Gonadotropin-releasing hormone

From Wikipedia, the free encyclopedia


Gonadotropin-releasing hormone 1 (luteinizing-releasing hormone)
from PDB 1YY1
Identifiers
Symbol(s) GNRH1; GNRH; GRH; LHRH; LNRH
External IDs OMIM: 152760 MGI: 95789 HomoloGene: 641
RNA expression pattern

More reference expression data
Orthologs
Human Mouse
Entrez 2796 14714
Ensembl ENSG00000147437 ENSMUSG00000015812
Uniprot P01148 Q14AC4
Refseq NM_000825 (mRNA)
NP_000816 (protein)		 NM_008145 (mRNA)
NP_032171 (protein)
Location Chr 8: 25.33 - 25.34 Mb Chr 14: 66.7 - 66.7 Mb
Pubmed search [1] [2]

Gonadotropin-releasing hormone 1 (GNRH1), also known as Luteinising-hormone releasing hormone (LHRH), is a peptide hormone responsible for the release of FSH and LH from the anterior pituitary. GNRH1 is synthesized and released by the hypothalamus.

Contents

[edit] Gene

The gene, GNRH1, for the GNRH1 precursor is located on chromosome 8. This precursor contains 92 amino acids and is processed to GNRH1, a decapeptide (10 amino acids) in mammals.

GnRH was previously called LHRH.

[edit] Structure

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.

[edit] GNRH1 as a neurohormone

GNRH1 is considered a neurohormone, a hormone produced in a specific neural cell and released at its 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, gonadotropin-releasing hormone receptor (GNRHR), located in the cell membrane.

GNRH1 is degraded by proteolysis within a few minutes.

[edit] Control of FSH and LH

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.

GNRH1 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

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, hyperinsulinemia 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.[1] Kisspeptin appears to be an important regulator of GNRH release.[2] GNRH release can also be regulated by estrogen. It has been reported that there are kisspeptin-producing neurons that also express estrogen receptor alpha.[3]

[edit] GNRH1 in other organs

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.

[edit] Medication

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.

[edit] Agonists and antagonists

While GNRH1 has been synthesized and become available, its short half-life requires infusion pumps for its clinical use. Modifications of the decapeptide structure of GNRH1 have led to GNRH1 analog medications that either stimulate (GNRH1 agonists) or suppress (GNRH1 antagonists) the gonadotropins. It is important to note that, through downregulation, agonists are also able to exert a prolonged suppression effect.

[edit] References

  1. ^ R.E. Brown. An Introduction to Neuroenocrinology; Cambridge University Press 1994.
  2. ^ 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
  3. ^ 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

[edit] Further reading

  • Flanagan CA, Millar RP, Illing N (1998). "Advances in understanding gonadotrophin-releasing hormone receptor structure and ligand interactions.". Rev. Reprod. 2 (2): 113-20. PMID 9414473. 
  • Leung PC, Cheng CK, Zhu XM (2004). "Multi-factorial role of GnRH-I and GnRH-II in the human ovary.". Mol. Cell. Endocrinol. 202 (1-2): 145-53. PMID 12770744. 
  • Gründker C, Emons G (2004). "Role of gonadotropin-releasing hormone (GnRH) in ovarian cancer.". Reprod. Biol. Endocrinol. 1: 65. doi:10.1186/1477-7827-1-65. PMID 14594454. 
  • Limonta P, Moretti RM, Marelli MM, Motta M (2004). "The biology of gonadotropin hormone-releasing hormone: role in the control of tumor growth and progression in humans.". Frontiers in neuroendocrinology 24 (4): 279-95. PMID 14726258. 
  • Janáky T, Juhász A, Bajusz S, et al. (1992). "Analogues of luteinizing hormone-releasing hormone containing cytotoxic groups.". Proc. Natl. Acad. Sci. U.S.A. 89 (3): 972-6. doi:10.1073/pnas.89.3.972. PMID 1310542. 
  • Healey SC, Martin NG, Chenevix-Trench G (1991). "NcoI RFLP of the human LHRH gene on chromosome 8p.". Nucleic Acids Res. 19 (21): 6059. doi:10.1093/nar/19.21.6059. PMID 1682898. 
  • Williamson P, Lang J, Boyd Y (1992). "The gonadotropin-releasing hormone (Gnrh) gene maps to mouse chromosome 14 and identifies a homologous region on human chromosome 8.". Somat. Cell Mol. Genet. 17 (6): 609-15. PMID 1767338. 
  • Hayflick JS, Adelman JP, Seeburg PH (1989). "The complete nucleotide sequence of the human gonadotropin-releasing hormone gene.". Nucleic Acids Res. 17 (15): 6403-4. doi:10.1093/nar/17.15.6403. PMID 2671939. 
  • Nikolics K, Mason AJ, Szönyi E, et al. (1985). "A prolactin-inhibiting factor within the precursor for human gonadotropin-releasing hormone.". Nature 316 (6028): 511-7. doi:10.1038/316511a0. PMID 2863757. 
  • Adelman JP, Mason AJ, Hayflick JS, Seeburg PH (1986). "Isolation of the gene and hypothalamic cDNA for the common precursor of gonadotropin-releasing hormone and prolactin release-inhibiting factor in human and rat.". Proc. Natl. Acad. Sci. U.S.A. 83 (1): 179-83. doi:10.1073/pnas.83.1.179. PMID 2867548. 
  • Yang-Feng TL, Seeburg PH, Francke U (1986). "Human luteinizing hormone-releasing hormone gene (LHRH) is located on short arm of chromosome 8 (region 8p11.2----p21).". Somat. Cell Mol. Genet. 12 (1): 95-100. doi:10.1007/BF01560732. PMID 3511544. 
  • Seeburg PH, Adelman JP (1984). "Characterization of cDNA for precursor of human luteinizing hormone releasing hormone.". Nature 311 (5987): 666-8. doi:10.1038/311666a0. PMID 6090951. 
  • Tan L, Rousseau P (1983). "The chemical identity of the immunoreactive LHRH-like peptide biosynthesized in the human placenta.". Biochem. Biophys. Res. Commun. 109 (3): 1061-71. PMID 6760865. 
  • Dong KW, Yu KL, Roberts JL (1994). "Identification of a major up-stream transcription start site for the human progonadotropin-releasing hormone gene used in reproductive tissues and cell lines.". Mol. Endocrinol. 7 (12): 1654-66. PMID 8145771. 
  • Kakar SS, Jennes L (1996). "Expression of gonadotropin-releasing hormone and gonadotropin-releasing hormone receptor mRNAs in various non-reproductive human tissues.". Cancer Lett. 98 (1): 57-62. PMID 8529206. 
  • Nagy A, Schally AV, Armatis P, et al. (1996). "Cytotoxic analogs of luteinizing hormone-releasing hormone containing doxorubicin or 2-pyrrolinodoxorubicin, a derivative 500-1000 times more potent.". Proc. Natl. Acad. Sci. U.S.A. 93 (14): 7269-73. doi:10.1073/pnas.93.14.7269. PMID 8692981. 
  • Chegini N, Rong H, Dou Q, et al. (1996). "Gonadotropin-releasing hormone (GnRH) and GnRH receptor gene expression in human myometrium and leiomyomata and the direct action of GnRH analogs on myometrial smooth muscle cells and interaction with ovarian steroids in vitro.". J. Clin. Endocrinol. Metab. 81 (9): 3215-21. doi:10.1210/jc.81.9.3215. PMID 8784072. 
  • Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery.". Genome Res. 6 (9): 791-806. PMID 8889548. 
  • Dong KW, Yu KL, Chen ZG, et al. (1997). "Characterization of multiple promoters directing tissue-specific expression of the human gonadotropin-releasing hormone gene.". Endocrinology 138 (7): 2754-62. doi:10.1210/en.138.7.2754. PMID 9202214.