Gonadoliberin-1
From DrugPedia: A Wikipedia for Drug discovery
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==Description== | ==Description== | ||
| - | + | '''Gonadotropin-releasing hormone''' ('''GNRH'''), also known as '''Luteinizing-hormone releasing hormone''' ('''LHRH'''), is a [[tropic hormone|tropic]] [[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 neurons within the [[hypothalamus]]. | |
| + | |||
| + | ==Production== | ||
| + | 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. | ||
| + | |||
| + | ==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 CONH2. | ||
| + | |||
| + | ==GNRH as a 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, that contains most of the GNRH-secreting neurons. GNRH is secreted in the 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. | ||
| + | |||
| + | ==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). 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. | ||
| + | |||
| + | There are differences in GNRH secretion between females and males. In males, GNRH 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 GNRH just before ovulation. | ||
| + | |||
| + | GNRH secretion is pulsatile in all vertebrates, 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. | ||
| + | |||
| + | ==Activity== | ||
| + | GNRH 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, 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]]. | ||
| + | |||
| + | 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.<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> | ||
| + | |||
| + | ==GNRH in 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]]. | ||
| + | |||
| + | ==Medication== | ||
| + | GNRH 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]]. | ||
| + | {{main|Leuprolide}} | ||
| + | its analogue [[Leuprolide]], is used for continuous infusion, to treat [[Breast carcinoma]] ,[[endometriosis]] ,[[prostate carcinoma]] , and [[precocious puberty]] | ||
| + | |||
| + | ==Agonists and antagonists== | ||
| + | While GNRH has been synthesized and become available, its short half-life requires [[infusion pump]]s for its clinical use. Modifications of the decapeptide structure of GNRH have led to [[GnRH analog|GNRH1 analog]] medications that either stimulate ([[GnRH agonist|GNRH1 agonist]]s) or suppress ([[GnRH antagonist|GNRH antagonist]]s) the gonadotropins. It is important to note that, through [[downregulation]], agonists are also able to exert a prolonged suppression effect. | ||
| + | |||
==Source Organism== | ==Source Organism== | ||
Haplochromis burtoni (Burton's mouthbrooder). | Haplochromis burtoni (Burton's mouthbrooder). | ||
| Line 18: | Line 53: | ||
==GeneID== | ==GeneID== | ||
| + | ==References== | ||
| + | {{reflist}} | ||
| + | ==Further reading== | ||
| + | {{refbegin | 2}} | ||
| + | {{PBB_Further_reading | ||
| + | | citations = | ||
| + | *{{cite journal | author=Flanagan CA, Millar RP, Illing N |title=Advances in understanding gonadotrophin-releasing hormone receptor structure and ligand interactions |journal=Rev. Reprod. |volume=2 |issue= 2 |pages= 113–20 |year= 1998 |pmid= 9414473 |doi= }} | ||
| + | *{{cite journal | author=Leung PC, Cheng CK, Zhu XM |title=Multi-factorial role of GnRH-I and GnRH-II in the human ovary |journal=Mol. Cell. Endocrinol. |volume=202 |issue= 1-2 |pages= 145–53 |year= 2004 |pmid= 12770744 |doi= }} | ||
| + | *{{cite journal | author=Gründker C, Emons G |title=Role of gonadotropin-releasing hormone (GnRH) in ovarian cancer |journal=Reprod. Biol. Endocrinol. |volume=1 |issue= |pages= 65 |year= 2004 |pmid= 14594454 |doi= 10.1186/1477-7827-1-65 }} | ||
| + | *{{cite journal | author=Limonta P, Moretti RM, Marelli MM, 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 |year= 2004 |pmid= 14726258 |doi= }} | ||
| + | *{{cite journal | author=Janáky T, Juhász A, Bajusz S, ''et al.'' |title=Analogues of luteinizing hormone-releasing hormone containing cytotoxic groups |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=89 |issue= 3 |pages= 972–6 |year= 1992 |pmid= 1310542| doi=10.1073/pnas.89.3.972}} | ||
| + | *{{cite journal | author=Healey SC, Martin NG, Chenevix-Trench G |title=NcoI RFLP of the human LHRH gene on chromosome 8p |journal=Nucleic Acids Res. |volume=19 |issue= 21 |pages= 6059 |year= 1991 |pmid= 1682898| doi=10.1093/nar/19.21.6059}} | ||
| + | *{{cite journal | author=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=Somat. Cell Mol. Genet. |volume=17 |issue= 6 |pages= 609–15 |year= 1992 |pmid= 1767338 |doi= }} | ||
| + | *{{cite journal | author=Hayflick JS, Adelman JP, Seeburg PH |title=The complete nucleotide sequence of the human gonadotropin-releasing hormone gene |journal=Nucleic Acids Res. |volume=17 |issue= 15 |pages= 6403–4 |year= 1989 |pmid= 2671939| doi=10.1093/nar/17.15.6403}} | ||
| + | *{{cite journal | author=Nikolics K, Mason AJ, Szönyi E, ''et al.'' |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 | author=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=Proc. Natl. Acad. Sci. U.S.A. |volume=83 |issue= 1 |pages= 179–83 |year= 1986 |pmid= 2867548| doi=10.1073/pnas.83.1.179}} | ||
| + | *{{cite journal | author=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=Somat. Cell Mol. Genet. |volume=12 |issue= 1 |pages= 95–100 |year= 1986 |pmid= 3511544| doi=10.1007/BF01560732}} | ||
| + | *{{cite journal | author=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 | author=Tan L, Rousseau P |title=The chemical identity of the immunoreactive LHRH-like peptide biosynthesized in the human placenta |journal=Biochem. Biophys. Res. Commun. |volume=109 |issue= 3 |pages= 1061–71 |year= 1983 |pmid= 6760865 |doi= }} | ||
| + | *{{cite journal | author=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=Mol. Endocrinol. |volume=7 |issue= 12 |pages= 1654–66 |year= 1994 |pmid= 8145771 |doi= }} | ||
| + | *{{cite journal | author=Kakar SS, Jennes L |title=Expression of gonadotropin-releasing hormone and gonadotropin-releasing hormone receptor mRNAs in various non-reproductive human tissues |journal=Cancer Lett. |volume=98 |issue= 1 |pages= 57–62 |year= 1996 |pmid= 8529206 |doi= }} | ||
| + | *{{cite journal | author=Nagy A, Schally AV, Armatis P, ''et al.'' |title=Cytotoxic analogs of luteinizing hormone-releasing hormone containing doxorubicin or 2-pyrrolinodoxorubicin, a derivative 500-1000 times more potent |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=93 |issue= 14 |pages= 7269–73 |year= 1996 |pmid= 8692981| doi=10.1073/pnas.93.14.7269}} | ||
| + | *{{cite journal | author=Chegini N, Rong H, Dou Q, ''et al.'' |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=J. Clin. Endocrinol. Metab. |volume=81 |issue= 9 |pages= 3215–21 |year= 1996 |pmid= 8784072| doi=10.1210/jc.81.9.3215}} | ||
| + | *{{cite journal | author=Bonaldo MF, Lennon G, Soares MB |title=Normalization and subtraction: two approaches to facilitate gene discovery |journal=Genome Res. |volume=6 |issue= 9 |pages= 791–806 |year= 1997 |pmid= 8889548 |doi= }} | ||
| + | *{{cite journal | author=Dong KW, Yu KL, Chen ZG, ''et al.'' |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 |year= 1997 |pmid= 9202214| doi=10.1210/en.138.7.2754}} | ||
| + | }} | ||
| - | [[ | + | [[Category:Hormones]] |
| + | [[Category:HMRbase]] | ||
Current revision
[edit] Description
Gonadotropin-releasing hormone (GNRH), also known as Luteinizing-hormone releasing hormone (LHRH), is a tropic peptide hormone responsible for the release of FSH and LH from the anterior pituitary. GNRH is synthesized and released from neurons within the hypothalamus.
[edit] Production
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.
[edit] 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 CONH2.
[edit] GNRH as a 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, that contains most of the GNRH-secreting neurons. GNRH is secreted in the 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, 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.
[edit] 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). 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.
There are differences in GNRH secretion between females and males. In males, GNRH 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 GNRH just before ovulation.
GNRH secretion is pulsatile in all vertebrates, 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.
[edit] Activity
GNRH 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, 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.
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.<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 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>
[edit] GNRH in 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.
[edit] Medication
GNRH 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.
its analogue Leuprolide, is used for continuous infusion, to treat Breast carcinoma ,endometriosis ,prostate carcinoma , and precocious puberty
[edit] Agonists and antagonists
While GNRH has been synthesized and become available, its short half-life requires infusion pumps for its clinical use. Modifications of the decapeptide structure of GNRH have led to GNRH1 analog medications that either stimulate (GNRH1 agonists) or suppress (GNRH antagonists) the gonadotropins. It is important to note that, through downregulation, agonists are also able to exert a prolonged suppression effect.
[edit] Source Organism
Haplochromis burtoni (Burton's mouthbrooder).
[edit] Taxomomy
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;Actinopterygii; Neopterygii; Teleostei; Euteleostei; Neoteleostei;Acanthomorpha; Acanthopterygii; Percomorpha; Perciformes; Labroidei;Cichlidae; African cichlids; Pseudocrenilabrinae; Haplochromini;Astatotilapia.
[edit] Subcellular Localization
Secreted protein.
[edit] Developmental Stage
[edit] Similarity
Belongs to the GnRH family.
[edit] Post translational Modification
[edit] Function
Stimulates the secretion of gonadotropins. May be responsible for the regulation of the hypothalamic-pituitary-gonadal axis
