The roles of RFamide-related peptides (RFRPs), mammalian gonadotropin-inhibitory hormone (GnIH) orthologues in female reproduction

Document Type: Review Article

Authors

1 Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences; Institute of Acupuncture and Moxibustion, Fudan Institutes of Integrative Medicine, Fudan University, Shanghai, China

2 Research and Clinical Center for Infertility, Yazd Reproduction Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

3 The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran

4 Department of Physiology, Faculty of Biological Sciences and Technology, Shahid Beheshti University, Tehran, Iran

5 Laboratory of Integrative Brain Sciences, Department of Biology and Center for Medical Life Science, Waseda University, Tokyo, Japan

6 Department of Animal Science, College of Agriculture, Shiraz University, Shiraz, Iran

Abstract

Objective(s): To benefit from reproduction and deal with challenges in the environmental conditions, animals must adapt internal physiology to maximize the reproduction rate. Maladaptive variations in the neurochemical systems and reproductive system can lead to manifestation of several significant mammalian reprocesses, including mammalian ovarian lifespan. RFamide-related peptide (RFRP, Rfrp), mammalian orthologues of gonadotropin-inhibitory hormone (GnIH), which is a regulator to prevent the gonadotropin-releasing hormone (GnRH) neural activity, is known to be related to reproductive traits. This review aimed to summarize recent five-year observations to outline historic insights and novel perspectives into the functions of RFRPs in coding the mammalian reproductive physiology, especially highlight recent advances in the impact on RFRPs in regulating mammalian ovary lifespan.
Materials and Methods: We reviewed the recent five-year important findings of RFRP system involved in mammalian ovary development. Data for this review were collected from Google Scholar and PubMed using the RFRP keyword combined with the keywords related to physiological or pathological reproductive functions.
Results: Recent discoveries are focused on three major fronts in research on RFRP role in female reproduction including reproductive functions, energy balance, and stress regulation. The roles of RFRPs in various development phases of mammal reproduction including prepuberty, puberty, estrous cycle, pregnancy, milking, menopause, and/or ovarian diseases have been shown.
Conclusion: Overall, these recent advances demonstrate that RFRPs serve as critical mediators in mammalian ovarian development.

Keywords

Main Subjects


1. Tsutsui K, Saigoh E, Ukena K, Teranishi H, Fujisawa Y, Kikuchi M, et al. A novel avian hypothalamic peptide inhibiting gonadotropin release. Biochem Biophys Res Commun 2000;275:661-667.
2. Umatani C, Abe H, Oka Y. Neuropeptide RFRP inhibits the pacemaker activity of terminal nerve GnRH neurons. J Neurophysiol 2013;109:2354-2363.
3. Ullah R, Batool A, Wazir M, Naz R, Rahman TU, Wahab F, et al. Gonadotropin inhibitory hormone and RF9 stimulate hypothalamic-pituitary-adrenal axis in adult male rhesus monkeys. Neuropeptides 2017;66:1-7.
4. Jennings KJ, Chang J, Cho H, Piekarski DJ, Russo KA, Kriegsfeld LJ. Aggressive interactions are associated with reductions in RFamide-related peptide, but not kisspeptin, neuronal activation in mice. Horm Behav 2016;78:127-134.
5. Henningsen JB, Poirel VJ, Mikkelsen JD, Tsutsui K, Simonneaux V, Gauer F. Sex differences in the photoperiodic regulation of RF-Amide related peptide (RFRP) and its receptor GPR147 in the syrian hamster. J Comp Neurol 2016;524:1825-1838.
6. Saenz de Miera C, Monecke S, Bartzen-Sprauer J, Laran-Chich MP, Pevet P, Hazlerigg DG, et al. A circannual clock drives expression of genes central for seasonal reproduction. Curr Biol 2014;24:1500-1506.
7. Kovacs A, Laszlo K, Galosi R, Toth K, Ollmann T, Peczely L, et al. Microinjection of RFRP-1 in the central nucleus of amygdala decreases food intake in the rat. Brain Res Bull 2012;88:589-595.
8. Ullah R, Shen Y, Zhou YD, Huang K, Fu JF, Wahab F, et al. Expression and actions of GnIH and its orthologs in vertebrates: Current status and advanced knowledge. Neuropeptides 2016;59:9-20.
9. Decourt C, Anger K, Robert V, Lomet D, Bartzen-Sprauer J, Caraty A, et al. No evidence that RFamide-related peptide 3 directly modulates LH secretion in the ewe. Endocrinology 2016;157:1566-1575.
10. Henningsen JB, Ancel C, Mikkelsen JD, Gauer Fo, Simonneaux Vr. Roles of RFRP-3 in the daily and seasonal regulation of reproductive activity in female Syrian hamsters. Endocrinology 2017;158:652-663.
11. Han X, He Y, Zeng G, Wang Y, Sun W, Liu J, et al. Intracerebroventricular injection of RFRP-3 delays puberty onset and stimulates growth hormone secretion in female rats. Reprod Biol Endocrinol 2017;15:35.
12. Peragine DE, Pokarowski M, Mendoza-Viveros L, Swift-Gallant A, Cheng HM, Bentley GE, et al. RFamide-related peptide-3 (RFRP-3) suppresses sexual maturation in a eusocial mammal. Proc Natl Acad Sci U S A 2017;114:1207-1212.
13. Ancel C, Inglis MA, Anderson GM. Central RFRP-3 stimulates LH secretion in male mice and has cycle stage-dependent inhibitory effects in females. Endocrinology 2017:en.2016-1902.
14. Talbi R, Klosen P, Laran-Chich MP, El Ouezzani S, Simonneaux V. Coordinated seasonal regulation of metabolic and reproductive hypothalamic peptides in the desert jerboa. J Comp Neurol 2016;524:3717-3728.
15. Simonneaux Vr, Ancel C. RFRP neurons are critical gatekeepers for the photoperiodic control of reproduction. Front Endocrinol 2012;3:225-233.
16. Zhao L, Zhong M, Xue H-L, Ding J-S, Wang S, Xu J-H, et al. Effect of RFRP-3 on reproduction is sex-and developmental status-dependent in the striped hamster (Cricetulus barabensis). Gene 2014;547:273-279.
17. Thorson JF, Heidorn NL, Ryu V, Czaja K, Nonneman DJ, Barb CR, et al. Relationship of neuropeptide FF receptors with pubertal maturation of gilts. Biol Reprod 2017;96:617-634.
18. Zheng L, Su J, Fang R, Jin M, Lei Z, Hou Y, et al. Developmental changes in the role of gonadotropin-inhibitory hormone (GnIH) and its receptors in the reproductive axis of male Xiaomeishan pigs. Anim Reprod Sci 2015;154:113-120.
19. Dan X, Liu X, Han Y, Liu Q, Yang L. Effect of the novel DNA vaccine fusing inhibin α (1-32) and the RF-amide related peptide-3 genes on immune response, hormone levels and fertility in Tan sheep. Anim Reprod Sci 2016;164:105-110.
20. Huang DW, Di R, Wang JX, Chu MX, He JN, Cao GL, et al. Analysis on DNA sequence of goat RFRP gene and its possible association with average daily sunshine duration. Mol Biol Rep 2012;39:9167-9177.
21. Tanco VM, Whitlock BK, Jones MA, Wilborn RR, Brandebourg TD, Foradori CD. Distribution and regulation of gonadotropin-releasing hormone, kisspeptin, RF-amide related peptide-3, and dynorphin in the bovine hypothalamus. Peer J 2016;4:e1833.
22. Wahab F, Drummer C, Schlatt S, Behr Rd. Dynamic regulation of hypothalamic DMXL2, KISS1, and RFRP expression during postnatal development in non-human primates. Mol Neurobiol 2017;54:8447-8457.
23. George JT, Hendrikse M, Veldhuis JD, Clarke IJ, Anderson RA, Millar RP. Effect of gonadotropin-inhibitory hormone on luteinizing hormone secretion in humans. Clin Endocrinol (Oxf) 2017;86:731-738.
24. Smith JT, Young IR, Veldhuis JD, Clarke IJ. Gonadotropin-inhibitory hormone (GnIH) secretion into the ovine hypophyseal portal system. Endocrinology 2012;153:3368-3375.
25. Russo KA, La JL, Stephens SBZ, Poling MC, Padgaonkar NA, Jennings KJ, et al. Circadian control of the female reproductive axis through gated responsiveness of the RFRP-3 system to VIP signaling. Endocrinology 2015;156:2608-2618.
26. Salehi MS, Tamadon A, Shirazi MRJ, Namavar MR, Zamiri MJ. The role of arginine-phenylalanine-amide-related peptides in mammalian reproduction. Int J Fertil Steril 2015;9:268-276.
27. Jørgensen SR, Andersen MD, Overgaard A, Mikkelsen JD. Changes in RFamide-related peptide-1 (RFRP-1)-immunoreactivity during postnatal development and the estrous cycle. Endocrinology 2014;155:4402-4410.
28. Xiang W, Zhang B, Lv F, Ma Y, Chen H, Chen L, et al. The inhibitory effects of RFamide-related peptide 3 on luteinizing hormone release involves an estradiol-dependent manner in prepubertal but not in adult female mice. Biol Reprod 2015;93:30.
29. Lima CJG, Cardoso SC, Lemos EFL, Zingler E, Capanema C, Menezes LD, et al. Mutational analysis of the genes encoding RFamide-related peptide-3, the human orthologue of gonadotrophin-inhibitory hormone, and its receptor (GPR147) in patients with gonadotrophin-releasing hormone-dependent pubertal disorders. J Neuroendocrinol 2014;26:817-824.
30. León S, García-Galiano D, Ruiz-Pino F, Barroso A, Manfredi-Lozano M, Romero-Ruiz A, et al. Physiological roles of gonadotropin-inhibitory hormone signaling in the control of mammalian reproductive axis: studies in the NPFF1 receptor null mouse. Endocrinology 2014;155:2953-2965.
31. Smith P, Wilhelm D, Rodgers RJ. Development of mammalian ovary. J Endocrinol 2014;221:R145-161.
32. Iwasa T, Matsuzaki T, Yano K, Irahara M. Gonadotropin-inhibitory hormone plays roles in stress-induced reproductive dysfunction. Front Endocrinol 2017;8:62.
33. Fang MX, Huang YS, Ye J, Zhang W, Li Y, Nie QH. Identification and characterization of RFRP gene in pigs and its association with reproductive traits. Genet Mol Res 2014;13:1661-1671.
34. Li X, Su J, Fang R, Zheng L, Lei R, Wang X, et al. The effects of RFRP-3, the mammalian ortholog of GnIH, on the female pig reproductive axis in vitro. Mol Cell Endocrinol 2013;372:65-72.
35. Thorson JF, Desaulniers AT, Lee C, White BR, Ford JJ, Lents CA. The role of RFamide-related peptide 3 (RFRP3) in regulation of the neuroendocrine reproductive and growth axes of the boar. Anim Reprod Sci 2015;159:60-65.
36. Jafarzadeh Shirazi MR, Pazoohi F, Zamiri MJ, Salehi MS, Namavar MR, Tamadon A, et al. Expression of RFamide-related peptide in the dorsomedial nucleus of hypothalamus during the estrous cycle of rats. Physiol Pharmacol 2013;17:72-79.
37. Salehi MS, Shirazi MRJ, Zamiri MJ, Pazhoohi F, Namavar MR, Niazi A, et al. Hypothalamic expression of KiSS1 and RFamide-related peptide-3 mRNAs during the estrous cycle of rats. Int J Fertil Steril 2013;6:304-309.
38. Geraghty AC, Muroy SE, Kriegsfeld LJ, Bentley GE, Kaufer D. The role of RFamide-related peptide-3 in age-related reproductive decline in female rats. Front Endocrinol 2016;7:71.
39. Calisi RM, Geraghty AC, Avila A, Kaufer D, Bentley GE, Wingfield JC. Patterns of hypothalamic GnIH change over the reproductive period in starlings and rats. Gen Comp Endocrinol 2016;237:140-146.
40. Noroozi A, Shirazi MRJ, Tamadon A, Moghadam A, Niazi A. Increased litter size and suckling intensity stimulate mRNA of RFamide-related peptide in rats. Int J Fertil Steril 2015;9:380-386.
41. Poling MC, Kim J, Dhamija S, Kauffman AS. Development, sex steroid regulation, and phenotypic characterization of RFamide-related peptide (Rfrp) gene expression and RFamide receptors in the mouse hypothalamus. Endocrinology 2012;153:1827-1840.42.
42. Kim JS, Brownjohn PW, Dyer BS, Beltramo M, Walker CS, Hay DL, et al. Anxiogenic and stressor effects of the hypothalamic neuropeptide RFRP-3 are overcome by the NPFFR antagonist GJ14. Endocrinology 2015;156:4152-4162.
43. Poling MC, Quennell JH, Anderson GM, Kauffman AS. Kisspeptin neurones do not directly signal to RFRP-3 neurones but RFRP-3 may directly modulate a subset of hypothalamic kisspeptin cells in mice. J Neuroendocrinol 2013;25:876-886.
44. Ancel C, Bentsen AH, Sébert M-E, Tena-Sempere M, Mikkelsen JD, Simonneaux Vr. Stimulatory effect of RFRP-3 on the gonadotrophic axis in the male Syrian hamster: the exception proves the rule. Endocrinology 2012;153:1352-1363.
45. Piekarski DJ, Zhao S, Jennings KJ, Iwasa T, Legan SJ, Mikkelsen JD, et al. Gonadotropin-inhibitory hormone reduces sexual motivation but not lordosis behavior in female Syrian hamsters (Mesocricetus auratus). Horm Behav 2013;64:501-510.
46. Bentley GE, Wilsterman K, Ernst DK, Lynn SE, Dickens MJ, Calisi RM, et al. Neural Versus Gonadal GnIH: Are they Independent Systems? A Mini-Review. Integr Comp Biol 2017;57:1194-1203.
47. Clarke IJ, Sari IP, Qi Y, Smith JT, Parkington HC, Ubuka T, et al. Potent action of RFamide-related peptide-3 on pituitary gonadotropes indicative of a hypophysiotropic role in the negative regulation of gonadotropin secretion. Endocrinology 2008;149:5811-5821.
48. Murakami M, Matsuzaki T, Iwasa T, Yasui T, Irahara M, Osugi T, et al. Hypophysiotropic role of RFamide-related peptide-3 in the inhibition of LH secretion in female rats. J Endocrinol 2008;199:105-112.
49. Johnson MA, Tsutsui K, Fraley GS. Rat RFamide-related peptide-3 stimulates GH secretion, inhibits LH secretion, and has variable effects on sex behavior in the adult male rat. Horm Behav 2007;51:171-180.
50. Kriegsfeld LJ, Mei DF, Bentley GE, Ubuka T, Mason AO, Inoue K, et al. Identification and characterization of a gonadotropin-inhibitory system in the brains of mammals. Proc Natl Acad Sci U S A 2006;103:2410-2415.
51. Tsutsui K, Ubuka T. GnIH Control of Feeding and Reproductive Behaviors. Front Endocrinol (Lausanne) 2016;7:170.
52. Gibson EM, Humber SA, Jain S, Williams WP, 3rd, Zhao S, Bentley GE, et al. Alterations in RFamide-related peptide expression are coordinated with the preovulatory luteinizing hormone surge. Endocrinology 2008;149:4958-4969.
53. Ducret E, Anderson GM, Herbison AE. RFamide-related peptide-3, a mammalian gonadotropin-inhibitory hormone ortholog, regulates gonadotropin-releasing hormone neuron firing in the mouse. Endocrinology 2009;150:2799-2804.
54. Gojska NM, Belsham DD. Glucocorticoid receptor-mediated regulation of Rfrp (GnIH) and Gpr147 (GnIH-R) synthesis in immortalized hypothalamic neurons. Mol Cell Endocrinol 2014;384:23-31.
55. Ubuka T, Ukena K, Sharp PJ, Bentley GE, Tsutsui K. Gonadotropin-inhibitory hormone inhibits gonadal development and maintenance by decreasing gonadotropin synthesis and release in male quail. Endocrinology 2006;147:1187-1194.
56. Bentley GE, Ubuka T, McGuire NL, Chowdhury VS, Morita Y, Yano T, et al. Gonadotropin-inhibitory hormone and its receptor in the avian reproductive system. Gen Comp Endocrinol 2008;156:34-43.
57. Sethi S, Chaturvedi CM. Physiological evidence of an inverse correlation between the gonadal function and rfrp-3 neurons in mice. Int J Bioassays 2015;4:4022-4024.
58. Soga T, Dalpatadu SL, Wong DW, Parhar IS. Neonatal dexamethasone exposure down-regulates GnRH expression through the GnIH pathway in female mice. Neuroscience 2012;218:56-64.
59. Losa-Ward SM, Todd KL, McCaffrey KA, Tsutsui K, Patisaul HB. Disrupted organization of RFamide pathways in the hypothalamus is associated with advanced puberty in female rats neonatally exposed to bisphenol A. Biol Reprod 2012;87:28.
60. Howdeshell KL, Hotchkiss AK, Thayer KA, Vandenbergh   JG, vom Saal FS. Exposure to bisphenol A advances puberty. Nature 1999;401:763-764.
61. Adewale HB, Jefferson WN, Newbold RR, Patisaul HB. Neonatal bisphenol-a exposure alters rat reproductive development and ovarian morphology without impairing activation of gonadotropin-releasing hormone neurons. Biol Reprod 2009;81:690-699.
62. Iwasa T, Matsuzaki T, Murakami M, Kinouchi R, Osugi T, Gereltsetseg G, et al. Developmental changes in the mammalian gonadotropin-inhibitory hormone (GnIH) ortholog RFamide-related peptide (RFRP) and its cognate receptor GPR147 in the rat hypothalamus. Int J Dev Neurosci 2012;30:31-37.
63. Iwasa T, Matsuzaki T, Tungalagsuvd A, Munkhzaya M, Kuwahara A, Yasui T, et al. The advancement of the onset of vaginal opening in female rats subjected to chronic testosterone treatment occurs independently of hypothalamic Kiss1 and RFRP expression. Neuroendocrinol Lett 2015;36:767-770.
64. Li H, Song H, Huang M, Nie H, Wang Z, Wang F. Impact of food restriction on ovarian development, RFamide-related peptide-3 and the hypothalamic-pituitary-ovarian axis in pre-pubertal ewes. Reprod Domest Anim 2014;49:831-838.
65. Poling MC, Kauffman AS. Regulation and function of RFRP-3 (GnIH) neurons during postnatal development. Front Endocrinol 2015;6:150.
66. Kiyohara M, Son YL, Tsutsui K. Involvement of gonadotropin-inhibitory hormone in pubertal disorders induced by thyroid status. Sci Rep 2017;7:1042.
67. Li X, Su J, Lei Z, Zhao Y, Jin M, Fang R, et al. 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 2012;36:176-185.
68. Williams WP, 3rd, Kriegsfeld LJ. Circadian control of neuroendocrine circuits regulating female reproductive function. Front Endocrinol (Lausanne) 2012;3:60.
69. Legan SJ, Karsch FJ. A daily signal for the LH surge in the rat. Endocrinology 1975;96:57-62.
70. Kriegsfeld LJ, Korets R, Silver R. Expression of the circadian clock gene Period 1 in neuroendocrine cells: an investigation using mice with a Per1:: GFP transgene. Eur J Neurosci 2003;17:212-220.
71. Khan AR, Kauffman AS. The role of kisspeptin and RFamide-related peptide-3 neurones in the circadian-timed preovulatory luteinising hormone surge. J Neuroendocrinol 2012;24:131-143.
72. Kadokawa H, Shibata M, Tanaka Y, Kojima T, Matsumoto K, Oshima K, et al. Bovine C-terminal octapeptide of RFamide-related peptide-3 suppresses luteinizing hormone (LH) secretion from the pituitary as well as pulsatile LH secretion in bovines. Domest Anim Endocrinol 2009;36:219-224.
73. Sethi S, Tsutsui K, Chaturvedi CM. Temporal phase relation of circadian neural oscillations alters RFamide-related peptide-3 and testicular function in the mouse. Neuroendocrinology 2010;91:189-199.
74. Sethi S, Chaturvedi CM. Temporal synergism of neurotransmitters and role of RFamide-related peptide-3. Biomed Res 2016;1:16-35.
75. Clarke IJ, Qi Y, Puspita Sari I, Smith JT. Evidence that RF-amide related peptides are inhibitors of reproduction in mammals. Front Neuroendocrinol 2009;30:371-378.
76. Zhao S, Zhu E, Yang C, Bentley GE, Tsutsui K, Kriegsfeld LJ. RFamide-related peptide and messenger ribonucleic acid expression in mammalian testis: association with the spermatogenic cycle. Endocrinology 2010;151:617-627.
77. Nequin LG, Alvarez J, ScHwartz NB. Steroid control of gonadotropin release. J Steroid Biochem 1975;6:1007-1012.
78. Bentley GE, Perfito N, Ukena K, Tsutsui K, Wingfield JC. Gonadotropin-inhibitory peptide in song sparrows (Melospiza melodia) in different reproductive conditions, and in house sparrows (Passer domesticus) relative to chicken-gonadotropin-releasing hormone. J Neuroendocrinol 2003;15:794-802.
79. Calisi RM, Diaz-Munoz SL, Wingfield JC, Bentley GE. Social and breeding status are associated with the expression of GnIH. Genes Brain Behav 2011;10:557-564.
80. McGuire NL, Koh A, Bentley GE. The direct response of the gonads to cues of stress in a temperate songbird species is season-dependent. PeerJ 2013;1:e139.
81. Calisi RM, Rizzo NO, Bentley GE. Seasonal differences in hypothalamic EGR-1 and GnIH expression following capture-handling stress in house sparrows (Passer domesticus). Gen Comp Endocrinol 2008;157:283-287.
82. Buchanan GD, Younglai EV. Plasma progesterone levels during pregnancy in the little brown bat Myotis lucifugus (Vespertilionidae). Biol Reprod 1986;34:878-884.
83. Yarim G, Karahan S. Regional brain and sex differences in the plasma progesterone concentration of sheep. Small Ruminant Res 2007;71:98-102.
84. Benton NA, Russo KA, Brozek JM, Andrews R, Kim V, Kriegsfeld LJ, et al. Food restriction-induced changes in motivation differ with stages of the estrous cycle and are closely linked to RFamide-related peptide-3 but not kisspeptin in Syrian hamsters. Physiol Behav 2018;190:43-60.
85. Ubuka T, Bentley GE, Tsutsui K. Neuroendocrine regulation of gonadotropin secretion in seasonally breeding birds. Front Neurosci 2013;7:38.
86. Bentley G, Ubuka T, McGuire N, Calisi R, Perfito N, Kriegsfeld L, et al. Gonadotrophin-inhibitory hormone: a multifunctional neuropeptide. J Neuroendocrinol 2009;21:276-281.
87. Sarvestani FS, Tamadon A, Koohi-Hosseinabadi O, Nezhad SM, Rahmanifar F, Shirazi MRJ, et al. Expression of RFamide-related peptide-3 (RFRP-3) mRNA in dorsomedial hypothalamic nucleus and KiSS-1 mRNA in arcuate nucleus of rat during pregnancy. Int J Fertil Steril 2014;8:333-340.
88. Yap CC, Wharfe MD, Mark PJ, Waddell BJ, Smith JT. Diurnal regulation of hypothalamic kisspeptin is disrupted during mouse pregnancy. J Endocrinol 2016;229:307-318.
89. Butler WR. Nutritional interactions with reproductive performance in dairy cattle. Anim Reprod Sci 2000;60-61:449-457.
90. Fox SR, Smith MS. The suppression of pulsatile luteinizing hormone secretion during lactation in the rat. Endocrinology 1984;115:2045-2051.
91. Asadi Yousefabad SL, Tamadon A, Rahmanifar F, Jafarzadeh Shirazi MR, Sabet Sarvestani F, Tanideh N, et al. Lactation effect on the mRNAs expression of RFRP-3 and KiSS-1 in dorsomedial and arcuate nuclei of the rat hypothalamus. Physiol Pharmacol 2013;17:277-285.
92. Hernández-Angeles C, Castelo-Branco C. Early menopause: A hazard to a woman’s health. Indian J Med Res 2016;143:420.
93. Liu PY. Assessing new peptides that may be involved in the physiological regulation of the gonadal axis in humans: gonadotrophin inhibitory hormone. Clin Endocrinol (Oxf) 2017;86:658-659.
94. Kim YJ, Tamadon A, Park HT, Kim H, Ku S-Y. The role of sex steroid hormones in the pathophysiology and treatment of sarcopenia. Osteoporos Sarcopenia 2016;2:140-155.
95. Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol 2011;7:219-231.
96. Rahmanifar F, Nooranizadeh MH, Tamadon A, Rajabi-Aslani J, Koohi-Hosseinabadi O, Shirazi MRJ, et al. Histomorphometric comparison of induction of polycystic ovary syndrome by exposure to constant light in primiparous and nulliparous rats. Iran J Sci Technol A Sci 2018;42:421-430.
97. Tsutsui K, Son YL, Kiyohara M, Miyata I. Mini-review: Discovery of GnIH and its role in hypothyroidism-induced delayed puberty. Endocrinology 2018;159:62-68.
98. Louis GMB, Lum KJ, Sundaram R, Chen Z, Kim S, Lynch CD, et al. Stress reduces conception probabilities across the fertile window: evidence in support of relaxation. Fertil Steril 2011;95:2184-2189.
99. Geraghty AC, Muroy SE, Zhao S, Bentley GE, Kriegsfeld LJ, Kaufer D. Knockdown of hypothalamic RFRP3 prevents chronic stress-induced infertility and embryo resorption. Elife 2015;4:e04316.
100. Rudolph LM, Bentley GE, Calandra RS, Paredes AH, Tesone M, Wu TJ, et al. Peripheral and central mechanisms involved in the hormonal control of male and female reproduction. J Neuroendocrinol 2016;28:1-12.
101. Fauser BC, Tarlatzis BC, Rebar RW, Legro RS, Balen AH, Lobo R, et al. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril 2012;97:28-38. e25.
102. Shaaban Z, Shirazi MRJ, Nooranizadeh MH, Tamadon A, Rahmanifar F, Ahmadloo S, et al. Decreased expression of arginine-phenylalanine-amide-related peptide-3 gene in dorsomedial hypothalamic nucleus of constant light exposure model of polycystic ovarian syndrome. Int J Fertil Steril 2018;12:43-50.
103. Walters KA, Allan CM, Handelsman DJ. Rodent models for human polycystic ovary syndrome. Biol Reprod 2012;149:141-112.
104. Iwasa T, Matsuzaki T, Tungalagsuvd A, Munkhzaya M, Yiliyasi M, Kato T, et al. Effects of chronic DHEA treatment on central and peripheral reproductive parameters, the onset of vaginal opening and the estrous cycle in female rats. Gynecol Endocrinol 2016;32:752-755.
105. He Y, Sun W, Yu J. Is precocious puberty linked to hypothalamic expression of arginine-phenylalanine-amide-related peptide? Iran J Basic Med Sci 2017;20:1074-1078.
106. Katagiri F, Kotani M, Hirai T, Kagawa J. The relationship between circulating kisspeptin and sexual hormones levels in healthy females. Biochem Biophys Res Commun 2015;458:663-666.
107. Elhabazi K, Humbert J-P, Bertin I, Quillet R, Utard Vr, Schneider Sv, et al. RF313, an orally bioavailable neuropeptide FF receptor antagonist, opposes effects of RF-amide-related peptide-3 and opioid-induced hyperalgesia in rodents. Neuropharmacology 2017;118:188-198.
108. McGuire NL, Bentley GE. Neuropeptides in the Gonads: From Evolution to Pharmacology. Front Pharmacol 2010;1:114.
109. Bentley GE, Kriegsfeld LJ, Osugi T, Ukena K, O’Brien S, Perfito N, et al. Interactions of gonadotropin-releasing hormone (GnRH) and gonadotropin-inhibitory hormone (GnIH) in birds and mammals. J Exp Zool A Comp Exp Biol 2006;305:807-814.
110. Bentley GE, Ubuka T, McGuire NL, Calisi R, Perfito N, Kriegsfeld LJ, et al. Gonadotrophin-inhibitory hormone: a multifunctional neuropeptide. J Neuroendocrinol 2009;21:276-281.