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{{Short description|Mammalian protein found in Homo sapiens}}{{About|GnRH as a hormone|its use as a medication|Gonadorelin}}{{More citations needed|date=January 2013}}

factoids

Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released from GnRH neurons within the hypothalamus. The peptide belongs to gonadotropin-releasing hormone family. It constitutes the initial step in the hypothalamic–pituitary–gonadal axis.{{citation needed|date=September 2023}}

Structure

The identityJOURNAL, Kochman, K., vanc, Evolution of gonadotropin-releasing hormone (GnRH) structure and its receptor, Journal of Animal and Feed Sciences, 2012, 21, 1, 6, 10.22358/jafs/66031/2012,weblink free, of GnRH was clarified by the 1977 Nobel Laureates Roger Guillemin and Andrew V. Schally:WEB, The Nobel Prize in Physiology or Medicine 1977,weblink www.nobelprize.org, Nobel Media AB 2014, 24 June 2016, pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2As is standard for peptide representation, the sequence is given from amino terminus to carboxyl terminus; also standard is omission of the designation of chirality, with assumption that all amino acids are in their L- form. The abbreviations are the standard abbreviations for the corresponding proteinogenic amino acids, except for pyroGlu, which refers to pyroglutamic acid, a derivative of glutamic acid. The NH2 at the carboxyl terminus indicates that rather than terminating as a free carboxylate, it terminates as a carboxamide.

Synthesis

The gene, GNRH1, for the GnRH precursor is located on chromosome 8. In mammals, the linear decapeptide end-product is synthesized from an 89-amino acid preprohormone in the preoptic anterior hypothalamus. It is the target of various regulatory mechanisms of the hypothalamic–pituitary–gonadal axis, such as being inhibited by increased estrogen levels in the body.

Function

GnRH is secreted in the hypophysial portal bloodstream at the median eminence. The portal blood carries the GnRH to the pituitary gland, which contains the gonadotrope cells, where GnRH activates its own receptor, gonadotropin-releasing hormone receptor (GnRHR), a seven-transmembrane G-protein-coupled receptor that stimulates the beta isoform of Phosphoinositide phospholipase C, which goes on to mobilize calcium and protein kinase C. This results in the activation of proteins involved in the synthesis and secretion of the gonadotropins LH and FSH. GnRH is degraded by proteolysis within a few minutes.GnRH activity is very low during childhood, and is activated at puberty or adolescence. During the reproductive years, pulse activity is critical for successful reproductive function as controlled by feedback loops. However, once a pregnancy is established, GnRH activity is not required. Pulsatile activity can be disrupted by hypothalamic-pituitary disease, either dysfunction (i.e., hypothalamic suppression) or organic lesions (trauma, tumor). Elevated prolactin levels decrease GnRH activity. In contrast, hyperinsulinemia increases pulse activity leading to disorderly LH and FSH activity, as seen in polycystic ovary syndrome (PCOS). GnRH formation is congenitally absent in Kallmann syndrome.

Control of FSH and LH

At the pituitary, GnRH stimulates the synthesis and secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These processes are controlled by the size and frequency of GnRH pulses, as well as by feedback from androgens and estrogens. Low-frequency GnRH pulses are required for FSH release, whereas high-frequency GnRH pulses stimulate LH pulses in a one-to-one manner.JOURNAL, Jayes FC, Britt JH, Esbenshade KL, Role of gonadotropin-releasing hormone pulse frequency in differential regulation of gonadotropins in the gilt, Biology of Reproduction, 56, 4, 1012–9, April 1997, 9096885, 10.1095/biolreprod56.4.1012, free, There are differences in GnRH secretion between females and males. In males, GnRH is secreted in pulses at a constant frequency; however, in females, the frequency of the pulses varies during the menstrual cycle, and there is a large surge of GnRH just before ovulation.JOURNAL, Ehlers K, Halvorson L, Gonadotropin-releasing Hormone (GnRH) and the GnRH Receptor (GnRHR),weblink The Global Library of Women's Medicine, 5 November 2014, 10.3843/GLOWM.10285, 2013, GnRH secretion is pulsatile in all vertebrates,JOURNAL, Tsutsumi R, Webster NJ, GnRH pulsatility, the pituitary response and reproductive dysfunction, Endocrine Journal, 56, 6, 729–37, 17 July 2009, 19609045, 4307809, 10.1507/endocrj.K09E-185, and is necessary for correct reproductive function. Thus, a single hormone, GnRH1, controls a complex process of follicular growth, ovulation, and corpus luteum maintenance in the female, and spermatogenesis in the male.

Neurohormone

GnRH is considered a neurohormone, a hormone produced in a specific neural cell and released at its neural terminal. A key area for production of GnRH is the preoptic area of the hypothalamus, which contains most of the GnRH-secreting neurons. GnRH neurons originate in the nose and migrate into the brain, where they are scattered throughout the medial septum and hypothalamus and connected by very long >1-millimeter-long dendrites. These bundle together so they receive shared synaptic input, a process that allows them to synchronize their GnRH release.JOURNAL, Rebecca Campbell (scientist), Campbell RE, Gaidamaka G, Han SK, Herbison AE, June 2009, Dendro-dendritic bundling and shared synapses between gonadotropin-releasing hormone neurons, Proceedings of the National Academy of Sciences of the United States of America, 106, 26, 10835–40, 2009PNAS..10610835C, 10.1073/pnas.0903463106, 2705602, 19541658, free, The GnRH neurons are regulated by many different afferent neurons, using several different transmitters (including norepinephrine, GABA, glutamate). For instance, dopamine appears to stimulate LH release (through GnRH) in estrogen-progesterone-primed females; dopamine may inhibit LH release in ovariectomized females.BOOK, Brown RM, An introduction to Neuroendocrinology, Cambridge University Press, Cambridge, UK, 1994, 978-0-521-42665-7, Kisspeptin appears to be an important regulator of GnRH release.JOURNAL, Dungan HM, Clifton DK, Steiner RA, Minireview: kisspeptin neurons as central processors in the regulation of gonadotropin-releasing hormone secretion, Endocrinology, 147, 3, 1154–8, March 2006, 16373418, 10.1210/en.2005-1282, free, GnRH release can also be regulated by estrogen. It has been reported that there are kisspeptin-producing neurons that also express estrogen receptor alpha.JOURNAL, Franceschini I, Lomet D, Cateau M, Delsol G, Tillet Y, Caraty A, Kisspeptin immunoreactive cells of the ovine preoptic area and arcuate nucleus co-express estrogen receptor alpha, Neuroscience Letters, 401, 3, 225–30, July 2006, 16621281, 10.1016/j.neulet.2006.03.039, 37619383,

Other organs

GnRH is found in organs outside of the hypothalamus and pituitary, and its role in other life processes is poorly understood. For instance, there is likely to be a role for GnRH1 in the placenta and in the gonads. GnRH and GnRH receptors are also found in cancers of the breast, ovary, prostate, and endometrium.JOURNAL, Schally AV, Luteinizing hormone-releasing hormone analogs: their impact on the control of tumorigenesis, Peptides, 20, 10, 1247–62, 1999, 10573298, 10.1016/S0196-9781(99)00130-8, 37855824,

Effects of behavior

GnRH production/release is one of the few confirmed examples in which behavior influences hormones, rather than the other way around.{{citation needed|date=December 2013}} Cichlid fish that become socially dominant in turn experience an upregulation of GnRH secretion whereas cichlid fish that are socially subordinate have a down regulation of GnRH secretion.JOURNAL, Chee SS, Espinoza WA, Iwaniuk AN, Pakan JM, Gutiérrez-Ibáñez C, Wylie DR, Hurd PL, Social status, breeding state, and GnRH soma size in convict cichlids (Cryptoheros nigrofasciatus), Behavioural Brain Research, 237, 318–24, January 2013, 23000535, 10.1016/j.bbr.2012.09.023, 9918871, Besides secretion, the social environment as well as their behavior affects the size of GnRH neurons. Specifically, males that are more territorial have larger GnRH neurons than males that are less territorial. Differences are also seen in females, with brooding females having smaller GnRH neurons than either spawning or control females.JOURNAL, White SA, Nguyen T, Fernald RD, Social regulation of gonadotropin-releasing hormone, The Journal of Experimental Biology, 205, Pt 17, 2567–81, September 2002, 10.1242/jeb.205.17.2567, 12151363,weblink These examples suggest that GnRH is a socially regulated hormone.{{citation needed|date=April 2022}}Multiple neuronal regions in the limbic system send signals to the hypothalamus to modulate the amount of GnRH production and the frequency of pulses. This provides a possible explanation for why psychic influences typically affect female sexual function.Mills EGA, O'Byrne KT, Comninos AN. The Roles of the Amygdala Kisspeptin System. Semin Reprod Med. 2019 Mar;37(2):64-70. doi: 10.1055/s-0039-3400462. Epub 2019 Dec 17. PMID 31847026.

Medical uses

Natural GnRH was previously prescribed as gonadorelin hydrochloride (Factrel)Drugs.com Factrel: {{Drugs.com|CDI|Factrel}} and gonadorelin diacetate tetrahydrate (Cystorelin)Drugs.com Cystorelin: {{Drugs.com|pro|Cystorelin}} for use in treating human diseases. Modifications of the decapeptide structure of GnRH to increase half life have led to GnRH1 analog medications that either stimulate (GnRH1 agonists) or suppress (GnRH antagonists) the gonadotropins. These synthetic analogs have replaced the natural hormone in clinical use.Its analogue leuprorelin is used for continuous infusion, to treat breast cancer, endometriosis, prostate cancer, and following research in the 1980s by researchers, including Dr. Florence Comite of Yale University, it was used to treat precocious puberty.JOURNAL, Comite F, Cutler GB, Rivier J, Vale WW, Loriaux DL, Crowley WF, Short-term treatment of idiopathic precocious puberty with a long-acting analogue of luteinizing hormone-releasing hormone. A preliminary report, The New England Journal of Medicine, 305, 26, 1546–50, December 1981, 6458765, 10.1056/NEJM198112243052602, JOURNAL, Sonis WA, Comite F, Pescovitz OH, Hench K, Rahn CW, Cutler GB, Loriaux DL, Klein RP, Biobehavioral aspects of precocious puberty, Journal of the American Academy of Child Psychiatry, 25, 5, 674–9, September 1986, 3760417, 10.1016/S0002-7138(09)60293-4, A Cochrane Review is available which investigates whether GnRH analogues, given before or alongside chemotherapy, could prevent damage to women's ovaries caused by chemotherapy.JOURNAL, Chen H, Xiao L, Li J, Cui L, Huang W, Adjuvant gonadotropin-releasing hormone analogues for the prevention of chemotherapy-induced premature ovarian failure in premenopausal women, The Cochrane Database of Systematic Reviews, 3, CD008018, March 2019, 8, 30827035, 6397718, 10.1002/14651858.cd008018.pub3, GnRH agonists appear to be effective in protecting the ovaries during chemotherapy, in terms of menstruation recovery or maintenance, premature ovarian failure and ovulation.

Animal sexual behavior

GnRH activity influences a variety of sexual behaviors. Increased levels of GnRH facilitate sexual displays and behavior in females. GnRH injections enhance copulation solicitation (a type of courtship display) in white-crowned sparrows.JOURNAL, Maney DL, Richardson RD, Wingfield JC, Central administration of chicken gonadotropin-releasing hormone-II enhances courtship behavior in a female sparrow, Hormones and Behavior, 32, 1, 11–8, August 1997, 9344687, 10.1006/hbeh.1997.1399, 31523984, In mammals, GnRH injections facilitate sexual behavior of female display behaviors as shown with the musk shrew’s (Suncus murinus) reduced latency in displaying rump presents and tail wagging towards males.JOURNAL, Schiml PA, Rissman EF, Effects of gonadotropin-releasing hormones, corticotropin-releasing hormone, and vasopressin on female sexual behavior, Hormones and Behavior, 37, 3, 212–20, May 2000, 10868484, 10.1006/hbeh.2000.1575, 133262, An elevation of GnRH raises males’ testosterone capacity beyond a male's natural testosterone level. Injections of GnRH in male birds immediately after an aggressive territorial encounter results in higher testosterone levels than is observed naturally during an aggressive territorial encounter.JOURNAL, DeVries MS, Winters CP, Jawor JM, Testosterone elevation and response to gonadotropin-releasing hormone challenge by male northern cardinals (Cardinalis cardinalis) following aggressive behavior, Hormones and Behavior, 62, 1, 99–105, June 2012, 22613708, 10.1016/j.yhbeh.2012.05.008, 5551538, A compromised GnRH system has adverse effects on reproductive physiology and maternal behavior. In comparison to female mice with a normal GnRH system, female mice with a 30% decrease in GnRH neurons are poor caregivers to their offspring. These mice are more likely to leave their pups scattered rather than grouped together, and will take significantly longer to retrieve their pups.JOURNAL, Brooks LR, Le CD, Chung WC, Tsai PS, Maternal behavior in transgenic mice with reduced fibroblast growth factor receptor function in gonadotropin-releasing hormone neurons, Behavioral and Brain Functions, 8, 47, 2012, 22950531, 3503805, 10.1186/1744-9081-8-47, free,

Veterinary use

The natural hormone is also used in veterinary medicine as a treatment for cattle with cystic ovarian disease. The synthetic analogue deslorelin is used in veterinary reproductive control through a sustained-release implant.

Other names

As with many hormones, GnRH has been called by various names in the medical literature over the decades since its existence was first inferred. They are as follows:

• Gonadotropin-releasing factor (GnRF, GRF); Gonadotropin-releasing hormone (GnRH, GRH)
• Follicle-stimulating hormone-releasing factor (FRF, FSH-RF); Follicle-stimulating hormone-releasing hormone (FRH, FSH-RH)
• Luteinizing hormone-releasing factor (LRF, LHRF); Luteinizing hormone-releasing hormone (LRH, LHRH)
• Follicle-stimulating hormone and luteinizing hormone–releasing factor (FSH/LH-RF); Follicle-stimulating hormone and luteinizing hormone-releasing hormone (FSH/LH-RH)
• Luteinizing hormone and follicle-stimulating hormone–releasing factor (LH/FSH-RF); Luteinizing hormone and follicle-stimulating hormone-releasing hormone (LH/FSH-RH)
• Gonadorelin (INN for pharmaceutical form)
• Gonadoliberin

See also

• Gonadotropin-releasing hormone receptor § Agonists
• GnRH modulator
• Progonadotropin
• Gonadotropin surge-attenuating factor
• GNRH2, a similar gene
• Gonadotropin-inhibitory hormone
• Breastfeeding and fertility

References

{{Reflist|35em}}

Further reading

• JOURNAL, Flanagan CA, Millar RP, Illing N, Advances in understanding gonadotrophin-releasing hormone receptor structure and ligand interactions, Reviews of Reproduction, 2, 2, 113–20, May 1997, 9414473, 10.1530/ror.0.0020113,
• JOURNAL, Leung PC, Cheng CK, Zhu XM, Multi-factorial role of GnRH-I and GnRH-II in the human ovary, Molecular and Cellular Endocrinology, 202, 1–2, 145–53, April 2003, 12770744, 10.1016/S0303-7207(03)00076-5, 24945436,
• JOURNAL, Gründker C, Emons G, Role of gonadotropin-releasing hormone (GnRH) in ovarian cancer, Reproductive Biology and Endocrinology, 1, 65, October 2003, 14594454, 239893, 10.1186/1477-7827-1-65, free,
• JOURNAL, Limonta P, Moretti RM, Montagnani Marelli M, Motta M, The biology of gonadotropin hormone-releasing hormone: role in the control of tumor growth and progression in humans, Frontiers in Neuroendocrinology, 24, 4, 279–95, December 2003, 14726258, 10.1016/j.yfrne.2003.10.003, 33327806,
• JOURNAL, Janáky T, Juhász A, Bajusz S, Csernus V, Srkalovic G, Bokser L, Milovanovic S, Redding TW, Rékási Z, Nagy A, Analogues of luteinizing hormone-releasing hormone containing cytotoxic groups, Proceedings of the National Academy of Sciences of the United States of America, 89, 3, 972–6, February 1992, 1310542, 48367, 10.1073/pnas.89.3.972, 1992PNAS...89..972J, free,
• JOURNAL, Healey SC, Martin NG, Chenevix-Trench G, NcoI RFLP of the human LHRH gene on chromosome 8p, Nucleic Acids Research, 19, 21, 6059, November 1991, 1682898, 329079, 10.1093/nar/19.21.6059,
• JOURNAL, Williamson P, Lang J, Boyd Y, The gonadotropin-releasing hormone (Gnrh) gene maps to mouse chromosome 14 and identifies a homologous region on human chromosome 8, Somatic Cell and Molecular Genetics, 17, 6, 609–15, November 1991, 1767338, 10.1007/BF01233626, 41687915,
• JOURNAL, Hayflick JS, Adelman JP, Seeburg PH, The complete nucleotide sequence of the human gonadotropin-releasing hormone gene, Nucleic Acids Research, 17, 15, 6403–4, August 1989, 2671939, 318303, 10.1093/nar/17.15.6403,
• JOURNAL, Nikolics K, Mason AJ, Szönyi E, Ramachandran J, Seeburg PH, A prolactin-inhibiting factor within the precursor for human gonadotropin-releasing hormone, Nature, 316, 6028, 511–7, 1985, 2863757, 10.1038/316511a0, 1985Natur.316..511N, 4276604,
• JOURNAL, Adelman JP, Mason AJ, Hayflick JS, Seeburg PH, Isolation of the gene and hypothalamic cDNA for the common precursor of gonadotropin-releasing hormone and prolactin release-inhibiting factor in human and rat, Proceedings of the National Academy of Sciences of the United States of America, 83, 1, 179–83, January 1986, 2867548, 322815, 10.1073/pnas.83.1.179, 1986PNAS...83..179A, free,
• JOURNAL, Yang-Feng TL, Seeburg PH, Francke U, Human luteinizing hormone-releasing hormone gene (LHRH) is located on short arm of chromosome 8 (region 8p11.2----p21), Somatic Cell and Molecular Genetics, 12, 1, 95–100, January 1986, 3511544, 10.1007/BF01560732, 2067940,
• JOURNAL, Seeburg PH, Adelman JP, Characterization of cDNA for precursor of human luteinizing hormone releasing hormone, Nature, 311, 5987, 666–8, 1984, 6090951, 10.1038/311666a0, 1984Natur.311..666S, 4286007,
• JOURNAL, Tan L, Rousseau P, The chemical identity of the immunoreactive LHRH-like peptide biosynthesized in the human placenta, Biochemical and Biophysical Research Communications, 109, 3, 1061–71, December 1982, 6760865, 10.1016/0006-291X(82)92047-2,
• JOURNAL, Dong KW, Yu KL, Roberts JL, Identification of a major up-stream transcription start site for the human progonadotropin-releasing hormone gene used in reproductive tissues and cell lines, Molecular Endocrinology, 7, 12, 1654–66, December 1993, 10.1210/mend.7.12.8145771, 8145771, free,
• JOURNAL, Kakar SS, Jennes L, Expression of gonadotropin-releasing hormone and gonadotropin-releasing hormone receptor mRNAs in various non-reproductive human tissues, Cancer Letters, 98, 1, 57–62, November 1995, 8529206, 10.1016/S0304-3835(06)80010-8,
• JOURNAL, Nagy A, Schally AV, Armatis P, Szepeshazi K, Halmos G, Kovacs M, Zarandi M, Groot K, Miyazaki M, Jungwirth A, Horvath J, Cytotoxic analogs of luteinizing hormone-releasing hormone containing doxorubicin or 2-pyrrolinodoxorubicin, a derivative 500-1000 times more potent, Proceedings of the National Academy of Sciences of the United States of America, 93, 14, 7269–73, July 1996, 8692981, 38972, 10.1073/pnas.93.14.7269, 1996PNAS...93.7269N, free,
• JOURNAL, Chegini N, Rong H, Dou Q, Kipersztok S, Williams RS, Gonadotropin-releasing hormone (GnRH) and GnRH receptor gene expression in human myometrium and leiomyomata and the direct action of GnRH analogs on myometrial smooth muscle cells and interaction with ovarian steroids in vitro, The Journal of Clinical Endocrinology and Metabolism, 81, 9, 3215–21, September 1996, 10.1210/jcem.81.9.8784072, 8784072, 45976322,
• JOURNAL, Bonaldo MF, Lennon G, Soares MB, Normalization and subtraction: two approaches to facilitate gene discovery, Genome Research, 6, 9, 791–806, September 1996, 8889548, 10.1101/gr.6.9.791, free,
• JOURNAL, Dong KW, Yu KL, Chen ZG, Chen YD, Roberts JL, Characterization of multiple promoters directing tissue-specific expression of the human gonadotropin-releasing hormone gene, Endocrinology, 138, 7, 2754–62, July 1997, 9202214, 10.1210/endo.138.7.5249, free,
• JOURNAL, Twan WH, Hwang JS, Lee YH, Jeng SR, Yueh WS, Tung YH, Wu HF, Dufour S, Chang CF, The presence and ancestral role of gonadotropin-releasing hormone in the reproduction of scleractinian coral, Euphyllia ancora, Endocrinology, 147, 1, 397–406, January 2006, 16195400, 10.1210/en.2005-0584, free,

External links

• {{PDBe-KB2|P01148|Progonadoliberin-1}}

{{GnRH and gonadotropins}}{{Hormones}}{{Neuropeptides}}{{GnRH and gonadotropin receptor modulators}}