Gonadotropin-releasing hormone

Gonadotropin-releasing hormone 1 (luteinizing-releasing hormone)
from PDB: 1YY1​
Identifiers
Symbols	GNRH1 ; GNRH; GRH; HH12; LHRH; LNRH
External IDs	OMIM: 152760 MGI: 95789 HomoloGene: 641 GeneCards: GNRH1 Gene
Gene ontology Molecular function • hormone activity • gonadotropin hormone-releasing hormone activity • gonadotropin-releasing hormone receptor binding Cellular component • extracellular region • extracellular space • mitochondrion • Golgi-associated vesicle • dendrite • perikaryon • axon terminus • cytoplasmic side of rough endoplasmic reticulum membrane • neurosecretory vesicle Biological process • reproduction • signal transduction • cell-cell signaling • multicellular organismal development • female pregnancy • aging • negative regulation of cell proliferation • regulation of gene expression • male sex determination • response to corticosteroid • response to lipopolysaccharide • negative regulation of immature T cell proliferation • response to testosterone • response to prostaglandin E • response to potassium ion • negative regulation of apoptotic process • estrous cycle • response to ethanol • regulation of hormone secretion • response to prolactin • regulation of ovarian follicle development • negative regulation of neuron migration Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2796	14714
Ensembl	ENSG00000147437	ENSMUSG00000015812
UniProt	P01148	P13562
RefSeq (mRNA)	NM_000825	NM_008145
RefSeq (protein)	NP_000816	NP_032171
Location (UCSC)	Chr 8: 25.42 – 25.42 Mb	Chr 14: 67.75 – 67.75 Mb
PubMed search

Gonadotropin-releasing hormone (GnRH), also known as follicle-stimulating hormone–releasing hormone (FSH-RH), luteinizing hormone–releasing hormone (LHRH), gonadoliberin, and by various other names in its endogenous form and as gonadorelin (INN) in its pharmaceutical form, 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.

Structure

The identity of GnRH was clarified by the 1977 Nobel Laureates Roger Guillemin and Andrew V. Schally:

pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2

As 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 appearing are to standard 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 a 92-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.^[1] 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 the gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH).^[2] 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.^[3]

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.^[4]

GnRH secretion is pulsatile in all vertebrates [there is no evidence that this is correct—the only empirical evidence to date is for a handful of mammals], 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.^[1]

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.^[2] Kisspeptin appears to be an important regulator of GnRH release.^[5] GnRH release can also be regulated by estrogen. It has been reported that there are kisspeptin-producing neurons that also express estrogen receptor alpha.^[6]

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.^[7]

Effects of behavior

GnRH production/release is one of the few confirmed examples of behavior influencing hormones, rather than the other way around. 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.^[8] 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 males. Differences are also seen in females, with breeding females having smaller GnRH neurons than controls females.^[9] These examples suggest that GnRH is a socially regulated hormone.

Medical uses

Natural GnRH was previously prescribed as gonadorelin hydrochloride (Factrel)^[10] and gonadorelin diacetate tetrahydrate (Cystorelin)^[11] 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 Leuprolide is used for continuous infusion, to treat Breast carcinoma, endometriosis, prostate carcinoma, and following research in the 1980s by researchers, including Dr. Florence Comite of Yale University, it was used to treat precocious puberty.^[12][13]

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.^[14] 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.^[15]

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 what is observed naturally during an aggressive territorial encounter.^[16]

A compromised GnRH system has aversive 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.^[17]

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.

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:

name	symbol	other symbols	endogenous or pharmaceutical
gonadotropin-releasing factor	GnRF	GRF	endogenous
gonadotropin-releasing hormone	GnRH	GRH	endogenous
follicle-stimulating hormone–releasing factor	FRF	FSH-RF	endogenous
follicle-stimulating hormone–releasing hormone	FRH	FSH-RH	endogenous
luteinizing hormone–releasing factor	LRF	LHRF	endogenous
luteinizing hormone–releasing hormone	LRH	LHRH	endogenous
gonadoliberin			endogenous
luliberin			endogenous
gonadorelin			pharmaceutical (INN)

References

1. Campbell RE, Gaidamaka G, Han SK, Herbison AE (Jun 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. doi:10.1073/pnas.0903463106. PMC 2705602. PMID 19541658.
2. Brown RM (1994). An introduction to Neuroendocrinology. Cambridge, UK: Cambridge University Press. ISBN 0-521-42665-0.
3. Jayes FC, Britt JH, Esbenshade KL (Apr 1997). "Role of gonadotropin-releasing hormone pulse frequency in differential regulation of gonadotropins in the gilt" (PDF). Biology of Reproduction 56 (4): 1012–1019. doi:10.1095/biolreprod56.4.1012. PMID 9096885.
4. Ehlers K, Halvorson L (2013). "Gonadotropin-releasing Hormone (GnRH) and the GnRH Receptor (GnRHR)". The Global Library of Women's Medicine. doi:10.3843/GLOWM.10285. Retrieved 5 November 2014.
5. Dungan HM, Clifton DK, Steiner RA (Mar 2006). "Minireview: kisspeptin neurons as central processors in the regulation of gonadotropin-releasing hormone secretion". Endocrinology 147 (3): 1154–8. doi:10.1210/en.2005-1282. PMID 16373418.
6. Franceschini I, Lomet D, Cateau M, Delsol G, Tillet Y, Caraty A (Jul 2006). "Kisspeptin immunoreactive cells of the ovine preoptic area and arcuate nucleus co-express estrogen receptor alpha". Neuroscience Letters 401 (3): 225–30. doi:10.1016/j.neulet.2006.03.039. PMID 16621281.
7. Schally AV (1999). "Luteinizing hormone-releasing hormone analogs: their impact on the control of tumorigenesis". Peptides 20 (10): 1247–62. doi:10.1016/S0196-9781(99)00130-8. PMID 10573298.
8. Chee SS, Espinoza WA, Iwaniuk AN, Pakan JM, Gutiérrez-Ibáñez C, Wylie DR, Hurd PL (Jan 2013). "Social status, breeding state, and GnRH soma size in convict cichlids (Cryptoheros nigrofasciatus)". Behavioural Brain Research 237: 318–24. doi:10.1016/j.bbr.2012.09.023. PMID 23000535.
9. White SA, Nguyen T, Fernald RD (Sep 2002). "Social regulation of gonadotropin-releasing hormone" (PDF). The Journal of Experimental Biology 205 (Pt 17): 2567–81. PMID 12151363.
10. Drugs.com Factrel: Consumer Drug Information
11. Drugs.com Cystorelin: FDA Professional Drug Information
12. Comite F, Cutler GB, Rivier J, Vale WW, Loriaux DL, Crowley WF (Dec 1981). "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): 1546–1550. doi:10.1056/NEJM198112243052602. PMID 6458765.
13. Sonis WA, Comite F, Pescovitz OH, Hench K, Rahn CW, Cutler GB, Loriaux DL, Klein RP (Sep 1986). "Biobehavioral aspects of precocious puberty". Journal of the American Academy of Child Psychiatry 25 (5): 674–9. doi:10.1016/S0002-7138(09)60293-4. PMID 3760417.
14. Maney DL, Richardson RD, Wingfield JC (Aug 1997). "Central administration of chicken gonadotropin-releasing hormone-II enhances courtship behavior in a female sparrow". Hormones and Behavior 32 (1): 11–8. doi:10.1006/hbeh.1997.1399. PMID 9344687.
15. Schiml PA, Rissman EF (May 2000). "Effects of gonadotropin-releasing hormones, corticotropin-releasing hormone, and vasopressin on female sexual behavior". Hormones and Behavior 37 (3): 212–20. doi:10.1006/hbeh.2000.1575. PMID 10868484.
16. DeVries MS, Winters CP, Jawor JM (Jun 2012). "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. doi:10.1016/j.yhbeh.2012.05.008. PMID 22613708.
17. Brooks LR, Le CD, Chung WC, Tsai PS (2012). "Maternal behavior in transgenic mice with reduced fibroblast growth factor receptor function in gonadotropin-releasing hormone neurons". Behavioral and Brain Functions 8: 47. doi:10.1186/1744-9081-8-47. PMC 3503805. PMID 22950531.

Further reading

• Flanagan CA, Millar RP, Illing N (May 1997). "Advances in understanding gonadotrophin-releasing hormone receptor structure and ligand interactions". Reviews of Reproduction 2 (2): 113–20. doi:10.1530/ror.0.0020113. PMID 9414473.
• Leung PC, Cheng CK, Zhu XM (Apr 2003). "Multi-factorial role of GnRH-I and GnRH-II in the human ovary". Molecular and Cellular Endocrinology 202 (1-2): 145–53. doi:10.1016/S0303-7207(03)00076-5. PMID 12770744.
• Gründker C, Emons G (Oct 2003). "Role of gonadotropin-releasing hormone (GnRH) in ovarian cancer". Reproductive Biology and Endocrinology 1: 65. doi:10.1186/1477-7827-1-65. PMC 239893. PMID 14594454.
• Limonta P, Moretti RM, Montagnani Marelli M, Motta M (Dec 2003). "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. doi:10.1016/j.yfrne.2003.10.003. PMID 14726258.
• Janáky T, Juhász A, Bajusz S, Csernus V, Srkalovic G, Bokser L, Milovanovic S, Redding TW, Rékási Z, Nagy A (Feb 1992). "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. doi:10.1073/pnas.89.3.972. PMC 48367. PMID 1310542.
• Healey SC, Martin NG, Chenevix-Trench G (Nov 1991). "NcoI RFLP of the human LHRH gene on chromosome 8p". Nucleic Acids Research 19 (21): 6059. doi:10.1093/nar/19.21.6059. PMC 329079. PMID 1682898.
• Williamson P, Lang J, Boyd Y (Nov 1991). "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. doi:10.1007/BF01233626. PMID 1767338.
• Hayflick JS, Adelman JP, Seeburg PH (Aug 1989). "The complete nucleotide sequence of the human gonadotropin-releasing hormone gene". Nucleic Acids Research 17 (15): 6403–4. doi:10.1093/nar/17.15.6403. PMC 318303. PMID 2671939.
• Nikolics K, Mason AJ, Szönyi E, Ramachandran J, Seeburg PH (1985). "A prolactin-inhibiting factor within the precursor for human gonadotropin-releasing hormone". Nature 316 (6028): 511–7. doi:10.1038/316511a0. PMID 2863757.
• Adelman JP, Mason AJ, Hayflick JS, Seeburg PH (Jan 1986). "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. doi:10.1073/pnas.83.1.179. PMC 322815. PMID 2867548.
• Yang-Feng TL, Seeburg PH, Francke U (Jan 1986). "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. doi:10.1007/BF01560732. PMID 3511544.
• Seeburg PH, Adelman JP (1984). "Characterization of cDNA for precursor of human luteinizing hormone releasing hormone". Nature 311 (5987): 666–8. doi:10.1038/311666a0. PMID 6090951.
• Tan L, Rousseau P (Dec 1982). "The chemical identity of the immunoreactive LHRH-like peptide biosynthesized in the human placenta". Biochemical and Biophysical Research Communications 109 (3): 1061–71. doi:10.1016/0006-291X(82)92047-2. PMID 6760865.
• Dong KW, Yu KL, Roberts JL (Dec 1993). "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. doi:10.1210/me.7.12.1654. PMID 8145771.
• Kakar SS, Jennes L (Nov 1995). "Expression of gonadotropin-releasing hormone and gonadotropin-releasing hormone receptor mRNAs in various non-reproductive human tissues". Cancer Letters 98 (1): 57–62. doi:10.1016/S0304-3835(06)80010-8. PMID 8529206.
• Nagy A, Schally AV, Armatis P, Szepeshazi K, Halmos G, Kovacs M, Zarandi M, Groot K, Miyazaki M, Jungwirth A, Horvath J (Jul 1996). "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. doi:10.1073/pnas.93.14.7269. PMC 38972. PMID 8692981.
• Chegini N, Rong H, Dou Q, Kipersztok S, Williams RS (Sep 1996). "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. doi:10.1210/jc.81.9.3215. PMID 8784072.
• Bonaldo MF, Lennon G, Soares MB (Sep 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
• Dong KW, Yu KL, Chen ZG, Chen YD, Roberts JL (Jul 1997). "Characterization of multiple promoters directing tissue-specific expression of the human gonadotropin-releasing hormone gene". Endocrinology 138 (7): 2754–62. doi:10.1210/en.138.7.2754. PMID 9202214.
• Twan WH, Hwang JS, Lee YH, Jeng SR, Yueh WS, Tung YH, Wu HF, Dufour S, Chang CF (Jan 2006). "The presence and ancestral role of gonadotropin-releasing hormone in the reproduction of scleractinian coral, Euphyllia ancora". Endocrinology 147 (1): 397–406. doi:10.1210/en.2005-0584. PMID 16195400.