Follicle-stimulating hormone

2019-01-13T17:28:24Z

2601:541:4500:1760:F15B:BD17:85DA:A1BE: improve

{{infobox protein
| Name = [[Alpha subunit of glycoprotein hormones|glycoprotein hormones, alpha polypeptide]]
| caption =FSH (α-FSH (green), β-FSH (orange)) with receptors (blue)
| image =FSHA+B+receptor 1XWD.png
| width =
| HGNCid = 1885
| Symbol = [[Alpha subunit of glycoprotein hormones|CGA]]
| AltSymbols =
| EntrezGene = 1081
| OMIM = 118850
| RefSeq = NM_000735
| UniProt = P01215
| PDB =
| ECnumber =
| Chromosome = 6
| Arm = q
| Band = 14
| LocusSupplementaryData = -q21
}}
{{infobox protein
| Name = [[FSHB|follicle stimulating hormone, beta polypeptide]]
| caption = Follicle-stimulating hormone
| image = Follitropine.gif
| width = 320

| HGNCid = 3964
| Symbol = [[FSHB]]
| AltSymbols =
| EntrezGene = 2488
| OMIM = 136530
| RefSeq = NM_000510
| UniProt = P01225
| PDB =
| ECnumber =
| Chromosome = 11
| Arm = p
| Band = 13
| LocusSupplementaryData =
}}

'''Follicle-stimulating hormone''' ('''FSH''') is a [[gonadotropin]], a [[glycoprotein]] [[polypeptide]] [[hormone]]. FSH is synthesized and secreted by the [[gonadotropic cell]]s of the [[anterior pituitary gland]],<ref>{{cite web|url=https://www.webmd.com/women/follicle-stimulating-hormone#1|title=Follicle-Stimulating Hormone|website=WebMD}}</ref> and regulates the development, growth, [[puberty|pubertal maturation]], and reproductive processes of the body. FSH and [[luteinizing hormone]] (LH) work together in the [[reproductive system]].

==Structure==
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{{refimprove section|date=February 2013}}
{{confusing|section|date=February 2013}}
{{technical|section '''needs attention from an expert from either [[WP:WikiProject Molecular and Cellular Biology|Molecular Biology]] or [[WP:WikiProject Medicine|Medicine]] because it'''|date=February 2013}}
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FSH is a 35.5 kDa [[glycoprotein]] [[protein dimer|heterodimer]], consisting of two [[polypeptide]] units, alpha and beta. Its structure is similar to those of [[luteinizing hormone]] (LH), [[thyroid-stimulating hormone]] (TSH), and [[human chorionic gonadotropin]] (hCG). The [[chorionic gonadotropin alpha|alpha subunits]] of the glycoproteins LH, FSH, TSH, and hCG are identical and consist of 96 [[amino acids]], while the beta subunits vary.<ref name=pierce1981>{{cite journal|last1=Pierce|first1=John G.|last2=Parsons|first2=Thomas F.|title=Glycoprotein Hormones: Structure and Function|journal=Annual Review of Biochemistry|date=July 1981|volume=50|issue=1|pages=465–495|doi=10.1146/annurev.bi.50.070181.002341|url=http://www.annualreviews.org/doi/abs/10.1146/annurev.bi.50.070181.002341|accessdate=9 December 2014|pmid=6267989|url-access=subscription}}</ref><ref>{{cite web|title=CGA glycoprotein hormones, alpha polypeptide [Homo sapiens (human)]|url=https://www.ncbi.nlm.nih.gov/gene/1081|website=[[National Center for Biotechnology Information|NCBI]]|accessdate=2 January 2016}}</ref> 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]].<ref name="pmid22802634">{{cite journal|last1=Jiang|first1=Xuliang|last2=Liu|first2=Heli|last3=Chen|first3=Xiaoyan|last4=Chen|first4=Po-Han|last5=Fischer|first5=David|last6=Sriraman|first6=Venkataraman|last7=Yu|first7=Henry N.|last8=Arkinstall|first8=Steve|last9=He|first9=Xiaolin|last-author-amp=y|date=2012-07-31|orig-year=Published online ahead of print 2012-07-16|editor1-last=Hendrickson|editor1-first=Wayne A.|editor1-link=Wayne Hendrickson|title=Structure of follicle-stimulating hormone in complex with the entire ectodomain of its receptor|url=http://www.pnas.org/content/109/31/12491.full.pdf|format=PDF|journal=[[Proceedings of the National Academy of Sciences of the United States of America|PNAS]]|location=New York|volume=109|issue=31|pages=12491–12496|eissn=1091-6490|pmid=22802634|doi=10.1073/pnas.1206643109||doi-access=free|pmc=3411987|archive-url= |archive-date= |dead-url= |via= |layurl= |laysource= |laydate= |quote= |postscript= |ref= }}</ref> The sugar portion of the hormone is covalently bonded to [[asparagine]], and is composed of [[N-acetylgalactosamine]], [[mannose]], [[N-acetylglucosamine]], [[galactose]], and [[sialic acid]].

==Genes==

In humans, the gene for the [[Alpha subunit of glycoprotein hormones|alpha subunit]] is located at cytogenetic location 6q14.3.<ref>{{OMIM|118850|CHORIONIC GONADOTROPIN, ALPHA CHAIN; CGA}}</ref> 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]].

==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 cell]]s.
* In ''males'', FSH induces [[Sertoli cells]] to secrete [[androgen-binding protein]]s (ABPs), regulated by [[activin and inhibin|inhibin]]'s [[negative feedback]] mechanism on the [[anterior pituitary]]. Specifically, activation of Sertoli cells by FSH sustains spermatogenesis and stimulates inhibin B secretion.
* In ''females'', FSH initiates follicular growth, specifically affecting [[granulosa cell]]s. 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,<ref>{{cite journal|last1=Dalkin|first1=Alan C.|last2=Haisenleder|first2=Daniel J.|last3=Gilrain|first3=J. T.|last4=Aylor|first4=Kevin W.|last5=Yasin|first5=M.|last6=Marshall|first6=John. C.|last-author-amp=y|date=1998-04-28|title=Gonadotropin-Releasing Hormone Regulation of Gonadotropin Subunit Gene Expression in Female Rats: Actions on Follicle-Stimulating Hormoneβ Messenger Ribonucleic Acid (mRNA) Involve Differential Expression of Pituitary Activin (β-B) and Follistatin mRNAs|url=https://academic.oup.com/endo/article/140/2/903/2990714/Gonadotropin-Releasing-Hormone-Regulation-of|journal=Endocrinology|publisher=The Endocrine Society|publication-date=1999-02-01|volume=40|issue=2|pages=903-908|doi=10.1210/endo.140.2.6483|doi-access=free|issn=0013-7227|eissn=1945-7170|pmid=9927322}}</ref> but is not directly correlated with an increase in circulating FSH.<ref>{{cite journal|last1=Sharma|first1=Tejinder P.|last2=Nett|first2=Terry M.|last3=Karsch|first3=Fred J.|last4=Phillips|first4=David J.|last5=Lee|first5=James S.|last6=Herkimer|first6=Carol|last7=Padmanabhan|first7=Vasantha|last-author-amp=y|date=2012-01-04|orig-year=Published online before print 2012-03-14|title=Neuroendocrine Control of FSH Secretion: IV. Hypothalamic Control of Pituitary FSH-Regulatory Proteins and Their Relationship to Changes in FSH Synthesis and Secretion|url=https://academic.oup.com/biolreprod/article/2530647/Neuroendocrine-Control-of-FSH-Secretion-IV|journal=[[Biology of Reproduction]]|publisher=the Society for the Study of Reproduction|publication-date=2012-06-01|volume=86|issue=6|at=article 171, p. 1-9|pmc=3386145|doi=10.1095/biolreprod.111.098442|doi-access=free|issn=0006-3363|pmid=22423050|eissn=1529-7268}}</ref> 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.

[[File:Follicle-stimulating hormone (FSH) during menstrual cycle.png|thumb|450px|[[Reference ranges for blood tests|Reference ranges for the blood content]] of follicle-stimulating hormone levels during the [[menstrual cycle]].<ref name="Häggström2014">{{cite journal|date=2014-03-25|orig-year=Last updated 2017-04-04|publication-date=2014-03-26|title=Reference ranges for estradiol, progesterone, luteinizing hormone and follicle-stimulating hormone during the menstrual cycle|journal=WikiJournal of Medicine|volume=1|issue=1|url=https://en.wikiversity.org/wiki/WikiJournal_of_Medicine/Reference_ranges_for_estradiol,_progesterone,_luteinizing_hormone_and_follicle-stimulating_hormone_during_the_menstrual_cycle|doi=10.15347/wjm/2014.001|doi-access=free|issn=2002-4436|last1=Häggström|first1=Mikael}}</ref>
<br>- The ranges denoted '''By biological stage''' may be used in closely monitored menstrual cycles in regard to other markers of its biological progression, with the time scale being compressed or stretched to how much faster or slower, respectively, the cycle progresses compared to an average cycle.
<br>- The ranges denoted '''Inter-cycle variability''' are more appropriate to use in non-monitored cycles with only the beginning of menstruation known, but where the woman accurately knows her average cycle lengths and time of ovulation, and that they are somewhat averagely regular, with the time scale being compressed or stretched to how much a woman's average cycle length is shorter or longer, respectively, than the average of the population.
<br>- The ranges denoted '''Inter-woman variability''' are more appropriate to use when the average cycle lengths and time of ovulation are unknown, but only the beginning of menstruation is given.]]

===Effects in females===
FSH stimulates the growth and recruitment of immature [[ovarian follicle]]s in the [[ovary]]. 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]] (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]] 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.<ref name="pmid14748688">{{cite journal|last1=Fowler|first1=Paul Alfred Francois|last2=Sorsa-Leslie|first2=Tarja Kristina|last3=Harris|first3=William Joseph|last4=Mason|first4=Helen D.|last-author-amp=y| title=Ovarian gonadotrophin surge-attenuating factor (GnSAF): where are we after 20 years of research?|journal=[[Reproduction (journal)|Reproduction]]|volume=126|issue=6|pages=689–99|date=2003-12-01|pmid=14748688|doi=10.1530/rep.0.1260689|doi-access=free|url=http://www.reproduction-online.org/content/126/6/689.full.pdf|format=PDF|publisher=Society for Reproduction and Fertility|issn=1470-1626|eissn=1741-7899}}</ref>

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.<ref name="pmid8865134">{{cite journal | author = Vihko KK | title=Gonadotropins and ovarian gonadotropin receptors during the perimenopausal transition period | journal = Maturitas | volume = 23 | issue = Supplement | pages = S19–22 | date=May 1996 | pmid = 8865134 | doi=10.1016/s0378-5122(96)90009-2}}</ref>

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 [[Luteinizing hormone|LH]] surge results.

The increase in serum [[estradiol]] levels cause a decrease in FSH production by inhibiting [[GnRH]] production in the hypothalamus.<ref name="isbn0-07-147899-X">{{cite book |vauthors=Dickerson LM, Shrader SP, Diaz VA |veditors=Wells BG, DiPiro JT, Talbert RL, Yee GC, Matzke GR | title = Pharmacotherapy: a pathophysiologic approach | edition = | language = | publisher = McGraw-Hill Medical | location = | year = 2008 | chapter = Chapter 8: Contraception | pages = 1313–28 | quote = | isbn = 0-07-147899-X | oclc = | doi = | url = | accessdate = }}</ref>

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 cell]]s of the [[testes]] by binding to [[FSH receptor]]s on their [[basolateral]] membranes,<ref name="isbn1-4160-2328-3">{{cite book |vauthors=Boulpaep EL, Boron WF | title = Medical physiology: a cellular and molecular approach | edition = | language = | publisher = Elsevier Saunders | location = St. Louis, Mo | year = 2005 | origyear = | pages = 1125 | quote = | isbn = 1-4160-2328-3 | oclc = | doi = | url = | accessdate = }}</ref> and is critical for the initiation of [[spermatogenesis]].

==Measurement==

Follicle stimulating hormone is typically measured in the early [[follicular 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 the [[menstrual cycle]]. 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]] (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.<ref>[http://whqlibdoc.who.int/trs/WHO_TRS_565.pdf World Health Organization Technical Report Series N0. 565.] WHO Expert Committee on Biological Standardization. Twenty-sixth Report. [[World Health Organization]]. Geneva. 1975</ref> For recombinant FSH, one IU corresponds to approximately 0.065 to 0.075 [[microgram|µg]] of a "fill-by-mass" product.<ref>{{cite journal | title = Gonadotropin preparations: Past, present, and future perspectives | journal = Fertility and Sterility | volume = 90 | issue = 5 Suppl | pages = S13-20 | year = 2008 | pmid = 19007609 | doi = 10.1016/j.fertnstert.2008.08.031 }}</ref>

==Disease states==
{{Unreferenced section|date=September 2010}}

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.

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]]
# [[Castration]]
# [[Swyer syndrome]]
# Certain forms of [[Congenital adrenal hyperplasia|CAH]]
# Testicular failure.
# [[Klinefelter syndrome]]
# [[Systemic Lupus Erythematosus]] also known as Lupus <ref>{{cite journal|doi=10.1002/art.21436 | volume=52 | issue=12 | title=Pituitary hormones and systemic lupus erythematosus | journal=Arthritis & Rheumatism | pages=3701–3712}}</ref>

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]]
# [[Hyperprolactinemia]]
# [[Gonadotropin deficiency]]
# 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.<ref name=Misgar2019>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 </ref>

==Use as therapy==
{{Further information|Gonadotropin preparations|Controlled ovarian hyperstimulation}}
FSH is used commonly in infertility therapy, mainly for [[Controlled ovarian hyperstimulation|ovarian hyperstimulation]] as part of [[IVF]]. In some cases, it is used for reversal of [[anovulation]] as well.

FSH is available mixed with LH activity in various [[menotropins]] including more purified forms of urinary [[gonadotropins]] such as [[Menopur]], 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).<ref name="pmid20961245">{{cite journal |vauthors=Radu A, Pichon C, Camparo P, Antoine M, Allory Y, Couvelard A, Fromont G, Hai MT, Ghinea N | title = Expression of follicle-stimulating hormone receptor in tumor blood vessels | journal = N. Engl. J. Med. | volume = 363 | issue = 17 | pages = 1621–30 | date = October 2010 | pmid = 20961245 | doi = 10.1056/NEJMoa1001283 | url = }}</ref>

==References==
{{Reflist}}

==External links==
{{commons category}}
* [http://labtestsonline.org/understanding/analytes/fsh/tab/test FSH] - Lab Tests Online

{{GnRH and gonadotropins}}
{{Hormones}}
{{Assisted reproductive technology}}
{{GnRH and gonadotropin receptor modulators}}

{{DEFAULTSORT:Follicle-Stimulating Hormone}}

[[Category:Recombinant proteins]]
[[Category:Glycoproteins]]
[[Category:Peptide hormones]]
[[Category:Sex hormones]]
[[Category:Human hormones]]
[[Category:In vitro fertilisation]]
[[Category:Hormones of the hypothalamus-pituitary-gonad axis]]
[[Category:Anterior pituitary hormones]]
[[Category:Human female endocrine system]]

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Follicle-stimulating hormone