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Gonadotropin-inhibitory hormone

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Gonadotropin-inhibitory hormone (GnIH) is a RFamide-related peptide coded by the NPVF gene in mammals.

Discovery

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GnIH was discovered in 2000. It is an RFamide peptide that significantly reduced luteinizing hormone release in Coturnix Japonica (Japanese quail). This peptide emerged as the first tropic hormone known to inhibit gonadotropin secretion in the hypothalamic-pituitary-gonadal axis of vertebrates.[1] Subsequent research identified GnIH peptide homologs in variety of mammals, including humans.[2]

Structure

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GnIH is a neurohormone classified as an RFamide (RFa) or RFamide-related peptide (RFRP), coded by the NPVF gene in mammals. The complete amino acid sequence varies by species, but all RFa and RFRP peptides contain an arginine-phenylalanine-amine sequence at the C-terminal. This is seen in both Coturnix Japonica GnIH RFa (Ser-Ile-Lys-Pro-Ser-Ala-Tyr-Leu-Pro-Leu-Arg-Phe-NH2), and the human homolog, RFRP-3 (Val-Pro-Asp-Leu-Pro-Glu-Arg-Phe-NH2).[1][3]

Production

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GnIH neurons reside primarily in the dorsomedial nucleus of the hypothalamus (humans and rodents) and the paraventricular nucleus of the hypothalamus (avian species). Some GnIH neuron terminals in both mammalian and avian species project to the median eminence.[4][5][6] GnIH and GnRH (gonadotropin releasing hormone) neurons exist in close proximity in the hypothalamus, which may enable the direct inhibition of GnRH neurons by GnIH.[7] GnIH enters the bloodstream via the hypothalamo-hypophyseal portal system, the vascular network supplying both the hypothalamus and the pituitary.[8]

GnIH and GnIH receptor (GnIH-R) mRNA is expressed in the hypothalamus, pituitary, and ovaries.[5] GnIH expression is highest during proestrus and lowest during estrus, suggesting the estrus cycle influences release of the hormone. Furthermore, GnIH neuronal cell counts in multiple vertebrates fluctuate with an organism’s parental status.[9] GnIH cell count may also vary with breeding season in some species. For instance, European starlings (Sturnus vulgaris) with greater reproductive success exhibited higher quantities of GnIH-producing cells than did those that were less successful, but this effect did not appear until mid-breeding season.[9][10][11]

Receptor action

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GnIH binds to the Gαi protein coupled receptor GPR147 to suppress adenylyl cyclase formation of cAMP and inhibit protein kinase cascades affecting gene expression. GnIH inhibits the same signaling pathway that GnRH activates to promote follicle stimulating hormone (FSH) and luteinizing hormone (LH) expression.[12][13] The compound RF9 is a known GPR147 receptor antagonist.[14]

Effects and physiological function

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GnIH-R expression in the pituitary and other brain regions implies GnIH acts directly on the pituitary to downregulate gonadotropin production, impacting reproductive behaviors.[6][15][16][17] This neurohormone also acts on the hypothalamus to inhibit the expression of GnRH, which may further inhibit gonadotropin secretion, and kisspeptin, which may inhibit kisspeptin-mediated stimulation of GnRH neurons prior to the preovulatory hormonal surge. GnIH also spurs the production of cytochrome P450 aromatase, promoting the synthesis of neuroestrogen in the brains of quails and reducing aggressivity in reproductive behaviors.[7][18][19]

In male vertebrates, GnIH reduces testis size, lowers testosterone secretion, and increases the incidence of apoptosis in germ cells and Sertoli cells of the seminiferous tubules.[20][21] These gonadal changes, in addition to GnIH and GnIH-R mRNA expression in the seminiferous tubules, Sertoli cells, and spermatogonia, implicate function in spermatogenesis. In female vertebrates, high doses of GnIH increases ovarian mass and produce follicle irregularities, such as vacuole formation in nuclei and distorted morphology.[22] Ovarian changes in response to GnIH administration, as well as GnIH/GnIH-R mRNA expression in granulosa cells and luteal cells in different stages of the estrus cycle, implicate function in development of follicles and atresia.[21]

Additional biological roles

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Stress-induced adrenal hormone increase may upregulate GnIH release, as some GnIH neurons have adrenal glucocorticoid receptors. GnIH may therefore mediate interactions between the HPG and HPA (hypothalamic-pituitary-adrenal) axes and play a role in stress-related infertility.[23] GnIH neurons of the paraventricular nucleus in the hypothalamus also express melatonin receptors. Because melatonin secretion is modulated by environmental light patterns, melatonin influence on GnIH production may enable photoperiodic regulation of reproduction in seasonally breeding birds, rodents, and sheep.[24]

GnIH increases food consumption, implying a role in appetite. This finding is consistent with the location of most GnIH neurons, as the dorsomedial nucleus of the hypothalamus is involved in appetite regulation. GnIH may allow the energy reserves of an organism to modulate reproduction.[6]

Higher levels of thyroid hormone suppress GnIH expression, and lower levels of thyroid hormone are associated with higher GnIH levels. The inactivation of GnIH expression prevents delayed puberty caused by hypothyroidism, demonstrating that GnIH mediates interactions between the HPG and HPT (hypothalamic-pituitary-thyroid) axes.[25] Furthermore, thyroid hormone may function in a pathway for photoperiodic regulation of reproduction involving GnIH and energy status. Melatonin modulates thyroid-stimulating hormone (TSH) production in the anterior pituitary, and TSH promotes thyroid hormone production. Thyroid hormone production influences metabolism and GnIH production, both of which impact reproduction.[26]

References

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  1. ^ a b Tsutsui K, Saigoh E, Ukena K, Teranishi H, Fujisawa Y, Kikuchi M, Ishii S, Sharp PJ (August 2000). "A novel avian hypothalamic peptide inhibiting gonadotropin release". Biochemical and Biophysical Research Communications. 275 (2): 661–7. doi:10.1006/bbrc.2000.3350. PMID 10964719.
  2. ^ Fukusumi S, Habata Y, Yoshida H, Iijima N, Kawamata Y, Hosoya M, Fujii R, Hinuma S, Kitada C, Shintani Y, Suenaga M, Onda H, Nishimura O, Tanaka M, Ibata Y, Fujino M (September 2001). "Characteristics and distribution of endogenous RFamide-related peptide-1". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1540 (3): 221–32. doi:10.1016/S0167-4889(01)00135-5. PMID 11583817.
  3. ^ Findeisen M, Rathmann D, Beck-Sickinger AG (2011). "RFamide Peptides: Structure, Function, Mechanisms and Pharmaceutical Potential". Pharmaceuticals. 4 (9): 1248–1280. doi:10.3390/ph4091248. PMC 4058657.
  4. ^ Kriegsfeld LJ, Mei DF, Bentley GE, Ubuka T, Mason AO, Inoue K, Ukena K, Tsutsui K, Silver R (February 2006). "Identification and characterization of a gonadotropin-inhibitory system in the brains of mammals". Proceedings of the National Academy of Sciences of the United States of America. 103 (7): 2410–5. Bibcode:2006PNAS..103.2410K. doi:10.1073/pnas.0511003103. PMC 1413747. PMID 16467147.
  5. ^ a b Ubuka T, Morgan K, Pawson AJ, Osugi T, Chowdhury VS, Minakata H, Tsutsui K, Millar RP, Bentley GE (December 2009). "Identification of human GnIH homologs, RFRP-1 and RFRP-3, and the cognate receptor, GPR147 in the human hypothalamic pituitary axis". PLOS ONE. 4 (12): e8400. Bibcode:2009PLoSO...4.8400U. doi:10.1371/journal.pone.0008400. PMC 2791420. PMID 20027225.
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  7. ^ a b Smith JT, Shahab M, Pereira A, Pau KY, Clarke IJ (October 2010). "Hypothalamic expression of KISS1 and gonadotropin inhibitory hormone genes during the menstrual cycle of a non-human primate". Biology of Reproduction. 83 (4): 568–77. doi:10.1095/biolreprod.110.085407. PMC 2957156. PMID 20574054.
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  9. ^ a b Li X, Su J, Lei Z, Zhao Y, Jin M, Fang R, Zheng L, Jiao Y (August 2012). "Gonadotropin-inhibitory hormone (GnIH) and its receptor in the female pig: cDNA cloning, expression in tissues and expression pattern in the reproductive axis during the estrous cycle". Peptides. 36 (2): 176–85. doi:10.1016/j.peptides.2012.05.008. PMID 22664321. S2CID 902250.
  10. ^ Calisi RM, Díaz-Muñoz SL, Wingfield JC, Bentley GE (July 2011). "Social and breeding status are associated with the expression of GnIH". Genes, Brain and Behavior. 10 (5): 557–64. doi:10.1111/j.1601-183X.2011.00693.x. PMID 21466656.
  11. ^ Calisi RM, Geraghty AC, Avila A, Kaufer D, Bentley GE, Wingfield JC (October 2016). "Patterns of hypothalamic GnIH change over the reproductive period in starlings and rats". General and Comparative Endocrinology. 237: 140–146. doi:10.1016/j.ygcen.2016.08.015. PMID 27591072.
  12. ^ Ubuka T, Son YL, Tobari Y, Tsutsui K (2012). "Gonadotropin-inhibitory hormone action in the brain and pituitary". Frontiers in Endocrinology. 3: 148. doi:10.3389/fendo.2012.00148. PMC 3515997. PMID 23233850.
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  14. ^ Caraty A, Blomenröhr M, Vogel GM, Lomet D, Briant C, Beltramo M (May 2012). "RF9 powerfully stimulates gonadotrophin secretion in the ewe: evidence for a seasonal threshold of sensitivity". Journal of Neuroendocrinology. 24 (5): 725–36. doi:10.1111/j.1365-2826.2012.02283.x. PMID 22283564. S2CID 25770293.
  15. ^ Ubuka T, Ukena K, Sharp PJ, Bentley GE, Tsutsui K (March 2006). "Gonadotropin-inhibitory hormone inhibits gonadal development and maintenance by decreasing gonadotropin synthesis and release in male quail". Endocrinology. 147 (3): 1187–94. doi:10.1210/en.2005-1178. PMID 16293662.
  16. ^ Tsutsui K, Bentley GE, Ubuka T, Saigoh E, Yin H, Osugi T, Inoue K, Chowdhury VS, Ukena K, Ciccone N, Sharp PJ, Wingfield JC (2007-08-01). "The general and comparative biology of gonadotropin-inhibitory hormone (GnIH)". General and Comparative Endocrinology. Proceedings of the 23rd Conference of European Comparative Endocrinologists: Part 2. 153 (1–3): 365–70. doi:10.1016/j.ygcen.2006.10.005. PMID 17141777.
  17. ^ Bentley GE, Jensen JP, Kaur GJ, Wacker DW, Tsutsui K, Wingfield JC (April 2006). "Rapid inhibition of female sexual behavior by gonadotropin-inhibitory hormone (GnIH)". Hormones and Behavior. 49 (4): 550–5. doi:10.1016/j.yhbeh.2005.12.005. PMID 16460739. S2CID 1801090.
  18. ^ Paullada-Salmerón JA, Cowan M, Aliaga-Guerrero M, Morano F, Zanuy S, Muñoz-Cueto JA (June 2016). "Gonadotropin Inhibitory Hormone Down-Regulates the Brain-Pituitary Reproductive Axis of Male European Sea Bass (Dicentrarchus labrax)". Biology of Reproduction. 94 (6): 121. doi:10.1095/biolreprod.116.139022. PMC 6322450. PMID 26984999.
  19. ^ Tsutsui K, Ubuka T (2016). "GnIH Control of Feeding and Reproductive Behaviors". Frontiers in Endocrinology. 7: 170. doi:10.3389/fendo.2016.00170. PMC 5186799. PMID 28082949.
  20. ^ Ubuka T, Ukena K, Sharp P, Bentley G, Tsutsui K. Gonadotropin-inhibitory hormone inhibits gonadal development and maintenance by decreasing gonadotropin synthesis and release in male quail. Endocrinology. 2006; 147, 1187-1194. doi: 10.1210/en.2005-1178
  21. ^ a b Tsutsui K, Ubuka T, Bentley GE, Kriegsfeld LJ (July 2012). "Gonadotropin-inhibitory hormone (GnIH): discovery, progress and prospect". General and Comparative Endocrinology. Profiles in Comparative Endocrinology: Eric Roubos. 177 (3): 305–14. doi:10.1016/j.ygcen.2012.02.013. PMC 3378827. PMID 22391238.
  22. ^ Singh P, Krishna A, Tsutsui K (March 2011). "Effects of gonadotropin-inhibitory hormone on folliculogenesis and steroidogenesis of cyclic mice". Fertility and Sterility. 95 (4): 1397–404. doi:10.1016/j.fertnstert.2010.03.052. PMID 20452585.
  23. ^ Kirby ED, Geraghty AC, Ubuka T, Bentley GE, Kaufer D (July 2009). "Stress increases putative gonadotropin inhibitory hormone and decreases luteinizing hormone in male rats". Proceedings of the National Academy of Sciences of the United States of America. 106 (27): 11324–9. Bibcode:2009PNAS..10611324K. doi:10.1073/pnas.0901176106. PMC 2698887. PMID 19541621.
  24. ^ Tsutsui K, Bentley GE, Bedecarrats G, Osugi T, Ubuka T, Kriegsfeld LJ (July 2010). "Gonadotropin-inhibitory hormone (GnIH) and its control of central and peripheral reproductive function". Frontiers in Neuroendocrinology. 31 (3): 284–95. doi:10.1016/j.yfrne.2010.03.001. PMID 20211640. S2CID 10120758.
  25. ^ Kiyohara M, Son YL, Tsutsui K (April 2017). "Involvement of gonadotropin-inhibitory hormone in pubertal disorders induced by thyroid status". Scientific Reports. 7 (1): 1042. Bibcode:2017NatSR...7.1042K. doi:10.1038/s41598-017-01183-8. PMC 5430760. PMID 28432332.
  26. ^ Shinomiya A, Shimmura T, Nishiwaki-Ohkawa T, Yoshimura T (2014). "Regulation of seasonal reproduction by hypothalamic activation of thyroid hormone". Frontiers in Endocrinology. 5: 12. doi:10.3389/fendo.2014.00012. PMC 3930870. PMID 24600435.
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