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{{Refimprove|date=January 2013}}
{{About|GnRH as a hormone|its use as a medication|Gonadorelin}}
{{About|the GnRH protein|medical uses of GnRH |GnRH agonists}}
{{More citations needed|date=January 2013}}
{{Infobox gene}}
{{Infobox gene}}


'''Gonadotropin-releasing hormone''' ('''GnRH''') also known as '''gonadoliberin''', and [[#Names|by various other names]] in its [[endogeny (biology)|endogenous]] form and as '''gonadorelin''' ([[International Nonproprietary Name|INN]]) in its [[pharmaceutical drug|pharmaceutical]] form, is a [[releasing and inhibiting hormones|releasing hormone]] responsible for the release of [[follicle-stimulating hormone]] (FSH) and [[luteinizing hormone]] (LH) from the [[anterior pituitary]]. GnRH is a [[tropic hormone|tropic]] [[peptide hormone]] synthesized and released from [[GnRH Neuron|GnRH neurons]] within the [[hypothalamus]]. The peptide belongs to [[gonadotropin-releasing hormone family]]. It constitutes the initial step in the [[hypothalamic–pituitary–gonadal axis]].
'''Gonadotropin-releasing hormone''' ('''GnRH''') is a [[releasing and inhibiting hormones|releasing hormone]] responsible for the release of [[follicle-stimulating hormone]] (FSH) and [[luteinizing hormone]] (LH) from the [[anterior pituitary]]. GnRH is a [[tropic hormone|tropic]] [[peptide hormone]] synthesized and released from [[GnRH Neuron|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==
==Structure==
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==Synthesis==
==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 [[Hypothalamic–pituitary–gonadal axis#regulation|regulatory mechanisms of the hypothalamic–pituitary–gonadal axis]], such as being inhibited by increased [[estrogen]] levels in the body.
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 [[Hypothalamic–pituitary–gonadal axis#regulation|regulatory mechanisms of the hypothalamic–pituitary–gonadal axis]], such as being inhibited by increased [[estrogen]] levels in the body.


==Function==
==Function==
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===Control of FSH and LH===
===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).<ref name=isbn0-521-42665-0 /> 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.<ref>{{cite journal | vauthors = Jayes FC, Britt JH, Esbenshade KL | title = Role of gonadotropin-releasing hormone pulse frequency in differential regulation of gonadotropins in the gilt | journal = Biology of Reproduction | volume = 56 | issue = 4 | pages = 1012–9 | date = April 1997 | pmid = 9096885 | doi = 10.1095/biolreprod56.4.1012 | url = http://www.biolreprod.org/content/56/4/1012.full.pdf }}</ref>
At the pituitary, GnRH stimulates the synthesis and secretion of the [[gonadotropins]], [[follicle-stimulating hormone]] (FSH), and [[luteinizing hormone]] (LH).<ref name=isbn0-521-42665-0 /> 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.<ref>{{cite journal | vauthors = Jayes FC, Britt JH, Esbenshade KL | title = Role of gonadotropin-releasing hormone pulse frequency in differential regulation of gonadotropins in the gilt | journal = Biology of Reproduction | volume = 56 | issue = 4 | pages = 1012–9 | date = April 1997 | pmid = 9096885 | doi = 10.1095/biolreprod56.4.1012 | url = http://www.biolreprod.org/content/56/4/1012.full.pdf | deadurl = yes | archiveurl = https://web.archive.org/web/20150923190449/http://www.biolreprod.org/content/56/4/1012.full.pdf | archivedate = 2015-09-23 | df =  }}</ref>


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.<ref>{{cite web | last1 = Ehlers | first1 = K | last2 = Halvorson | first2 = L | title = Gonadotropin-releasing Hormone (GnRH) and the GnRH Receptor (GnRHR) | url = http://www.glowm.com/section_view/item/284/recordset/18975/value/284 | website = The Global Library of Women's Medicine | accessdate = 5 November 2014 | doi = 10.3843/GLOWM.10285 | date = 2013 | name-list-format = vanc }}</ref>
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.<ref>{{cite web | vauthors = Ehlers K, Halvorson L | title = Gonadotropin-releasing Hormone (GnRH) and the GnRH Receptor (GnRHR) | url = http://www.glowm.com/section_view/item/284/recordset/18975/value/284 | website = The Global Library of Women's Medicine | access-date = 5 November 2014 | doi = 10.3843/GLOWM.10285 | date = 2013 }}</ref>


GnRH secretion is pulsatile in all vertebrates {{citation needed|date=July 2017}}, and is necessary for correct reproductive function.  
GnRH secretion is [[Pulsatile secretion|pulsatile]] in all vertebrates,<ref>{{cite journal | vauthors = Tsutsumi R, Webster NJ | title = GnRH pulsatility, the pituitary response and reproductive dysfunction | journal = Endocrine Journal | volume = 56 | issue = 6 | pages = 729–37 | date = 17 July 2009 | pmid = 19609045 | pmc = 4307809 | doi = 10.1507/endocrj.K09E-185 }}</ref> and is necessary for correct reproductive function. Thus, a single hormone, GnRH1, controls a complex process of [[Ovarian follicle|follicular]] growth, [[ovulation]], and [[corpus luteum]] maintenance in the female, and [[spermatogenesis]] in the male.
Thus, a single hormone, GnRH1, controls a complex process of [[Ovarian follicle|follicular]] growth, [[ovulation]], and [[corpus luteum]] maintenance in the female, and [[spermatogenesis]] in the male.


===Neurohormone===
===Neurohormone===
GnRH is considered a [[neurohormone]], a [[hormone]] produced in a specific [[Neuron|neural cell]] and released at its [[Neuron#Anatomy and histology|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 Neuron|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 [[dendrite]]s. These bundle together so they receive shared [[Synapse|synaptic]] input, a process that allows them to synchronize their GnRH release.<ref name="pmid19541658">{{cite journal | vauthors = Campbell RE, Gaidamaka G, Han SK, Herbison AE | title = Dendro-dendritic bundling and shared synapses between gonadotropin-releasing hormone neurons | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 26 | pages = 10835–40 | date = June 2009 | pmid = 19541658 | pmc = 2705602 | doi = 10.1073/pnas.0903463106 }}</ref>
GnRH is considered a [[neurohormone]], a [[hormone]] produced in a specific [[Neuron|neural cell]] and released at its [[Neuron#Anatomy and histology|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 Neuron|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 [[dendrite]]s. These bundle together so they receive shared [[Synapse|synaptic]] input, a process that allows them to synchronize their GnRH release.<ref name="pmid19541658">{{cite journal | vauthors = Campbell RE, Gaidamaka G, Han SK, Herbison AE | title = Dendro-dendritic bundling and shared synapses between gonadotropin-releasing hormone neurons | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 26 | pages = 10835–40 | date = June 2009 | pmid = 19541658 | pmc = 2705602 | doi = 10.1073/pnas.0903463106 }}</ref>


The [[GnRH Neuron|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.<ref name="isbn0-521-42665-0">{{cite book | author = Brown RM | authorlink = | editor = | others = | title = An introduction to Neuroendocrinology | edition = | publisher = Cambridge University Press | location = Cambridge, UK | year = 1994 | origyear = | pages = | quote = | isbn = 0-521-42665-0 | oclc = | doi = | url = | accessdate = }}</ref> [[Kisspeptin]] appears to be an important regulator of GnRH release.<ref name="pmid16373418">{{cite journal | vauthors = Dungan HM, Clifton DK, Steiner RA | title = Minireview: kisspeptin neurons as central processors in the regulation of gonadotropin-releasing hormone secretion | journal = Endocrinology | volume = 147 | issue = 3 | pages = 1154–8 | date = March 2006 | pmid = 16373418 | doi = 10.1210/en.2005-1282 }}</ref> GnRH release can also be regulated by [[estrogen]]. It has been reported that there are kisspeptin-producing neurons that also express [[estrogen receptor|estrogen receptor alpha]].<ref name="pmid16621281">{{cite journal | vauthors = Franceschini I, Lomet D, Cateau M, Delsol G, Tillet Y, Caraty A | title = Kisspeptin immunoreactive cells of the ovine preoptic area and arcuate nucleus co-express estrogen receptor alpha | journal = Neuroscience Letters | volume = 401 | issue = 3 | pages = 225–30 | date = July 2006 | pmid = 16621281 | doi = 10.1016/j.neulet.2006.03.039 }}</ref>
The [[GnRH Neuron|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.<ref name="isbn0-521-42665-0">{{cite book | author = Brown RM | authorlink = | editor = | others = | title = An introduction to Neuroendocrinology | edition = | publisher = Cambridge University Press | location = Cambridge, UK | year = 1994 | origyear = | pages = | quote = | isbn = 0-521-42665-0 | oclc = | doi = | url = | accessdate = }}</ref> [[Kisspeptin]] appears to be an important regulator of GnRH release.<ref name="pmid16373418">{{cite journal | vauthors = Dungan HM, Clifton DK, Steiner RA | title = Minireview: kisspeptin neurons as central processors in the regulation of gonadotropin-releasing hormone secretion | journal = Endocrinology | volume = 147 | issue = 3 | pages = 1154–8 | date = March 2006 | pmid = 16373418 | doi = 10.1210/en.2005-1282 }}</ref> GnRH release can also be regulated by [[estrogen]]. It has been reported that there are [[KNDy neuron|kisspeptin-producing neurons]] that also express [[estrogen receptor|estrogen receptor alpha]].<ref name="pmid16621281">{{cite journal | vauthors = Franceschini I, Lomet D, Cateau M, Delsol G, Tillet Y, Caraty A | title = Kisspeptin immunoreactive cells of the ovine preoptic area and arcuate nucleus co-express estrogen receptor alpha | journal = Neuroscience Letters | volume = 401 | issue = 3 | pages = 225–30 | date = July 2006 | pmid = 16621281 | doi = 10.1016/j.neulet.2006.03.039 }}</ref>


===Other organs===
===Other organs===
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==Effects of behavior==
==Effects of behavior==
GnRH production/release is one of the few confirmed examples of behavior influencing 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.<ref name="pmid23000535">{{cite journal | vauthors = Chee SS, Espinoza WA, Iwaniuk AN, Pakan JM, Gutiérrez-Ibáñez C, Wylie DR, Hurd PL | title = Social status, breeding state, and GnRH soma size in convict cichlids (Cryptoheros nigrofasciatus) | journal = Behavioural Brain Research | volume = 237 | issue = | pages = 318–24 | date = January 2013 | pmid = 23000535 | doi = 10.1016/j.bbr.2012.09.023 }}</ref> Besides secretion, the social environment as well as their behavior affects the size of [[GnRH Neuron|GnRH neurons]]. Specifically, males that are more territorial have larger [[GnRH Neuron|GnRH neurons]] than males that are less territorial. Differences are also seen in females, with breeding females having smaller [[GnRH Neuron|GnRH neurons]] than control females.<ref name="pmid12151363">{{cite journal | vauthors = White SA, Nguyen T, Fernald RD | title = Social regulation of gonadotropin-releasing hormone | journal = The Journal of Experimental Biology | volume = 205 | issue = Pt 17 | pages = 2567–81 | date = September 2002 | pmid = 12151363 | doi = | url = http://jeb.biologists.org/content/205/17/2567.full.pdf }}</ref> These examples suggest that GnRH is a socially regulated hormone.
GnRH production/release is one of the few confirmed examples of behavior influencing 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.<ref name="pmid23000535">{{cite journal | vauthors = Chee SS, Espinoza WA, Iwaniuk AN, Pakan JM, Gutiérrez-Ibáñez C, Wylie DR, Hurd PL | title = Social status, breeding state, and GnRH soma size in convict cichlids (Cryptoheros nigrofasciatus) | journal = Behavioural Brain Research | volume = 237 | issue = | pages = 318–24 | date = January 2013 | pmid = 23000535 | doi = 10.1016/j.bbr.2012.09.023 }}</ref> Besides secretion, the social environment as well as their behavior affects the size of [[GnRH Neuron|GnRH neurons]]. Specifically, males that are more territorial have larger [[GnRH Neuron|GnRH neurons]] than males that are less territorial. Differences are also seen in females, with brooding females having smaller [[GnRH Neuron|GnRH neurons]] than either spawning or control females.<ref name="pmid12151363">{{cite journal | vauthors = White SA, Nguyen T, Fernald RD | title = Social regulation of gonadotropin-releasing hormone | journal = The Journal of Experimental Biology | volume = 205 | issue = Pt 17 | pages = 2567–81 | date = September 2002 | pmid = 12151363 | doi = | url = http://jeb.biologists.org/content/205/17/2567.full.pdf }}</ref> These examples suggest that GnRH is a socially regulated hormone.


==Medical uses==
==Medical uses==
{{main article|gonadotropin-releasing hormone agonist}}
{{Main article|Gonadorelin|Gonadotropin-releasing hormone agonist}}


Natural GnRH was previously prescribed as gonadorelin hydrochloride (Factrel)<ref>[[Drugs.com]] Factrel: {{Drugs.com|CDI|Factrel}}</ref> and gonadorelin diacetate tetrahydrate (Cystorelin)<ref>[[Drugs.com]] Cystorelin: {{Drugs.com|pro|Cystorelin}}</ref> for use in treating human diseases. Modifications of the [[decapeptide]] structure of GnRH to increase half life have led to [[GnRH analog|GnRH1 analog]] medications that either stimulate ([[GnRH agonist|GnRH1 agonist]]s) or suppress ([[GnRH antagonist]]s) the gonadotropins. These synthetic analogs have replaced the natural hormone in clinical use.
Natural GnRH was previously prescribed as [[gonadorelin]] hydrochloride (Factrel)<ref>[[Drugs.com]] Factrel: {{Drugs.com|CDI|Factrel}}</ref> and gonadorelin diacetate tetrahydrate (Cystorelin)<ref>[[Drugs.com]] Cystorelin: {{Drugs.com|pro|Cystorelin}}</ref> for use in treating human diseases. Modifications of the [[decapeptide]] structure of GnRH to increase half life have led to [[GnRH analog|GnRH1 analog]] medications that either stimulate ([[GnRH agonist|GnRH1 agonist]]s) or suppress ([[GnRH antagonist]]s) 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]].<ref name=nejm_PP>{{cite journal | vauthors = Comite F, Cutler GB, Rivier J, Vale WW, Loriaux DL, Crowley WF | title = Short-term treatment of idiopathic precocious puberty with a long-acting analogue of luteinizing hormone-releasing hormone. A preliminary report | journal = The New England Journal of Medicine | volume = 305 | issue = 26 | pages = 1546–50 | date = December 1981 | pmid = 6458765 | doi = 10.1056/NEJM198112243052602 }}</ref><ref name="AACS">{{cite journal | vauthors = Sonis WA, Comite F, Pescovitz OH, Hench K, Rahn CW, Cutler GB, Loriaux DL, Klein RP | title = Biobehavioral aspects of precocious puberty | journal = Journal of the American Academy of Child Psychiatry | volume = 25 | issue = 5 | pages = 674–9 | date = September 1986 | pmid = 3760417 | doi = 10.1016/S0002-7138(09)60293-4 }}</ref>
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]].<ref name=nejm_PP>{{cite journal | vauthors = Comite F, Cutler GB, Rivier J, Vale WW, Loriaux DL, Crowley WF | title = Short-term treatment of idiopathic precocious puberty with a long-acting analogue of luteinizing hormone-releasing hormone. A preliminary report | journal = The New England Journal of Medicine | volume = 305 | issue = 26 | pages = 1546–50 | date = December 1981 | pmid = 6458765 | doi = 10.1056/NEJM198112243052602 }}</ref><ref name="AACS">{{cite journal | vauthors = Sonis WA, Comite F, Pescovitz OH, Hench K, Rahn CW, Cutler GB, Loriaux DL, Klein RP | title = Biobehavioral aspects of precocious puberty | journal = Journal of the American Academy of Child Psychiatry | volume = 25 | issue = 5 | pages = 674–9 | date = September 1986 | pmid = 3760417 | doi = 10.1016/S0002-7138(09)60293-4 }}</ref>


==Animal sexual behavior==
==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 sparrow]]s.<ref name="pmid9344687">{{cite journal | vauthors = Maney DL, Richardson RD, Wingfield JC | title = Central administration of chicken gonadotropin-releasing hormone-II enhances courtship behavior in a female sparrow | journal = Hormones and Behavior | volume = 32 | issue = 1 | pages = 11–8 | date = August 1997 | pmid = 9344687 | doi = 10.1006/hbeh.1997.1399 }}</ref> 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.<ref name="pmid10868484">{{cite journal | vauthors = Schiml PA, Rissman EF | title = Effects of gonadotropin-releasing hormones, corticotropin-releasing hormone, and vasopressin on female sexual behavior | journal = Hormones and Behavior | volume = 37 | issue = 3 | pages = 212–20 | date = May 2000 | pmid = 10868484 | doi = 10.1006/hbeh.2000.1575 }}</ref>
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 sparrow]]s.<ref name="pmid9344687">{{cite journal | vauthors = Maney DL, Richardson RD, Wingfield JC | title = Central administration of chicken gonadotropin-releasing hormone-II enhances courtship behavior in a female sparrow | journal = Hormones and Behavior | volume = 32 | issue = 1 | pages = 11–8 | date = August 1997 | pmid = 9344687 | doi = 10.1006/hbeh.1997.1399 }}</ref> 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.<ref name="pmid10868484">{{cite journal | vauthors = Schiml PA, Rissman EF | title = Effects of gonadotropin-releasing hormones, corticotropin-releasing hormone, and vasopressin on female sexual behavior | journal = Hormones and Behavior | volume = 37 | issue = 3 | pages = 212–20 | date = May 2000 | pmid = 10868484 | doi = 10.1006/hbeh.2000.1575 }}</ref>


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.<ref name="pmid22613708">{{cite journal | vauthors = DeVries MS, Winters CP, Jawor JM | title = Testosterone elevation and response to gonadotropin-releasing hormone challenge by male northern cardinals (Cardinalis cardinalis) following aggressive behavior | journal = Hormones and Behavior | volume = 62 | issue = 1 | pages = 99–105 | date = June 2012 | pmid = 22613708 | doi = 10.1016/j.yhbeh.2012.05.008 }}</ref>
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.<ref name="pmid22613708">{{cite journal | vauthors = DeVries MS, Winters CP, Jawor JM | title = Testosterone elevation and response to gonadotropin-releasing hormone challenge by male northern cardinals (Cardinalis cardinalis) following aggressive behavior | journal = Hormones and Behavior | volume = 62 | issue = 1 | pages = 99–105 | date = June 2012 | pmid = 22613708 | doi = 10.1016/j.yhbeh.2012.05.008 }}</ref>


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 Neuron|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.<ref name="pmid22950531">{{cite journal | vauthors = Brooks LR, Le CD, Chung WC, Tsai PS | title = Maternal behavior in transgenic mice with reduced fibroblast growth factor receptor function in gonadotropin-releasing hormone neurons | journal = Behavioral and Brain Functions | volume = 8 | issue = | pages = 47 | year = 2012 | pmid = 22950531 | pmc = 3503805 | doi = 10.1186/1744-9081-8-47 }}</ref>
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 Neuron|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.<ref name="pmid22950531">{{cite journal | vauthors = Brooks LR, Le CD, Chung WC, Tsai PS | title = Maternal behavior in transgenic mice with reduced fibroblast growth factor receptor function in gonadotropin-releasing hormone neurons | journal = Behavioral and Brain Functions | volume = 8 | issue = | pages = 47 | year = 2012 | pmid = 22950531 | pmc = 3503805 | doi = 10.1186/1744-9081-8-47 }}</ref>


==Veterinary use==
==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.
{{Main|Gonadorelin}}


==Names==
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:
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:


{| class="wikitable sortable" border=1
* 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)
! scope="col" style="width: 55%;" | name
* Luteinizing hormone-releasing factor (LRF, LHRF); Luteinizing hormone-releasing hormone (LRH, LHRH)
! scope="col" style="width: 15%;" | symbol
* Follicle-stimulating hormone and luteinizing hormone–releasing factor (FSH/LH-RF); Follicle-stimulating hormone and luteinizing hormone-releasing hormone (FSH/LH-RH)
! scope="col" style="width: 15%;" | other symbols
* Luteinizing hormone and follicle-stimulating hormone–releasing factor (LH/FSH-RF); Luteinizing hormone and follicle-stimulating hormone-releasing hormone (LH/FSH-RH)
! scope="col" style="width: 15%;" | endogenous or pharmaceutical
* Gonadorelin ([[International nonproprietary name|INN]] for pharmaceutical form)
|-
*Gonadoliberin
| 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
|-
| follicle-stimulating hormone and luteinizing hormone–releasing factor || FSH/LH-RF || || endogenous
|-
| follicle-stimulating hormone and luteinizing hormone–releasing hormone || FSH/LH-RH || || endogenous
|-
| luteinizing hormone–releasing factor || LRF || LHRF || endogenous
|-
| luteinizing hormone–releasing hormone || LRH || LHRH || endogenous
|-
| luteinizing hormone and follicle-stimulating hormone–releasing factor || LH/FSH-RF || || endogenous
|-
| luteinizing hormone and follicle-stimulating hormone–releasing hormone || LH/FSH-RH || || endogenous
|-
| gonadoliberin || || || endogenous
|-
| luliberin || || || endogenous
|-
| gonadorelin || || || pharmaceutical ([[international nonproprietary name|INN]])  
|-
|}
 
*[[Fertirelin]] (TAP-031) is a synthetic nonapeptide analog of LH-RH and is a Gonad stimulating principle.<ref>drugfuture.com/chemdata/fertirelin.html</ref>
*[[Lutrelin]] is a [[LHRH agonist]].


==See also==
==See also==
* [[Gonadotropin-releasing hormone receptor#Agonists|Gonadotropin-releasing hormone receptor § Agonists]]
* [[GnRH modulator]]
* [[GnRH modulator]]
* [[Progonadotropin]]
* [[Progonadotropin]]
* [[Gonadotropin surge-attenuating factor]]


==References==
==References==
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{{refend}}
{{refend}}


{{Gonadotropins and GnRH}}
{{GnRH and gonadotropins}}
{{Hormones}}
{{Hormones}}
{{Neuropeptides}}
{{Neuropeptides}}
{{Signaling peptide/protein receptor modulators}}
{{GnRH and gonadotropin receptor modulators}}


[[Category:Animal reproductive system]]
[[Category:Animal reproductive system]]

Latest revision as of 08:49, 10 January 2019

This article is about GnRH as a hormone. For its use as a medication, see Gonadorelin.
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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.

Structure

The identity[1] of GnRH was clarified by the 1977 Nobel Laureates Roger Guillemin and Andrew V. Schally:[2]

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 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.[3] 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).[4] 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.[5]

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.[6]

GnRH secretion is pulsatile in all vertebrates,[7] 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.[3]

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.[4] Kisspeptin appears to be an important regulator of GnRH release.[8] GnRH release can also be regulated by estrogen. It has been reported that there are kisspeptin-producing neurons that also express estrogen receptor alpha.[9]

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.[10]

Effects of behavior

GnRH production/release is one of the few confirmed examples of behavior influencing 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.[11] 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.[12] These examples suggest that GnRH is a socially regulated hormone.

Medical uses

Main articles: Gonadorelin and Gonadotropin-releasing hormone agonist

Natural GnRH was previously prescribed as gonadorelin hydrochloride (Factrel)[13] and gonadorelin diacetate tetrahydrate (Cystorelin)[14] 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.[15][16]

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.[17] 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.[18]

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.[19]

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.[20]

Veterinary use

Main article: Gonadorelin

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

References

  1. ↑ Kochman K (2012). "Evolution of gonadotropin-releasing hormone (GnRH) structure and its receptor". Journal of Animal and Feed Sciences. 21 (1): 6.
  2. ↑ "The Nobel Prize in Physiology or Medicine 1977". www.nobelprize.org. Nobel Media AB 2014. Retrieved 24 June 2016.
  3. ↑ 3.0 3.1 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. doi:10.1073/pnas.0903463106. PMC 2705602. PMID 19541658.
  4. ↑ 4.0 4.1 Brown RM (1994). An introduction to Neuroendocrinology. Cambridge, UK: Cambridge University Press. ISBN 0-521-42665-0.
  5. ↑ Jayes FC, Britt JH, Esbenshade KL (April 1997). "Role of gonadotropin-releasing hormone pulse frequency in differential regulation of gonadotropins in the gilt" (PDF). Biology of Reproduction. 56 (4): 1012–9. doi:10.1095/biolreprod56.4.1012. PMID 9096885. Archived from the original (PDF) on 2015-09-23.
  6. ↑ 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.
  7. ↑ Tsutsumi R, Webster NJ (17 July 2009). "GnRH pulsatility, the pituitary response and reproductive dysfunction". Endocrine Journal. 56 (6): 729–37. doi:10.1507/endocrj.K09E-185. PMC 4307809. PMID 19609045.
  8. ↑ Dungan HM, Clifton DK, Steiner RA (March 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.
  9. ↑ 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. PMID 16621281.
  10. ↑ 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.
  11. ↑ Chee SS, Espinoza WA, Iwaniuk AN, Pakan JM, Gutiérrez-Ibáñez C, Wylie DR, Hurd PL (January 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.
  12. ↑ White SA, Nguyen T, Fernald RD (September 2002). "Social regulation of gonadotropin-releasing hormone" (PDF). The Journal of Experimental Biology. 205 (Pt 17): 2567–81. PMID 12151363.
  13. ↑ Drugs.com Factrel: Consumer Drug Information
  14. ↑ Drugs.com Cystorelin: FDA Professional Drug Information
  15. ↑ 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. PMID 6458765.
  16. ↑ 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. PMID 3760417.
  17. ↑ 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. PMID 9344687.
  18. ↑ 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.
  19. ↑ 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. PMID 22613708.
  20. ↑ 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

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