Gonadotropin-releasing hormone: Difference between revisions

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{{Protein
<div style="float: right;">
  |Name=Gonadotropin-releasing hormone
[[File:Gondarelin.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]</div>
  |image=GNRH1_structure.png
 
  |caption=The structure of GNRH1<br />(from {{PDB|1YY1}})
__NOTOC__
  |Symbol=GNRH1
 
  |AltSymbols=GnRH, LHRH
  |HGNCid=4419
  |Chromosome=8
  |Arm=p
  |Band=21-11.2
  |LocusSupplementaryData=
  |ECnumber=
  |OMIM=152760
  |EntrezGene=2796
  |RefSeq=NM_000825
  |UniProt=P01148
}}
{{SI}}
{{SI}}
__NOTOC__
{{GS}}


{{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 ==
The identity of GnRH was clarified by the 1977 [[Nobel Laureate]]s [[Roger Guillemin]] and [[Andrew V. Schally]]:
pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2
As is standard for [[peptide]] representation, the sequence is given from amino terminus to carboxyl terminus; also standard is omission of the designation of chirality, with assumption that all amino acids are in their L- form. The abbreviations appearing are to standard [[proteinogenic amino 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 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.
== 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.
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]].
=== 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 lead to FSH release, whereas high-frequency GnRH pulses stimulate LH release.<ref>{{vcite2 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 | page = 1012-1019 | date = Apr 1997 | pmid = 9096885 | doi = 10.1095/biolreprod56.4.1012 | url = http://www.biolreprod.org/content/56/4/1012.full.pdf }}</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>


'''Gonadotropin-releasing hormone 1''' ('''GNRH1'''), also known as '''Luteinising-hormone releasing hormone''' ('''LHRH'''), is a [[peptide]] [[hormone]] responsible for the release of [[follicle-stimulating hormone|FSH]] and [[luteinizing hormone|LH]] from the [[anterior pituitary]]. GNRH1 is synthesized and released by the [[hypothalamus]].
GnRH secretion is pulsatile in all vertebrates [there is no evidence that this is correct -- the only empirical evidence to date is for a handful of mammals], and is necessary for correct reproductive function.
Thus, a single hormone, GnRH1, controls a complex process of [[Ovarian follicle|follicular]] growth, [[ovulation]], and [[corpus luteum]] maintenance in the female, and [[spermatogenesis]] in the male.


==Gene==
=== Neurohormone ===
The [[gene]], ''GNRH1'', for the GNRH1 precursor is located on [[chromosome]] 8. This precursor contains 92 [[amino acid]]s and is processed to GNRH1, a [[decapeptide]] (10 amino acids) in mammals.


GnRH was previously called LHRH.
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">{{vcite2 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 = Jun 2009 | pmid = 19541658 | pmc = 2705602 | doi = 10.1073/pnas.0903463106 }}</ref>


==Structure==
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">{{vcite2 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 = Mar 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">{{vcite2 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 = Jul 2006 | pmid = 16621281 | doi = 10.1016/j.neulet.2006.03.039 }}</ref>
The identity of GNRH1 was clarified by the 1977 Nobel Laureates [[Roger Guillemin]] and [[Andrew V. Schally]]:


pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly CONH2.
=== Other organs ===


==GNRH1 as a neurohormone==
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>
GNRH1 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 GNRH1  is the preoptic area of the hypothalamus, that contains most of the GNRH1-secreting neurons. GNRH1 is secreted in the hypophysial portal bloodstream at the [[median eminence]]. The portal blood carries the GNRH1 to the [[pituitary gland]], which contains the [[gonadotrope]] cells, where GNRH1 activates its own [[receptor (biochemistry)|receptor]], [[gonadotropin-releasing hormone receptor]] (GNRHR), located in the [[cell membrane]].


GNRH1 is degraded by [[proteolysis]] within a few minutes.
== Effects of behavior ==


==Control of FSH and LH==
GnRH production/release is one of the few confirmed examples of behavior influencing hormones, rather than the other way around.{{fact|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">{{vcite2 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 = Jan 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 males. Differences are also seen in females, with breeding females having smaller [[GnRH_Neuron|GnRH neurons]] than controls females.<ref name="pmid12151363">{{vcite2 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 = Sep 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.
At the pituitary, GNRH1 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 GNRH1 pulses, as well as by feedback from [[androgens]] and [[estrogens]]. Low frequency GNRH1 pulses lead to FSH release, whereas high frequency GNRH1 pulses stimulate LH release.


There are differences in GNRH1 secretion between females and males. In males, GNRH1 is secreted in pulses at a constant frequency, but in females the frequency of the pulses varies during the menstrual cycle and there is a large surge of GNRH1 just before ovulation.
== Medical uses ==
{{main|gonadotropin-releasing hormone agonist}}


GNRH1 secretion is pulsatile in all vertebrates, and is necessary for correct reproductive function.  
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.
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.


==Activity==
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>{{vcite2 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 = 1546–1550 | date = Dec 1981 | pmid = 6458765 | doi = 10.1056/NEJM198112243052602 | url = http://www.nejm.org/doi/full/10.1056/NEJM198112243052602 }}</ref><ref name="AACS">{{vcite2 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 = Sep 1986 | pmid = 3760417 | doi = 10.1016/S0002-7138(09)60293-4 }}</ref>
GNRH1 activity is very low during childhood, and is activated at puberty. During the reproductive years, pulse activity is critical for successful reproductive function as controlled by feedback loops. However, once a pregnancy is established, GNRH1 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 GNRH1 activity. In contrast, hyper[[insulin]]emia increases pulse activity leading to disorderly LH and FSH activity, as seen in [[Polycystic ovary syndrome]] (PCOS). GNRH1 formation is congenitally absent in [[Kallmann syndrome]].


The GNRH1 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> R.E. Brown.  An Introduction to Neuroenocrinology; Cambridge University Press 1994.</ref> [[Kisspeptin]] appears to be an important regulator of GNRH release.<ref>H. M. Dungan, D. K. Clifton and R. A. Steiner (2006) "Minireview: kisspeptin neurons as central processors in the regulation of gonadotropin-releasing hormone secretion" in ''Endocrinology'' Volume 147, pages 1154-1158 PMID 16373418</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>I. Franceschini, D. Lomet, M. Cateau, G. Delsol, Y. Tillet and A. Caraty (2006) "Kisspeptin immunoreactive cells of the ovine preoptic area and arcuate nucleus co-express estrogen receptor alpha" in ''Neurosci Lett.'' 2Volume 401, pages 225-230. PMID 16621281</ref>
== Animal sexual behavior ==


==GNRH1 in other organs==
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">{{vcite2 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 = Aug 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">{{vcite2 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>
GNRH1 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]].


==Medication==
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">{{vcite2 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 = Jun 2012 | pmid = 22613708 | doi = 10.1016/j.yhbeh.2012.05.008 }}</ref>
GNRH1 is available as gonadorelin hydrochloride (Factrel) for injectable use. Studies have described it being used via an infusion pump system to induce ovulation in patients with hypothalamic [[hypogonadism]].


==Agonists and antagonists==
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">{{vcite2 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>
While GNRH1 has been synthesized and become available, its short half-life requires [[infusion pump]]s for its clinical use. Modifications of the decapeptide structure of GNRH1 have led to [[GnRH analog|GNRH1 analog]] medications that either stimulate ([[GnRH agonist|GNRH1 agonist]]s) or suppress ([[GnRH antagonist|GNRH1 antagonist]]s) the gonadotropins. It is important to note that, through [[downregulation]], agonists are also able to exert a prolonged suppression effect.


== Veterinary use ==


{{Pituitary and hypothalamic hormones and analogues}}
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.


[[Category:Genes on chromosome 8]]
== References ==
[[Category:Endocrinology]]
{{reflist|35em}}


[[de:Gonadorelin]]
== Further reading ==
[[dv:ގޯނާޑޮޓްރޮޕިން ރިލީސިންގ ހޯރމޯން]]
{{refbegin|35em}}
[[fr:Gonadolibérine]]
* {{vcite2 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 }}
[[lt:GnRH]]
* {{vcite2 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 = Apr 2003 | pmid = 12770744 | doi = 10.1016/S0303-7207(03)00076-5 }}
[[nl:Gonadotropin-Releasing hormone]]
* {{vcite2 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 = Oct 2003 | pmid = 14594454 | pmc = 239893 | doi = 10.1186/1477-7827-1-65 }}
[[ja:性腺刺激ホルモン放出ホルモン]]
* {{vcite2 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 = Dec 2003 | pmid = 14726258 | doi = 10.1016/j.yfrne.2003.10.003 }}
[[pl:Gonadoliberyna]]
* {{vcite2 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 = Feb 1992 | pmid = 1310542 | pmc = 48367 | doi = 10.1073/pnas.89.3.972 }}
[[pt:Hormona libertadora de gonadotropina]]
* {{vcite2 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 = Nov 1991 | pmid = 1682898 | pmc = 329079 | doi = 10.1093/nar/19.21.6059 }}
[[ru:Гонадолиберин]]
* {{vcite2 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 = Nov 1991 | pmid = 1767338 | doi = 10.1007/BF01233626 }}
* {{vcite2 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 = Aug 1989 | pmid = 2671939 | pmc = 318303 | doi = 10.1093/nar/17.15.6403 }}
* {{vcite2 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 }}
* {{vcite2 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 = Jan 1986 | pmid = 2867548 | pmc = 322815 | doi = 10.1073/pnas.83.1.179 }}
* {{vcite2 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 = Jan 1986 | pmid = 3511544 | doi = 10.1007/BF01560732 }}
* {{vcite2 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 }}
* {{vcite2 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 = Dec 1982 | pmid = 6760865 | doi = 10.1016/0006-291X(82)92047-2 }}
* {{vcite2 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 = Dec 1993 | pmid = 8145771 | doi = 10.1210/me.7.12.1654 }}
* {{vcite2 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 = Nov 1995 | pmid = 8529206 | doi = 10.1016/S0304-3835(06)80010-8 }}
* {{vcite2 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 = Jul 1996 | pmid = 8692981 | pmc = 38972 | doi = 10.1073/pnas.93.14.7269 }}
* {{vcite2 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 = Sep 1996 | pmid = 8784072 | doi = 10.1210/jc.81.9.3215 }}
* {{vcite2 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 = Sep 1996 | pmid = 8889548 | doi = 10.1101/gr.6.9.791 }}
* {{vcite2 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 = Jul 1997 | pmid = 9202214 | doi = 10.1210/en.138.7.2754 }}
* {{vcite2 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 = Jan 2006 | pmid = 16195400 | doi = 10.1210/en.2005-0584 }}
{{refend}}
==References==


{{reflist|2}}
{{Gonadotropins and GnRH}}
{{Hormones}}
{{Neuropeptides}}
{{Peptidergics}}


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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH) and luliberin, is a 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 neurons within the hypothalamus. The peptide belongs to gonadotropin-releasing hormone family. It constitutes the initial step in the hypothalamic–pituitary–gonadal axis.

Structure

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

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

As is standard for peptide representation, the sequence is given from amino terminus to carboxyl terminus; also standard is omission of the designation of chirality, with assumption that all amino acids are in their L- form. The abbreviations appearing are to standard proteinogenic amino acids, except for pyroGlu, which refers to pyroglutamic acid, a derivative of glutamic acid. The NH2 at the carboxyl terminus indicates that rather than terminating as a free carboxylate, it terminates as a carboxamide.

Synthesis

The gene, GNRH1, for the GnRH precursor is located on chromosome 8. In mammals, the linear decapeptide end-product is synthesized from a 92-amino acid preprohormone in the preoptic anterior hypothalamus. It is the target of various regulatory mechanisms of the hypothalamic–pituitary–gonadal axis, such as being inhibited by increased estrogen levels in the body.

Function

GnRH is secreted in the hypophysial portal bloodstream at the median eminence.[1] The portal blood carries the GnRH to the pituitary gland, which contains the gonadotrope cells, where GnRH activates its own receptor, gonadotropin-releasing hormone receptor (GnRHR), a seven-transmembrane G-protein-coupled receptor that stimulates the beta isoform of Phosphoinositide phospholipase C, which goes on to mobilize calcium and protein kinase C. This results in the activation of proteins involved in the synthesis and secretion of the gonadotropins LH and FSH. GnRH is degraded by proteolysis within a few minutes.

GnRH activity is very low during childhood, and is activated at puberty or adolescence. During the reproductive years, pulse activity is critical for successful reproductive function as controlled by feedback loops. However, once a pregnancy is established, GnRH activity is not required. Pulsatile activity can be disrupted by hypothalamic-pituitary disease, either dysfunction (i.e., hypothalamic suppression) or organic lesions (trauma, tumor). Elevated prolactin levels decrease GnRH activity. In contrast, hyperinsulinemia increases pulse activity leading to disorderly LH and FSH activity, as seen in polycystic ovary syndrome (PCOS). GnRH formation is congenitally absent in Kallmann syndrome.

Control of FSH and LH

At the pituitary, GnRH stimulates the synthesis and secretion of the gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH).[2] These processes are controlled by the size and frequency of GnRH pulses, as well as by feedback from androgens and estrogens. Low-frequency GnRH pulses lead to FSH release, whereas high-frequency GnRH pulses stimulate LH release.[3]

There are differences in GnRH secretion between females and males. In males, GnRH is secreted in pulses at a constant frequency; however, in females, the frequency of the pulses varies during the menstrual cycle, and there is a large surge of GnRH just before ovulation.[4]

GnRH secretion is pulsatile in all vertebrates [there is no evidence that this is correct -- the only empirical evidence to date is for a handful of mammals], and is necessary for correct reproductive function. Thus, a single hormone, GnRH1, controls a complex process of follicular growth, ovulation, and corpus luteum maintenance in the female, and spermatogenesis in the male.

Neurohormone

GnRH is considered a neurohormone, a hormone produced in a specific neural cell and released at its neural terminal. A key area for production of GNRH is the preoptic area of the hypothalamus, which contains most of the GnRH-secreting neurons. GnRH neurons originate in the nose and migrate into the brain, where they are scattered throughout the medial septum and hypothalamus and connected by very long >1-millimeter-long dendrites. These bundle together so they receive shared synaptic input, a process that allows them to synchronize their GnRH release.[1]

The GnRH neurons are regulated by many different afferent neurons, using several different transmitters (including norepinephrine, GABA, glutamate). For instance, dopamine appears to stimulate LH release (through GnRH) in estrogen-progesterone-primed females; dopamine may inhibit LH release in ovariectomized females.[2] Kisspeptin appears to be an important regulator of GnRH release.[5] GnRH release can also be regulated by estrogen. It has been reported that there are kisspeptin-producing neurons that also express estrogen receptor alpha.[6]

Other organs

GnRH is found in organs outside of the hypothalamus and pituitary, and its role in other life processes is poorly understood. For instance, there is likely to be a role for GnRH1 in the placenta and in the gonads. GnRH and GnRH receptors are also found in cancers of the breast, ovary, prostate, and endometrium.[7]

Effects of behavior

GnRH production/release is one of the few confirmed examples of behavior influencing hormones, rather than the other way around.[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.[8] Besides secretion, the social environment as well as their behavior affects the size of GnRH neurons. Specifically, males that are more territorial have larger GnRH neurons than males that are less territorial males. Differences are also seen in females, with breeding females having smaller GnRH neurons than controls females.[9] These examples suggest that GnRH is a socially regulated hormone.

Medical uses

Main article: gonadotropin-releasing hormone agonist

Natural GnRH was previously prescribed as gonadorelin hydrochloride (Factrel)[10] and gonadorelin diacetate tetrahydrate (Cystorelin)[11] for use in treating human diseases. Modifications of the decapeptide structure of GnRH to increase half life have led to GnRH1 analog medications that either stimulate (GnRH1 agonists) or suppress (GnRH antagonists) the gonadotropins. These synthetic analogs have replaced the natural hormone in clinical use.

Its analogue Leuprolide is used for continuous infusion, to treat Breast carcinoma, endometriosis, prostate carcinoma, and following research in the 1980s by researchers, including Dr. Florence Comite of Yale University, it was used to treat precocious puberty.[12][13]

Animal sexual behavior

GnRH activity influences a variety of sexual behaviors. Increased levels of GnRH facilitate sexual displays and behavior in females. GnRH injections enhance copulation solicitation (a type of courtship display) in white-crowned sparrows.[14] In mammals, GnRH injections facilitate sexual behavior of female display behaviors as shown with the musk shrew’s (Suncus murinus) reduced latency in displaying rump presents and tail wagging towards males.[15]

An elevation of GnRH raises males’ testosterone capacity beyond a male’s natural testosterone level. Injections of GnRH in male birds immediately after an aggressive territorial encounter results in higher testosterone levels than what is observed naturally during an aggressive territorial encounter.[16]

A compromised GnRH system has aversive effects on reproductive physiology and maternal behavior. In comparison to female mice with a normal GnRH system, female mice with a 30% decrease in GnRH neurons are poor caregivers to their offspring. These mice are more likely to leave their pups scattered rather than grouped together, and will take significantly longer to retrieve their pups.[17]

Veterinary use

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

References

  1. ↑ 1.0 1.1 Campbell RE, Gaidamaka G, Han SK, Herbison AE (Jun 2009). "Dendro-dendritic bundling and shared synapses between gonadotropin-releasing hormone neurons". Proceedings of the National Academy of Sciences of the United States of America. 106 (26): 10835–40. doi:10.1073/pnas.0903463106. PMC 2705602. PMID 19541658.
  2. ↑ 2.0 2.1 Brown RM (1994). An introduction to Neuroendocrinology. Cambridge, UK: Cambridge University Press. ISBN 0-521-42665-0.
  3. ↑ Jayes FC, Britt JH, Esbenshade KL (Apr 1997). "Role of gonadotropin-releasing hormone pulse frequency in differential regulation of gonadotropins in the gilt" (PDF). Biology of Reproduction. 56 (4): 1012-1019. doi:10.1095/biolreprod56.4.1012. PMID 9096885.
  4. ↑ Ehlers K, Halvorson L (2013). "Gonadotropin-releasing Hormone (GnRH) and the GnRH Receptor (GnRHR)". The Global Library of Women's Medicine. doi:10.3843/GLOWM.10285. Retrieved 5 November 2014.
  5. ↑ Dungan HM, Clifton DK, Steiner RA (Mar 2006). "Minireview: kisspeptin neurons as central processors in the regulation of gonadotropin-releasing hormone secretion". Endocrinology. 147 (3): 1154–8. doi:10.1210/en.2005-1282. PMID 16373418.
  6. ↑ Franceschini I, Lomet D, Cateau M, Delsol G, Tillet Y, Caraty A (Jul 2006). "Kisspeptin immunoreactive cells of the ovine preoptic area and arcuate nucleus co-express estrogen receptor alpha". Neuroscience Letters. 401 (3): 225–30. doi:10.1016/j.neulet.2006.03.039. PMID 16621281.
  7. ↑ Schally AV (1999). "Luteinizing hormone-releasing hormone analogs: their impact on the control of tumorigenesis". Peptides. 20 (10): 1247–62. doi:10.1016/S0196-9781(99)00130-8. PMID 10573298.
  8. ↑ Chee SS, Espinoza WA, Iwaniuk AN, Pakan JM, Gutiérrez-Ibáñez C, Wylie DR, et al. (Jan 2013). "Social status, breeding state, and GnRH soma size in convict cichlids (Cryptoheros nigrofasciatus)". Behavioural Brain Research. 237: 318–24. doi:10.1016/j.bbr.2012.09.023. PMID 23000535.
  9. ↑ White SA, Nguyen T, Fernald RD (Sep 2002). "Social regulation of gonadotropin-releasing hormone" (PDF). The Journal of Experimental Biology. 205 (Pt 17): 2567–81. PMID 12151363.
  10. ↑ Drugs.com Factrel: Consumer Drug Information
  11. ↑ Drugs.com Cystorelin: FDA Professional Drug Information
  12. ↑ Comite F, Cutler GB, Rivier J, Vale WW, Loriaux DL, Crowley WF (Dec 1981). "Short-term treatment of idiopathic precocious puberty with a long-acting analogue of luteinizing hormone-releasing hormone. A preliminary report". The New England Journal of Medicine. 305 (26): 1546–1550. doi:10.1056/NEJM198112243052602. PMID 6458765.
  13. ↑ Sonis WA, Comite F, Pescovitz OH, Hench K, Rahn CW, Cutler GB, et al. (Sep 1986). "Biobehavioral aspects of precocious puberty". Journal of the American Academy of Child Psychiatry. 25 (5): 674–9. doi:10.1016/S0002-7138(09)60293-4. PMID 3760417.
  14. ↑ Maney DL, Richardson RD, Wingfield JC (Aug 1997). "Central administration of chicken gonadotropin-releasing hormone-II enhances courtship behavior in a female sparrow". Hormones and Behavior. 32 (1): 11–8. doi:10.1006/hbeh.1997.1399. PMID 9344687.
  15. ↑ Schiml PA, Rissman EF (May 2000). "Effects of gonadotropin-releasing hormones, corticotropin-releasing hormone, and vasopressin on female sexual behavior". Hormones and Behavior. 37 (3): 212–20. doi:10.1006/hbeh.2000.1575. PMID 10868484.
  16. ↑ DeVries MS, Winters CP, Jawor JM (Jun 2012). "Testosterone elevation and response to gonadotropin-releasing hormone challenge by male northern cardinals (Cardinalis cardinalis) following aggressive behavior". Hormones and Behavior. 62 (1): 99–105. doi:10.1016/j.yhbeh.2012.05.008. PMID 22613708.
  17. ↑ Brooks LR, Le CD, Chung WC, Tsai PS (2012). "Maternal behavior in transgenic mice with reduced fibroblast growth factor receptor function in gonadotropin-releasing hormone neurons". Behavioral and Brain Functions. 8: 47. doi:10.1186/1744-9081-8-47. PMC 3503805. PMID 22950531.

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