotrophin surge-attenuating factor) cause a positive effect on the hypothalamus and pituitary and rapid GnRH pulses occur and an LH surge results. The increase in serum estradiol levels cause a decrease in FSH production by inhibiting GnRH production in the hypothalamus. 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.


Effects in males

FSH stimulates primary spermatocytes to undergo the first division of meiosis, to form secondary spermatocytes. FSH enhances the production of androgen-binding protein by the Sertoli cells of the testes by binding to FSH receptors on their basolateral membranes, and is critical for the initiation of
spermatogenesis Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubule ...
.


Measurement

Follicle stimulating hormone is typically measured in the early
follicular phase The follicular phase, also known as the preovulatory phase or proliferative phase, is the phase of the estrous cycle (or, in primates for example, the menstrual cycle) during which follicles in the ovary mature from primary follicle to a fully ...
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 the
menstrual cycle The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that make pregnancy possible. The ovarian cycle controls the production and release of eggs a ...
. FSH levels in this time is often called ''basal FSH'' levels, to distinguish from the increased levels when approaching ovulation. FSH is measured in
International Units In pharmacology, the international unit (IU) is a unit of measurement for the effect, not mass of a substance; the variance is based on the biological activity or effect, for the purpose of easier comparison across similar ''forms'' of substan ...
(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. For recombinant FSH, one IU corresponds to approximately 0.065 to 0.075 µg of a "fill-by-mass" product. The mean values for women before ovulation are around (3.8-8.8) mUI/mL. After ovulation these levels drop to between (1.8-5.1) mUI/mL. At the mid of the
menstrual cycle The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that make pregnancy possible. The ovarian cycle controls the production and release of eggs a ...
it reaches its highest value, between (4.5-22.5) mIU / mL. During menopause, the values goes up even more, between (16.74-113.59) mIU / mL. For men, the mean values are around (16.74-113.59 mUI/mL).


Disease states

FSH levels are normally low during childhood and, in females, high after menopause.


High FSH levels

The most common reason for high serum FSH concentration is in a female who is undergoing or has recently undergone menopause. 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. If high FSH levels occur during the reproductive years, it is abnormal. Conditions with high FSH levels include: # Premature menopause also known as Premature Ovarian Failure # Poor ovarian reserve also known as Premature Ovarian Aging # Gonadal dysgenesis, Turner syndrome, Klinefelter syndrome #
Castration Castration is any action, surgical, chemical, or otherwise, by which an individual loses use of the testicles: the male gonad. Surgical castration is bilateral orchiectomy (excision of both testicles), while chemical castration uses phar ...
# Swyer syndrome # Certain forms of CAH # Testicular failure #
Lupus Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Comm ...
Most of these conditions are associated with subfertility and/or infertility. Therefore, high FSH levels are an indication of subfertility and/or infertility.


Low FSH levels

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. Conditions with very low FSH secretions are: # Polycystic Ovarian Syndrome # Polycystic Ovarian Syndrome + Obesity + Hirsutism + Infertility # Kallmann syndrome #
Hypothalamic suppression Hypopituitarism is the decreased (''hypo'') secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain. If there is decreased secretion of one specific pituitary hormone, the condition is know ...
# Hypopituitarism # Hyperprolactinemia #
Gonadotropin deficiency Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low estrogen ...
# Gonadal suppression therapy ## GnRH antagonist ## GnRH agonist ( downregulation). 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.Misgar RA, Wani AI, Bankura B, Bashir MI, Roy A, Das M (2019) FSH β-subunit mutations in two sisters: the first report from the Indian sub-continent and review of previous cases. Gynecol Endocrinol 2:1-4


Use as therapy

FSH is used commonly in infertility therapy, mainly for ovarian hyperstimulation as part of IVF. In some cases, it is used in ovulation induction for reversal of anovulation as well. FSH is available mixed with LH activity in various
menotropins Menotropin (also called human menopausal gonadotropin or hMG) is a hormonally active medication for the treatment of fertility disturbances. Frequently the plural is used as the medication is a mixture of gonadotropins. Menotropins are extracted ...
including more purified forms of urinary gonadotropins such as
Menopur Menotropin (also called human menopausal gonadotropin or hMG) is a hormone, hormonally active medication for the treatment of fertility disturbances. Frequently the plural is used as the medication is a mixture of gonadotropins. Menotropins are ex ...
, as well as without LH activity as recombinant FSH (Gonapure, Gonal F, Follistim, Follitropin alpha).


Potential role in vascularization of solid tumors

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 the VEGF 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).


See also

* EFSH, a follicle-stimulating hormone obtained from equine species


References


External links


FSH
- Lab Tests Online {{DEFAULTSORT:Follicle-Stimulating Hormone Recombinant proteins Glycoproteins Peptide hormones Sex hormones Human hormones In vitro fertilisation Hormones of the hypothalamus-pituitary-gonad axis Anterior pituitary hormones Human female endocrine system