Is precocious puberty linked to hypothalamic expression of arginine-phenylalanine-amide-related peptide?

Document Type: Mini Review


Department of Traditional Chinese Medicine, Children’s Hospital of Fudan University, Shanghai, 200032, China


The up-regulator regulation and down-regulator regulation of gonadotropin-releasing hormone (GnRH) in central precocious puberty is not yet known. However, recent advances in neuroendocrinology have shown the controlling role of arginine-phenylalanine (RF)-amide-related peptides (RFRPs) on GnRH secretion in different phenomenon of reproduction such as estrus cycle and pregnancy, but the exact role of RFRPs in puberty and its related pathologic condition, precocious puberty, is not clear yet. This paper hypothesizes that RFRP is a regulatory peptide of puberty and might prevent the precocious puberty. On the basis of previous studies on hormonal fluctuations at the time of puberty, RFRP might have a role on controlling of premature secretion of GnRH and avoiding central precocious puberty.


1. Delemarre-van de Waal HA. Secular trend of timing of puberty. Endocr Dev 2005; 8:1-14.

2. Papathanasiou A, Hadjiathanasiou C. Precocious puberty. Pediatr Endocrinol Rev 2006; 3:182-187.

3. Terasawa E, Fernandez DL. Neurobiological mechanisms of the onset of puberty in primates. Endocr Rev 2001; 22:111-151.

4. Wang S, Zhu L, Yu J, Tian Z. Effect of nourishing "yin"-removing "fire" Chinese herbal mixture on hypothalamic NKB/NK3R expression in female precocious rats. Evid Based Complement Alternat Med 2014; 2014:Article number 217424.

5. Sun Y, Perry GN, Yu J, Chen B, Tian Z. Effect of nourishing "Yin"-removing "Fire" Chinese herbal mixture on hypothalamic kisspeptin expression in female precocious rats. J Ethnopharmacol 2010; 127:274-279.

6. Sun Y, Tian Z, Li J, Yu J, Wang Y. Effects of nourishing Yin removing Fire Chinese herbs on gene expression of hypothalamic ghrelin and its receptor in female precocious rats. Zhongguo Zhong Xi Yi Jie He Za Zhi 2015; 35:854-859.

7. Zeng G, Han X, Yu J, Wang Y, Tian Z. Effect of nourishing "yin" removing "fire" Chinese herbal mixture on hypothalamic mammalian target of rapamycin expression during onset of puberty in female rats. Evid Based Complement Alternat Med 2015; 2015:Article number 157846.

8. Hwan JC, Freeman ME. A physiological role for luteinizing hormone release-inhibiting factor of hypothalamic origin. Endocrinology 1987; 121:1099-1103.

9. 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.

10. Hinuma S, Shintani Y, Fukusumi S, Iijima N, Matsumoto Y, Hosoya M, et al. New neuropeptides containing carboxy-terminal RFamide and their receptor in mammals. Nat Cell Biol 2000; 2:703-708.

11. Ubuka T, Inoue K, Fukuda Y, Mizuno T, Ukena K, Kriegsfeld LJ, et al. Identification, expression, and physiological functions of Siberian hamster gonadotropin-inhibitory hormone. Endocrinology 2012; 153:373-385.

12. Fukusumi S, Habata Y, Yoshida H, Iijima N, Kawamata Y, Hosoya M, et al. Characteristics and distribution of endogenous RFamide-related peptide-1. Biochim Biophys Acta Mol Cell Res 2001; 1540:221-232.

13. Dardente H, Birnie M, Lincoln GA, Hazlerigg DG. RFamide-related peptide and its cognate receptor in the sheep: cDNA cloning, mRNA distribution in the hypothalamus and the effect of photoperiod. J Endocrinol 2008; 20:1252-1259.

14. 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.

15. Jafarzadeh Shirazi MR, Zamiri MJ, Salehi MS, Moradi S, Tamadon A, Namavar MR, et al. Differential expression of RFamide-related peptide, a mammalian gonadotrophin-inhibitory hormone orthologue, and kisspeptin in the hypothalamus of Abadeh ecotype does during breeding and anoestrous seasons. J Neuroendocrinol 2014; 26:186-194.

16. Ubuka T, Lai H, Kitani M, Suzuuchi A, Pham V, Cadigan PA, et al. Gonadotropin-inhibitory hormone identification, cDNA cloning, and distribution in rhesus macaque brain. J Comp Neurol 2009; 517:841-855.

17. Ubuka T, Morgan K, Pawson AJ, Osugi T, Chowdhury VS, Minakata H, et al. Identification of human GnIH homologs, RFRP-1 and RFRP-3, and the cognate receptor, GPR147 in the human hypothalamic pituitary axis. PLoS One 2009; 4:e8400.

18. Price DA, Greenberg MJ. Structure of a molluscan cardioexcitatory neuropeptide. Science 1977; 197:670-671.

19. Dockray GJ, Reeve JRJ, Shively J, Gayton RJ, Barnard CS. A novel active pentapeptide from chicken brain identified by antibodies to FMRFamide. Nature 1983; 305:328-330.

20. Salehi MS, Tamadon A, Jafarzadeh Shirazi MR, Namavar MR, Zamiri MJ. The role of arginine-phenylalanine-amide-related peptides in mammalian reproduction. Int J Fertil Steril 2015; 9:268-276.

21. Fukusumi S, Fujii R, Hinuma S. Recent advances in mammalian RFamide peptides: the discovery and functional analyses of PrRP, RFRPs and QRFP. Peptides 2006; 27:1073-1086.

22. Zhang Y, Li S, Liu Y, Lu D, Chen H, Huang X, et al. Structural diversity of the GnIH/GnIH receptor system in teleost: its involvement in early development and the negative control of LH release. Peptides 2010; 31:1034-1043.

23. 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.

24. 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.

25. Rizwan MZ, Porteous R, Herbison AE, Anderson GM. Cells expressing RFamide-related peptide-1/3, the mammalian gonadotropin-inhibitory hormone orthologs, are not hypophysiotropic neuroendocrine neurons in the rat. Endocrinology 2009; 150:1413-1420.

26. Jafarzadeh Shirazi MR, Namavar MR, Tamadon A. Expression of gonadotropin inhibitory hormone in the preoptic area and its relation with phases of estrous cycle of ewe. Physiol Pharmacol 2011; 15:90-96.

27. Jafarzadeh Shirazi MR, Tamadon A, Namavar MR. Coexpression of gonadotropin inhibitory hormone with Agouti-related peptide in the neurons of arcuate nucleus of ewe hypothalamus. Physiol Pharmacol 2011; 15:201-209.

28. Jafarzadeh Shirazi MR, Zamiri MJ, Salehi MS, Moradi S, Tamadon A, Namavar MR, et al. Differential expressions of RFamide-related peptide, a mammalian gonadotropin-inhibitory hormone ortholog, and kisspeptin in the hypothalamus of Abadeh ecotype does during breeding and anestrous seasons. J Neuroendocrinol 2014; 26:186-194.

29. Jafarzadeh Shirazi MR, Tamadon A. Intermediary role of kisspeptin in the stimulation of gonadotropin-releasing hormone neurons by estrogen in the preoptic area of sheep brain. Physiol Pharmacol 2010; 14:41-47.

30. 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.

31. Rizwan MZ, Poling MC, Corr M, Cornes PA, Augustine RA, Quennell JH, et al. RFamide-related peptide-3 receptor gene expression in GnRH and kisspeptin neurons and GnRH-dependent mechanism of action. Endocrinology 2012; 153:3770-3779.

32. Smith JT, Coolen LM, Kriegsfeld LJ, Sari IP, Jaafarzadeh Shirazi MR, Maltby M, et al. Variation in kisspeptin and RFamide-related peptide (RFRP) expression and terminal connections to gonadotropin-releasing hormone neurons in the brain: A novel medium for seasonal breeding in the sheep. Endocrinology 2008; 149:5770-5782.

33. Jafarzadeh Shirazi MR, Namavar MR, Tamadon A. Coexpression of gonadotropin inhibitory hormone and gonadotropin releasing hormone neurons in the preoptic area of hypothalamus in the phases of estrous cycle of the ewe. J Iran Anat Sci 2011; 9:63-70.

34. 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.

35. Wu M, Dumalska I, Morozova E, Van Den Pol AN, Alreja M. Gonadotropin inhibitory hormone inhibits basal forebrain vGluT2-gonadotropin-releasing hormone neurons via a direct postsynaptic mechanism. J Physiol 2009; 587:1401-1411.

36. 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.

37. 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.

38. Pineda R, Garcia-Galiano D, Sanchez-Garrido MA, Romero M, Ruiz-Pino F, Aguilar E, et al. Characterization of the potent gonadotropin-releasing activity of RF9, a selective antagonist of RF-amide-related peptides and neuropeptide FF receptors: physiological and pharmacological implications. Endocrinology 2010; 151:1902-1913.

39. Ancel C, Bentsen AH, Sébert M-E, Tena-Sempere M, Mikkelsen JD, Simonneaux V. Stimulatory effect of RFRP-3 on the gonadotrophic axis in the male Syrian hamster: the exception proves the rule. Endocrinology 2012; 153:1352-1363.

40. Caraty A, Blomenröhr M, Vogel GMT, Lomet D, Briant C, Beltramo M. RF9 powerfully stimulates gonadotrophin secretion in the ewe: evidence for a seasonal threshold of sensitivity. J Neuroendocrinol 2012; 24:725-736.

41. Anderson GM. Pituitary actions of RFamide peptides: a critique of the evidence. Open Neuroendocrinol J 2011; 4:51-63.

42. Gibson EM, Humber SA, Jain S, Williams WP, 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.

43. Bentley GE, Tsutsui K, Kriegsfeld LJ. Recent studies of gonadotropin-inhibitory hormone (GnIH) in the mammalian hypothalamus, pituitary and gonads. Brain Res 2010; 1364:62-71.

44. Quennell JH, Rizwan MZ, Relf HL, Anderson GM. Developmental and steroidogenic effects on the gene expression of RFamide related peptides and their receptor in the rat brain and pituitary gland. J Neuroendocrinol 2010; 22:309-316

45. Kirby ED, Geraghty AC, Ubuka T, Bentley GE, Kaufer D. Stress increases putative gonadotropin inhibitory hormone and decreases luteinizing hormone in male rats. Proc Natl Acad Sci U S A 2009; 106:11324-11329.

46. 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.

47. McGuire NL, Bentley GE. Neuropeptides in the gonads: from evolution to pharmacology. Front Pharmacol 2010; 1:114.

48. Singh P, Krishna A, Sridaran R, Tsutsui K. Immunohisto-chemical localization of GnRH and RFamide-related peptide-3 in the ovaries of mice during the estrous cycle. J Mol Histol 2011; 42:371-381.

49. Oishi H, Klausen C, Bentley GE, Osugi T, Tsutsui K, Gilks CB, et al. The human gonadotropin-inhibitory hormone ortholog RFamide-related peptide-3 suppresses gonadotropin-induced progesterone production in human granulosa cells. Endocrinology 2012; 153:3435-3445.

50. Karami Kheirabad M, Ahmadloo S, Namavar Jahromi B, Rahmanifar F, Tamadon A, Ramezani A, et al. Alterations of hypothalamic RF‐amide related peptide-3 and Kiss1 gene expressions during spermatogenesis of rat in chronic stress conditions. Vet Arhiv 2016; v86:841-856.

51. Choi JH, Yoo HW. Control of puberty: genetics, endocrinology, and environment. Curr Opin Endocrinol Diabetes Obes 2013; 20:62-68.

52. Jahanara M, Tamadon A, Jafarzadeh Shirazi MR, Rahmanifar F, Sabet Sarvestani F, Tanideh N, et al. Long term malnutrition and mRNAs expression of RFRP-3 and KiSS-1 in hypothalamus of female ovariectomized rats. Physiol Pharmacol 2014; 17:370-378.

53. 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.

54. 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.

55. Apter D, Pakarinen A, Vihko R. Serum prolactin, FSH and LH during puberty in girls and boys. Acta Paediatr Scand 1978; 67:417-423.

56. Anderson GM, Relf HL, Rizwan MZ, Evans JJ. Central and peripheral effects of RFamide-related peptide-3 on luteinizing hormone and prolactin secretion in rats. Endocrinology 2009; 150:1834-1840.

57. Noroozi A, Jafarzadeh Shirazi MR, 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.

58. Sabet Sarvestani F, Tamadon A, Koohi-Hosseinabadi O, Mohammadi Nezhad S, Rahmanifar F, Jafarzadeh Shirazi MR, 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.

59. Tian Z, Zhao H, Sun Y, Cai D, Chen B. Evaluation of the true precocious puberty rats induced by neonatal administration of Danazol: Therapeutic effects of nourishing "Yin"- removing "Fire" Chinese herb mixture. Reprod Biol Endocrinol 2005; 3:38.

60. Poling MC, Kauffman AS. Regulation and function of RFRP-3 (GnIH) neurons during postnatal development. Front Endocrinol 2015; 6:150.

61. Adavi H, Jafarzadeh Shirazi MR, Zamiri MJ, Namavar MR, Tanideh N, Tamadon A. Effect of lactation on the expression of gonadotropin-inhibitory hormone in dorsomedial and paraventricular nuclei of the rat hypothalamus. Physiol Pharmacol 2011; 15:164-172.

62. Molnar C, Allo I, Iposits Z, Rabovszky E. Estradiol down-regulates RF-amide-related peptide (RFRP) expression in the mouse hypothalamus. Endocrinology 2011; 152:1684-1690.

63. Yano T, Iijima N, Kakihara K, Hinuma S, Tanaka M, Ibata Y. Localization and neuronal response of RFamide related peptides in the rat central nervous system. Brain Res 2003; 982:156-167.

64. Smith JT, Shahab M, Pereira A, Pau KY, Clarke IJ. Hypothalamic expression of KISS1 and gonadotropin inhibitory hormone genes during the menstrual cycle of a non-human primate. Biol Reprod 2010; 83:568-577.

65. Salehi MS, Jafarzadeh Shirazi MR, Zamiri MJ, Pazhoohi F, Namavar MR, Niazi A, et al. Hypothalamic expression of KiSS-1 and RFamide-related peptide-3 mRNAs during the estrous cycle of rats. Int J Fertil Steril 2013; 6:304-309.

66. Smith JT, Ross Young I, Veldhuis JD, Clarke IJ. Gonadotropin-inhibitory hormone (GnIH) secretion into the ovine hypophyseal portal system. Endocrinology 2012; 53:3368-3375.