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Follicle-stimulating hormone

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Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone.[1] FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland[2] and regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and luteinizing hormone (LH) work together in the reproductive system.[3]

glycoprotein hormones, alpha polypeptide
FSH (α-FSH (green), β-FSH (orange)) with receptors (blue)
Identifiers
SymbolCGA
NCBI gene1081
HGNC1885
OMIM118850
RefSeqNM_000735
UniProtP01215
Other data
LocusChr. 6 q14-q21
Search for
StructuresSwiss-model
DomainsInterPro
Follicle-stimulating hormone, beta polypeptide
Follicle-stimulating hormone
Identifiers
SymbolFSHB
NCBI gene2488
HGNC3964
OMIM136530
RefSeqNM_000510
UniProtP01225
Other data
LocusChr. 11 p13
Search for
StructuresSwiss-model
DomainsInterPro

Structure

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FSH is a 35.5 kDa glycoprotein 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 alpha subunits of the glycoproteins LH, FSH, TSH, and hCG are identical and consist of 96 amino 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 the follicle-stimulating hormone receptor.[6] 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

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In humans, the gene for the alpha 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 by GnRH, inhibited by inhibin, and enhanced by activin.[citation needed]

Activity and functions

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FSH regulates the development, growth, pubertal maturation and reproductive processes of the human body.[8]

  • 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 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 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,[9] but is not directly correlated with an increase in circulating FSH.[10] 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.

 
Reference ranges for the blood content of follicle-stimulating hormone levels during the menstrual cycle.[11]
- 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.
- 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.
- 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

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FSH stimulates the growth and recruitment of immature ovarian follicles 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.[citation needed]

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.[12]

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.[13]

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 causes a decrease in FSH production by inhibiting GnRH production in the hypothalamus.[14]

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]

Effects in males

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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,[15] and is critical for the initiation of spermatogenesis.

Measurement

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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.[16]

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.[17] For recombinant FSH, one IU corresponds to approximately 0.065 to 0.075 μg of a "fill-by-mass" product.[18] The mean values for women before ovulation 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 the menstrual cycle it reaches its highest value, between (4.5-22.5) IU/L. During menopause, the values goes up even more, between (16.74-113.59) IU/L. For men, the mean values are around (16.74-113.59) IU/L.

Disease states

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

High FSH levels

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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.[19]

If high FSH levels occur during the reproductive years, it is abnormal. Conditions with high FSH levels include:

  1. Premature menopause also known as premature ovarian failure
  2. Poor ovarian reserve also known as premature ovarian aging
  3. Gonadal dysgenesis, Turner syndrome, Klinefelter syndrome
  4. Castration
  5. Swyer syndrome
  6. Certain forms of congenital adrenal hyperplasia
  7. Testicular failure
  8. Lupus[20]

Most of these conditions are associated with subfertility or infertility. Therefore, high FSH levels are an indication of subfertility or infertility.

Low FSH levels

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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:

  1. Polycystic Ovarian Syndrome[21]
  2. Polycystic ovarian syndrome + obesity + hirsutism + infertility
  3. Kallmann syndrome
  4. Aromatase excess syndrome
  5. Hypothalamic suppression
  6. Hypopituitarism
  7. Hyperprolactinemia
  8. Gonadotropin deficiency
  9. Gonadal suppression therapy
    1. GnRH antagonist
    2. 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.[22]

Use as therapy

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Further information: Gonadotropin preparations, Controlled ovarian hyperstimulation, and Ovulation induction

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 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

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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).[23]

See also

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

References

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  1. ^ Cahoreau C, Klett D, Combarnous Y (2015-02-26). "Structure-function relationships of glycoprotein hormones and their subunits' ancestors". Frontiers in Endocrinology. 6: 26. doi:10.3389/fendo.2015.00026. PMC 4341566. PMID 25767463.
  2. ^ "Follicle-Stimulating Hormone". WebMD.
  3. ^ Bowen R. "Luteinizing and Follicle Stimulating Hormones". www.vivo.colostate.edu. Retrieved 2019-05-06.
  4. ^ Pierce JG, Parsons TF (July 1981). "Glycoprotein hormones: structure and function". Annual Review of Biochemistry. 50 (1): 465–95. doi:10.1146/annurev.bi.50.070181.002341. PMID 6267989.
  5. ^ "CGA glycoprotein hormones, alpha polypeptide [Homo sapiens (human)]". NCBI. Retrieved 2 January 2016.
  6. ^ Jiang X, Liu H, Chen X, Chen PH, Fischer D, Sriraman V, et al. (July 2012) [Published online ahead of print 2012-07-16]. Hendrickson WA (ed.). "Structure of follicle-stimulating hormone in complex with the entire ectodomain of its receptor". Proceedings of the National Academy of Sciences of the United States of America. 109 (31): 12491–6. Bibcode:2012PNAS..10912491J. doi:10.1073/pnas.1206643109. eISSN 1091-6490. PMC 3411987. PMID 22802634.
  7. ^ Online Mendelian Inheritance in Man (OMIM): CHORIONIC GONADOTROPIN, ALPHA CHAIN; CGA - 118850
  8. ^ Ulloa-Aguirre A, Reiter E, Crépieux P (August 2018). "FSH Receptor Signaling: Complexity of Interactions and Signal Diversity". Endocrinology. 159 (8): 3020–3035. doi:10.1210/en.2018-00452. PMID 29982321.
  9. ^ Dalkin AC, Haisenleder DJ, Gilrain JT, Aylor K, Yasin M, Marshall JC (February 1999). "Gonadotropin-releasing hormone regulation of gonadotropin subunit gene expression in female rats: actions on follicle-stimulating hormone beta messenger ribonucleic acid (mRNA) involve differential expression of pituitary activin (beta-B) and follistatin mRNAs". Endocrinology. 140 (2) (published 1999-02-01): 903–8. doi:10.1210/endo.140.2.6483. eISSN 1945-7170. PMID 9927322.
  10. ^ Sharma TP, Nett TM, Karsch FJ, Phillips DJ, Lee JS, Herkimer C, et al. (June 2012) [Published online before print 2012-03-14]. "Neuroendocrine control of FSH secretion: IV. Hypothalamic control of pituitary FSH-regulatory proteins and their relationship to changes in FSH synthesis and secretion". Biology of Reproduction. 86 (6) (published 2012-06-01): 171. doi:10.1095/biolreprod.111.098442. PMC 3386145. PMID 22423050.
  11. ^ Häggström M (2014-03-25) [Last updated 2017-04-04]. "Reference ranges for estradiol, progesterone, luteinizing hormone and follicle-stimulating hormone during the menstrual cycle". WikiJournal of Medicine. 1 (1) (published 2014-03-26). doi:10.15347/wjm/2014.001. ISSN 2002-4436.
  12. ^ Fowler PA, Sorsa-Leslie T, Harris W, Mason HD (December 2003). "Ovarian gonadotrophin surge-attenuating factor (GnSAF): where are we after 20 years of research?". Reproduction. 126 (6): 689–99. CiteSeerX 10.1.1.516.1420. doi:10.1530/rep.0.1260689. eISSN 1741-7899. PMID 14748688.
  13. ^ Vihko KK (May 1996). "Gonadotropins and ovarian gonadotropin receptors during the perimenopausal transition period". Maturitas. 23 (Supplement): S19-22. doi:10.1016/s0378-5122(96)90009-2. PMID 8865134.
  14. ^ Dickerson LM, Shrader SP, Diaz VA (2008). "Chapter 8: Contraception". In Wells BG, DiPiro JT, Talbert RL, Yee GC, Matzke GR (eds.). Pharmacotherapy: a pathophysiologic approach. McGraw-Hill Medical. pp. 1313–28. ISBN 978-0-07-147899-1.
  15. ^ Boulpaep EL, Boron WF (2005). Medical physiology: a cellular and molecular approach. St. Louis, Mo: Elsevier Saunders. p. 1125. ISBN 978-1-4160-2328-9.
  16. ^ "FSH". labtestsonline.org. Retrieved 2019-05-06.
  17. ^ World Health Organization Technical Report Series N0. 565. WHO Expert Committee on Biological Standardization. Twenty-sixth Report. World Health Organization. Geneva. 1975
  18. ^ Practice Committee Of American Society For Reproductive Medicine B (November 2008). "Gonadotropin preparations: past, present, and future perspectives". Fertility and Sterility. 90 (5 Suppl): S13-20. doi:10.1016/j.fertnstert.2008.08.031. PMID 19007609.
  19. ^ Zhu D, Li X, Macrae VE, Simoncini T, Fu X (August 2018). "Extragonadal Effects of Follicle-Stimulating Hormone on Osteoporosis and Cardiovascular Disease in Women during Menopausal Transition" (PDF). Trends in Endocrinology and Metabolism. 29 (8): 571–580. doi:10.1016/j.tem.2018.06.001. hdl:20.500.11820/93f9b1f9-3c0d-4d4f-b18c-63842d2d075d. PMID 29983231. S2CID 51602238.
  20. ^ Li J, May W, McMurray RW (December 2005). "Pituitary hormones and systemic lupus erythematosus". Arthritis and Rheumatism. 52 (12): 3701–12. doi:10.1002/art.21436. PMID 16320320.
  21. ^ "Polycystic ovary syndrome: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 2019-05-06.
  22. ^ 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
  23. ^ Radu A, Pichon C, Camparo P, Antoine M, Allory Y, Couvelard A, et al. (October 2010). "Expression of follicle-stimulating hormone receptor in tumor blood vessels". The New England Journal of Medicine. 363 (17): 1621–30. doi:10.1056/NEJMoa1001283. PMID 20961245.
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