Authors : T. Arulmani; G. Sivakumar; D.K. Shanmuganathan

Volume/Issue : Volume 10 - 2025, Issue 8 - August

Google Scholar : https://tinyurl.com/zf3vpfy

Scribd : https://tinyurl.com/57c7nean

DOI : https://doi.org/10.38124/ijisrt/25aug1426

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Abstract : Precocious puberty, defined as the onset of secondary sexual characteristics before age 8 in girls and 9 in boys, occurs more frequently in females and carries significant medical, psychosocial, and long-term health consequences. This review synthesizes current knowledge on the molecular, genetic, epigenetic, and environmental determinants of early pubertal onset, with a particular focus on female precocious puberty. Central precocious puberty (CPP) arises from premature activation of the hypothalamic–pituitary–gonadal (HPG) axis, driven by dysregulation of kisspeptin–GPR54 signaling, neurokinin B pathways, and inhibitory factors such as MKRN3 and DLK1. Peripheral precocious puberty (PPP), by contrast, results from gonadotropin-independent estrogen production due to somatic mutations (e.g., GNAS1 in McCune- Albright syndrome) or hormone-secreting ovarian tumors. Environmental exposures, particularly endocrine-disrupting chemicals (EDCs), and metabolic factors such as obesity and leptin excess, further contribute by altering neuroendocrine signaling and inducing epigenetic modifications of key puberty-related genes. Current therapeutic standards rely on gonadotropin-releasing hormone (GnRH) agonists to suppress HPG activation, but emerging approaches—including kisspeptin and neurokinin B antagonists, epigenetic modulators, and gene-based strategies—offer promise for precision medicine. By integrating neuroendocrine biology, genetic architecture, and environmental risk factors, this review underscores the complexity of pubertal regulation and highlights future directions for early diagnosis and targeted therapy in precocious puberty.

Keywords : Precocious Puberty, Central Precocious Puberty (CPP), Peripheral Precocious Puberty (PPP), Hypothalamic– Pituitary–Gonadal (HPG) Axis, Kisspeptin–GPR54 Signaling, MKRN3, DLK1, Neurokinin B (TAC3/TACR3), Epigenetics, Obesity and Leptin, Pubertal Timing.

References :

1. Abreu, A. P., Dauber, A., Macedo, D. B., Noel, S. D., Brito, V. N., Gill, J. C., ... & Kaiser, U. B. (2013). Central precocious puberty caused by mutations in the imprinted gene MKRN3. New England Journal of Medicine, 368(26), 2467–2475.
2. Belsky, J., Steinberg, L., & Draper, P. (2007). Childhood experience, interpersonal development, and reproductive strategy: An evolutionary theory of socialization. Child Development, 62(4), 647–670.
3. Cabanes, A., Khoshnood, B., Saurel-Cubizolles, M. J., & de La Rochebrochard, E. (2009). Temporal trends in age at menarche and age at onset of regular menstrual cycling in France: results from a large population-based study. BMC Women's Health, 9(1), 17.
4. Carel, J. C., & Leger, J. (2008). Precocious puberty. New England Journal of Medicine, 358(22), 2366–2377.
5. Chen, Y., Zhang, Z., Yang, X., Zhao, D., & Cao, J. (2010). A secular trend of earlier puberty onset among Chinese children. International Journal of Endocrinology, 2010, 1–5.
6. Frontini, M. G., Srinivasan, S. R., & Berenson, G. S. (2003). Longitudinal changes in risk variables underlying metabolic syndrome from childhood to young adulthood in female individuals with a history of early menarche. Circulation, 107(10), 1402–1407.
7. Kaplowitz, P. (2008). Link between body fat and the timing of puberty. Pediatrics, 121(Supplement 3), S208–S217.
8. Kurian, J. R., Terasawa, E., & Keen, K. L. (2015). Epigenetic changes permit central activation of puberty-relevant genes in the rhesus monkey. Endocrinology, 156(2), 1131–1140.
9. Lakshman, R., Forouhi, N. G., Sharp, S. J., Luben, R., Bingham, S. A., Khaw, K. T., ... & Ong, K. K. (2009). Early age at menarche associated with cardiovascular disease and mortality. Journal of Clinical Endocrinology & Metabolism, 94(12), 4953–4960.
10. Mendle, J., Turkheimer, E., & Emery, R. E. (2007). Detrimental psychological outcomes associated with early pubertal timing in adolescent girls. Developmental Review, 27(2), 151–171.
11. Mouritsen, A., Aksglaede, L., Sorensen, K., Mogensen, S. S., Leffers, H., Main, K. M., ... & Juul, A. (2010). Hypothesis: exposure to endocrine-disrupting chemicals may interfere with timing of puberty. International Journal of Andrology, 33(2), 346–359.
12. Ojeda, S. R., Lomniczi, A., & Sandau, U. S. (2006). Glial–gonadotrophin hormone (GnRH) neuron interactions in the median eminence and the control of GnRH secretion. Journal of Neuroendocrinology, 20(6), 732–742.
13. Palmert, M. R., & Dunkel, L. (2012). Delayed puberty. New England Journal of Medicine, 366(5), 443–453.
14. Partsch, C. J., & Sippell, W. G. (2001). Pathogenesis and epidemiology of precocious puberty. Effects of environmental factors. Hormone Research, 55(Suppl 1), 15–19.
15. Plant, T. M. (2015). Neuroendocrine control of the onset of puberty. Frontiers in Neuroendocrinology, 38, 73–88.
16. Abreu AP, Kaiser UB. Pubertal development and regulation. Lancet Diabetes Endocrinol. 2016;4(3):254–64.
17. Seminara SB, Messager S, Chatzidaki EE, et al. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349(17):161427.
18. Teles MG, Bianco SDC, Brito VN, et al. A GPR54-activating mutation in a patient with central precocious puberty. N Engl J Med. 2008;358(7):709–15.
19. Topaloglu AK, Reimann F, Guclu M, et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nat Genet. 2009;41(3):354–8.
20. Abreu AP, Dauber A, Macedo DB, et al. Central precocious puberty caused by mutations in the imprinted gene MKRN3. N Engl J Med. 2013;368(26):2467–75.
21. Ojeda SR, Skinner MK. Puberty in the rat. In: Neill JD, editor. Knobil and Neill's Physiology of Reproduction. 3rd ed. Elsevier; 2006. p. 2061–126.
22. Navarro VM, Castellano JM, García-Galiano D, Tena-Sempere M. Neuroendocrine factors in the initiation of puberty: the emergent role of kisspeptin. Rev Endocr Metab Disord. 2007;8(1):11–20.
23. Clarkson J, d'Anglemont de Tassigny X, Moreno AS, Colledge WH, Herbison AE. Kisspeptin–GPR54 signaling is essential for prepubertal GnRH neuron activation and female puberty. J Neurosci. 2008;28(37):8826–34.
24. Abreu AP, Dauber A, Macedo DB, Noel SD, Brito VN, Gill JC, et al. Central precocious puberty caused by mutations in the imprinted gene MKRN3. N Engl J Med. 2013;368(26):2467–75.
25. Dauber A, Cunha-Silva M, Macedo DB, Brito VN, Abreu AP, Roberts SA, et al. Paternally inherited DLK1 mutation associated with familial central precocious puberty. J Clin Invest. 2017;127(5):1913–7.
26. Lomniczi A, Wright H, Castellano JM, Matagne V, Toro CA, Rodríguez HA, et al. Epigenetic regulation of puberty via zinc finger protein-mediated transcriptional repression. Nat Commun. 2015;6:10195.
27. Xie Y, Zhang Y, Hu J, Zhang Q, Yin Y, Fang M. Notch signaling regulates hypothalamic neurogenesis and GnRH neuron migration during embryonic development. Endocrinology. 2020;161(8):bqaa098.
28. Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med. 1991;325(24):1688–95.
29. Boyce AM, Collins MT. Fibrous dysplasia/McCune-Albright syndrome. In: De Groot LJ, Chrousos G, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–.
30. Feuillan PP, Foster CM, Pescovitz OH. Treatment of precocious puberty in girls with the McCune-Albright syndrome using testolactone. J Clin Endocrinol Metab. 1986;63(6):1363–9.
31. Young RH. Sex cord-stromal tumors of the ovary and testis: their similarities and differences with consideration of selected problems. Mod Pathol. 2005;18(Suppl 2):S81–98.
32. Gui T, Cao D, Shen K, Yang J, Zhang Y, Yu Q, et al. A clinicopathological analysis of 153 granulosa cell tumors of the ovary. Gynecol Oncol. 2011;121(2):241–6.
33. Woelfle J, Hoeflich A, Roth C, Blum WF. IGF-dependent and IGF-independent roles of GH/IGF-system components in granulosa cell tumors. Growth Horm IGF Res. 2005;15(4):241–6.
34. Rubin BS. Bisphenol A: An endocrine disruptor with widespread exposure and multiple effects. J Steroid Biochem Mol Biol. 2011;127(1–2):27–34.
35. Navarro VM, Tena-Sempere M. Endocrine disruptors and puberty timing. Trends Endocrinol Metab. 2011;22(7):205–11.
36. Kurian JR, Keen KL, Terasawa E. Epigenetic changes in the regulation of the Kiss1 gene by developmental exposure to endocrine disruptors. Endocrinology. 2010;151(2):1103–14.
37. Gore AC, Chappell VA, Fenton SE, Flaws JA, Nadal A, Prins GS, et al. EDC-2: The Endocrine Society’s second scientific statement on endocrine-disrupting chemicals. Endocr Rev. 2015;36(6):E1–150.
38. Ahima RS, Flier JS. Leptin. Annu Rev Physiol. 2000;62:413–37.
39. Sorensen K, Aksglaede L, Petersen JH, Leffers H, Juul A. Recent decline in age at breast development: The Copenhagen Puberty Study. Pediatrics. 2008;121(5):e932–9.
40. Ojeda SR, Lomniczi A. Puberty in 2013: Uncovering epigenetic triggers for the onset of puberty. Nat Rev Endocrinol. 2014;10(2):67–9.
41. Abreu AP, Dauber A, Macedo DB, Noel SD, Brito VN, Gill JC, et al. Central precocious puberty caused by mutations in the imprinted gene MKRN3. N Engl J Med. 2013;368(26):2467–75.
42. Tena-Sempere M. Roles of kisspeptins in the control of hypothalamic–pituitary–gonadal axis function. Front Horm Res. 2009;37:19–28.
43. Dauber A, Cunha-Silva M, Macedo DB, Brito VN, Abreu AP, Roberts SA, et al. Paternally inherited DLK1 deletion associated with familial central precocious puberty. J Clin Endocrinol Metab. 2017;102(5):1557–67.
44. Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD, Porter KM, et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nat Genet. 2009;41(3):354–8.
45. Boyce AM, Collins MT. McCune-Albright syndrome. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington; 1993–2024.
46. Silveira LG, Noel SD, Silveira-Neto AP, Abreu AP, Brito VN, Santos MG, et al. Mutations of the MKRN3 gene in central precocious puberty. J Clin Endocrinol Metab. 2010;95(10):4603–10.
47. Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, et al. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349(17):1614–27.
48. Guran T, Tolhurst G, Bereket A, Rocha N, Porter K, Turan S, et al. Hypogonadotropic hypogonadism caused by mutations in the DLK1 gene. Eur J Endocrinol. 2011;165(1):151–7.
49. Gianetti E, Tusset C, Noel SD, Au MG, Dwyer AA, Hughes VA, et al. TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in humans. N Engl J Med. 2010;362(19):1813–22.
50. Lumbroso S, Paris F, Sultan C. Activating Gsα mutations: analysis of 113 patients with signs of McCune-Albright syndrome – a European collaborative study. J Clin Endocrinol Metab. 2004;89(2):610–6.
51. Carel JC, Eugster EA, Rogol A, Ghizzoni L, Palmert MR. Consensus statement on the use of GnRH analogs in children. Pediatrics. 2009;123(4):e752–62.
52. Neely EK, Hintz RL, Parker B, Bachrach LK, Cohen P, Olney RC. Two-year results of treatment with depot leuprolide acetate for central precocious puberty. J Pediatr. 1995;127(6):851–6.
53. Lewis KA, Goldyn AK, West KW, Eugster EA. Experience with the histrelin implant in the treatment of central precocious puberty: a single center study. J Pediatr Endocrinol Metab. 2013;26(7–8):711–6.
54. Chan YM, Butler JP, Sidhoum VF, Pinnell NE, Seminara SB. Kisspeptin administration to women induces dose-dependent stimulation of gonadotropin secretion. J Clin Endocrinol Metab. 2011;96(8):E1228–36.
55. Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD, Porter KM, et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nat Genet. 2009;41(3):354
56. Lomniczi A, Wright H, Castellano JM, Sonmez K, Ojeda SR. Epigenetic regulation of puberty via repression of GnRH transcription. Endocrinology. 2015;156(9):3231–42.