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{{About|GnRH as a hormone|its use as a medication|Gonadorelin}}
[[File:Gondarelin.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]</div>
{{More citations needed|date=January 2013}}
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{{Infobox gene}}
{{SI}}
{{CMG}}
==Overview==
'''Gonadotropin-releasing hormone''' ('''GnRH'''), also known as '''luteinizing hormone-releasing hormone''' ('''LHRH''') and '''luliberin''', is a [[trophic hormone|trophic]] [[peptide]] [[hormone]] responsible for the release of [[follicle-stimulating hormone]] (FSH) and [[luteinizing hormone]] (LH) from the [[anterior pituitary]]. GnRH is 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 ==
'''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]].


The identity of GnRH was clarified by the 1977 [[Nobel Laureate]]s [[Roger Guillemin]] and [[Andrew V. Schally]]:
==Structure==
The identity<ref>{{cite journal|last1=Kochman|first1=K. | name-list-format = vanc | title = Evolution of gonadotropin-releasing hormone (GnRH) structure and its receptor | journal = Journal of Animal and Feed Sciences | date = 2012 | volume = 21 | issue = 1 | page = 6 | url = http://www.cabdirect.org/abstracts/20123164798.html }}</ref> of GnRH was clarified by the 1977 [[Nobel Laureate]]s [[Roger Guillemin]] and [[Andrew V. Schally]]:<ref>{{cite web|title=The Nobel Prize in Physiology or Medicine 1977|url=https://www.nobelprize.org/nobel_prizes/medicine/laureates/1977/|website=www.nobelprize.org|publisher=Nobel Media AB 2014|accessdate=24 June 2016}}</ref>


pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2
<div class="center" style="width: auto; margin-left: auto; margin-right: auto;">[[pyroglutamic acid|pyroGlu]]-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH<sub>2</sub></div>
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 acid]]s, 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]].


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 acid]]s, 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 [[Hypothalamic–pituitary–gonadal axis#regulation|regulatory mechanisms of the hypothalamic–pituitary–gonadal axis]], such as being inhibited by increased [[estrogen]] levels in the body.


== Synthesis ==
==Function==
GnRH is secreted in the [[Hypophyseal portal system|hypophysial]] portal bloodstream at the [[median eminence]].<ref name=pmid19541658 /> The portal blood carries the GnRH to the [[pituitary gland]], which contains the [[gonadotrope]] cells, where GnRH activates its own [[receptor (biochemistry)|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.


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]] pre[[prohormone]] 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.
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]].


== Function ==
===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 | 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>


GnRH is secreted in the [[Hypophyseal portal system|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 (biochemistry)|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.
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 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, [[insulin|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]].
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.


=== Control of FSH and LH ===
===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>


At the pituitary, GnRH stimulates the synthesis and secretion of the [[gonadotropins]], [[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 lead to FSH release, whereas high-frequency GnRH pulses stimulate LH release.
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>


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.
===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.<ref name="pmid10573298">{{cite journal | vauthors = Schally AV | title = Luteinizing hormone-releasing hormone analogs: their impact on the control of tumorigenesis | journal = Peptides | volume = 20 | issue = 10 | pages = 1247–62 | year = 1999 | pmid = 10573298 | doi = 10.1016/S0196-9781(99)00130-8 }}</ref>


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.  
==Effects of behavior==
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.
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.


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


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.
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.
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. [[Kisspeptin]] appears to be an important regulator of GnRH release. 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]].


=== Other organs ===
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>


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.<ref name="pmid10573298">{{vcite2 journal | vauthors = Schally AV | title = Luteinizing hormone-releasing hormone analogs: their impact on the control of tumorigenesis | journal = Peptides | volume = 20 | issue = 10 | pages = 1247–62 | year = 1999 | pmid = 10573298 | doi = 10.1016/S0196-9781(99)00130-8 }}</ref>
==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>


== Effects of behavior ==
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>


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. 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 males. Differences are also seen in females, with breeding females having smaller [[GnRH_Neuron|GnRH neurons]] than controls females. These examples suggest that GnRH is a socially regulated hormone.
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>


== Medical uses ==
==Veterinary use==
{{main|gonadotropin-releasing hormone agonist}}
{{Main|Gonadorelin}}


Natural GnRH was previously prescribed as gonadorelin hydrochloride (Factrel)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.
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.


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]].
==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:


== Animal sexual behavior ==
* 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 ([[International nonproprietary name|INN]] for pharmaceutical form)
*Gonadoliberin


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


==References==
==References==
{{reflist|2}}
{{Reflist|35em}}


==Further reading==
{{refbegin|35em}}
* {{cite journal | vauthors = Flanagan CA, Millar RP, Illing N | title = Advances in understanding gonadotrophin-releasing hormone receptor structure and ligand interactions | journal = Reviews of Reproduction | volume = 2 | issue = 2 | pages = 113–20 | date = May 1997 | pmid = 9414473 | doi = 10.1530/ror.0.0020113 }}
* {{cite journal | vauthors = Leung PC, Cheng CK, Zhu XM | title = Multi-factorial role of GnRH-I and GnRH-II in the human ovary | journal = Molecular and Cellular Endocrinology | volume = 202 | issue = 1-2 | pages = 145–53 | date = April 2003 | pmid = 12770744 | doi = 10.1016/S0303-7207(03)00076-5 }}
* {{cite journal | vauthors = Gründker C, Emons G | title = Role of gonadotropin-releasing hormone (GnRH) in ovarian cancer | journal = Reproductive Biology and Endocrinology | volume = 1 | issue = | pages = 65 | date = October 2003 | pmid = 14594454 | pmc = 239893 | doi = 10.1186/1477-7827-1-65 }}
* {{cite journal | vauthors = Limonta P, Moretti RM, Montagnani Marelli M, Motta M | title = The biology of gonadotropin hormone-releasing hormone: role in the control of tumor growth and progression in humans | journal = Frontiers in Neuroendocrinology | volume = 24 | issue = 4 | pages = 279–95 | date = December 2003 | pmid = 14726258 | doi = 10.1016/j.yfrne.2003.10.003 }}
* {{cite journal | vauthors = Janáky T, Juhász A, Bajusz S, Csernus V, Srkalovic G, Bokser L, Milovanovic S, Redding TW, Rékási Z, Nagy A | title = Analogues of luteinizing hormone-releasing hormone containing cytotoxic groups | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 3 | pages = 972–6 | date = February 1992 | pmid = 1310542 | pmc = 48367 | doi = 10.1073/pnas.89.3.972 }}
* {{cite journal | vauthors = Healey SC, Martin NG, Chenevix-Trench G | title = NcoI RFLP of the human LHRH gene on chromosome 8p | journal = Nucleic Acids Research | volume = 19 | issue = 21 | pages = 6059 | date = November 1991 | pmid = 1682898 | pmc = 329079 | doi = 10.1093/nar/19.21.6059 }}
* {{cite journal | vauthors = Williamson P, Lang J, Boyd Y | title = The gonadotropin-releasing hormone (Gnrh) gene maps to mouse chromosome 14 and identifies a homologous region on human chromosome 8 | journal = Somatic Cell and Molecular Genetics | volume = 17 | issue = 6 | pages = 609–15 | date = November 1991 | pmid = 1767338 | doi = 10.1007/BF01233626 }}
* {{cite journal | vauthors = Hayflick JS, Adelman JP, Seeburg PH | title = The complete nucleotide sequence of the human gonadotropin-releasing hormone gene | journal = Nucleic Acids Research | volume = 17 | issue = 15 | pages = 6403–4 | date = August 1989 | pmid = 2671939 | pmc = 318303 | doi = 10.1093/nar/17.15.6403 }}
* {{cite journal | vauthors = Nikolics K, Mason AJ, Szönyi E, Ramachandran J, Seeburg PH | title = A prolactin-inhibiting factor within the precursor for human gonadotropin-releasing hormone | journal = Nature | volume = 316 | issue = 6028 | pages = 511–7 | year = 1985 | pmid = 2863757 | doi = 10.1038/316511a0 }}
* {{cite journal | vauthors = Adelman JP, Mason AJ, Hayflick JS, Seeburg PH | title = Isolation of the gene and hypothalamic cDNA for the common precursor of gonadotropin-releasing hormone and prolactin release-inhibiting factor in human and rat | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 1 | pages = 179–83 | date = January 1986 | pmid = 2867548 | pmc = 322815 | doi = 10.1073/pnas.83.1.179 }}
* {{cite journal | vauthors = Yang-Feng TL, Seeburg PH, Francke U | title = Human luteinizing hormone-releasing hormone gene (LHRH) is located on short arm of chromosome 8 (region 8p11.2----p21) | journal = Somatic Cell and Molecular Genetics | volume = 12 | issue = 1 | pages = 95–100 | date = January 1986 | pmid = 3511544 | doi = 10.1007/BF01560732 }}
* {{cite journal | vauthors = Seeburg PH, Adelman JP | title = Characterization of cDNA for precursor of human luteinizing hormone releasing hormone | journal = Nature | volume = 311 | issue = 5987 | pages = 666–8 | year = 1984 | pmid = 6090951 | doi = 10.1038/311666a0 }}
* {{cite journal | vauthors = Tan L, Rousseau P | title = The chemical identity of the immunoreactive LHRH-like peptide biosynthesized in the human placenta | journal = Biochemical and Biophysical Research Communications | volume = 109 | issue = 3 | pages = 1061–71 | date = December 1982 | pmid = 6760865 | doi = 10.1016/0006-291X(82)92047-2 }}
* {{cite journal | vauthors = Dong KW, Yu KL, Roberts JL | title = Identification of a major up-stream transcription start site for the human progonadotropin-releasing hormone gene used in reproductive tissues and cell lines | journal = Molecular Endocrinology | volume = 7 | issue = 12 | pages = 1654–66 | date = December 1993 | pmid = 8145771 | doi = 10.1210/me.7.12.1654 }}
* {{cite journal | vauthors = Kakar SS, Jennes L | title = Expression of gonadotropin-releasing hormone and gonadotropin-releasing hormone receptor mRNAs in various non-reproductive human tissues | journal = Cancer Letters | volume = 98 | issue = 1 | pages = 57–62 | date = November 1995 | pmid = 8529206 | doi = 10.1016/S0304-3835(06)80010-8 }}
* {{cite journal | vauthors = Nagy A, Schally AV, Armatis P, Szepeshazi K, Halmos G, Kovacs M, Zarandi M, Groot K, Miyazaki M, Jungwirth A, Horvath J | title = Cytotoxic analogs of luteinizing hormone-releasing hormone containing doxorubicin or 2-pyrrolinodoxorubicin, a derivative 500-1000 times more potent | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 14 | pages = 7269–73 | date = July 1996 | pmid = 8692981 | pmc = 38972 | doi = 10.1073/pnas.93.14.7269 }}
* {{cite journal | vauthors = Chegini N, Rong H, Dou Q, Kipersztok S, Williams RS | title = 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 | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 81 | issue = 9 | pages = 3215–21 | date = September 1996 | pmid = 8784072 | doi = 10.1210/jc.81.9.3215 }}
* {{cite journal | vauthors = Bonaldo MF, Lennon G, Soares MB | title = Normalization and subtraction: two approaches to facilitate gene discovery | journal = Genome Research | volume = 6 | issue = 9 | pages = 791–806 | date = September 1996 | pmid = 8889548 | doi = 10.1101/gr.6.9.791 }}
* {{cite journal | vauthors = Dong KW, Yu KL, Chen ZG, Chen YD, Roberts JL | title = Characterization of multiple promoters directing tissue-specific expression of the human gonadotropin-releasing hormone gene | journal = Endocrinology | volume = 138 | issue = 7 | pages = 2754–62 | date = July 1997 | pmid = 9202214 | doi = 10.1210/en.138.7.2754 }}
* {{cite journal | vauthors = Twan WH, Hwang JS, Lee YH, Jeng SR, Yueh WS, Tung YH, Wu HF, Dufour S, Chang CF | title = The presence and ancestral role of gonadotropin-releasing hormone in the reproduction of scleractinian coral, Euphyllia ancora | journal = Endocrinology | volume = 147 | issue = 1 | pages = 397–406 | date = January 2006 | pmid = 16195400 | doi = 10.1210/en.2005-0584 }}
{{refend}}


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


[[Category:Animal reproductive system]]
[[Category:Antigonadotropins]]
[[Category:Gonadotropin-releasing hormone and gonadotropins]]
[[Category:Hormones of the hypothalamus-pituitary-gonad axis]]
[[Category:Human female endocrine system]]
[[Category:Peptide hormones]]
[[Category:Peptide hormones]]
[[Category:Precursor proteins]]
[[Category:Progonadotropins]]
[[Category:Sex hormones]]
[[Category:Sex hormones]]
[[Category:Drug]]
[[Category:World Anti-Doping Agency prohibited substances]]

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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