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 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.
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).[8] 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.[9]
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.[10]
GnRH secretion is pulsatile in all vertebrates,[11] 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.[7]
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.[8]Kisspeptin appears to be an important regulator of GnRH release.[12] GnRH release can also be regulated by estrogen. It has been reported that there are kisspeptin-producing neurons that also express estrogen receptor alpha.[13]
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.[14]
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]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.[15] 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.[16] These examples suggest that GnRH is a socially regulated hormone.[citation needed]
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.[17]
Natural GnRH was previously prescribed as gonadorelin hydrochloride (Factrel)[18] and gonadorelin diacetate tetrahydrate (Cystorelin)[19] 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.
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.[22] 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.[23] 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.[24]
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.[25]
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.[26]
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:
^Franceschini I, Lomet D, Cateau M, Delsol G, Tillet Y, Caraty A (July 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. PMID16621281. S2CID37619383.
^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.
^Comite F, Cutler GB, Rivier J, Vale WW, Loriaux DL, Crowley WF (December 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): 1546–50. doi:10.1056/NEJM198112243052602. PMID6458765.
^Sonis WA, Comite F, Pescovitz OH, Hench K, Rahn CW, Cutler GB, Loriaux DL, Klein RP (September 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. PMID3760417.
^Maney DL, Richardson RD, Wingfield JC (August 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. PMID9344687. S2CID31523984.
^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. PMID10868484. S2CID133262.
^DeVries MS, Winters CP, Jawor JM (June 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. PMID22613708. S2CID5551538.
Limonta P, Moretti RM, Montagnani Marelli M, Motta M (December 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. PMID14726258. S2CID33327806.
Williamson P, Lang J, Boyd Y (November 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. PMID1767338. S2CID41687915.
Yang-Feng TL, Seeburg PH, Francke U (January 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. PMID3511544. S2CID2067940.
Tan L, Rousseau P (December 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. PMID6760865.
Kakar SS, Jennes L (November 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. PMID8529206.
Chegini N, Rong H, Dou Q, Kipersztok S, Williams RS (September 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/jcem.81.9.8784072. PMID8784072. S2CID45976322.
