ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This review summarizes the role of macronutrients and hormones which regulate energy balance and sexual maturation by conveying energy availability information to the GnRH system.

30 years ago, Kennedy and Mitra were the first to use translational studies to show that nutrition is a key factor regulating puberty timing¹. Their seminal protocol modified the size of rat litters to affect weight increase and showed that nutritional status affected pubertal maturation¹. This study has paved the way for translational, clinical and epidemiological studies illustrating the importance of the regulation of reproductive maturation by energy accessibility. Human examples of this interaction between energy balance and pubertal onset cover earlier puberty associated with overweight as well as delayed puberty in conditions of undernutrition^2,3.

This review describes recent progress made in understanding the neuronal and glial circuitry regulating the reactivation of the GnRH network at the time of puberty⁴ as well as epigenetic mechanisms such as the metabolic sensor SIRT1 which links early nutritional status to puberty⁵. Population genetics as well as studies of individual patients with extreme perturbation of weight or puberty have also identified new key players in the crosstalk between sexual maturation and energy balance such as Delta-like homologue 1⁶ or melanocortin receptor 3⁷. As discussed by the authors, fully understanding the mechanisms that connect obesity and earlier onset of puberty deserves additional research efforts.

References: 1. Kennedy GC, Mitra J. Body weight and food intake as initiating factors for puberty in the rat. J Physiol. 1963;166(2):408-18. doi: 10.1113/jphysiol.1963.sp007112. PMID: 14031944; PMCID: PMC1359337.2. Reinehr, T. & Roth, C. L. Is there a causal relationship between obesity and puberty? Lancet Child. Adolesc. Health 2019; 3, 44–54 (2019).3. Argente J, Dunkel L, Kaiser UB, Latronico AC, Lomniczi A, Soriano-Guillén L, Tena-Sempere M. Molecular basis of normal and pathological puberty: from basic mechanisms to clinical implications. Lancet Diabetes Endocrinol. 2023;11(3):203-216. doi: 10.1016/S2213-8587(22)00339-4.4. Avendano, M. S., Vazquez, M. J. & Tena-Sempere, M. Disentangling puberty: novel neuroendocrine pathways and mechanisms for the control of mammalian puberty. Hum. Reprod. Update 2017; 23, 737–763.5. Vazquez MJ, Toro CA, Castellano JM, Ruiz-Pino F, Roa J, Beiroa D, Heras V, Velasco I, Dieguez C, Pinilla L, Gaytan F, Nogueiras R, Bosch MA, Rønnekleiv OK, Lomniczi A, Ojeda SR, Tena-Sempere M. SIRT1 mediates obesity- and nutrient-dependent perturbation of pubertal timing by epigenetically controlling Kiss1 expression. Nat Commun. 2018 Oct 10;9(1):4194. doi: 10.1038/s41467-018-06459-9. PMID: 30305620; PMCID: PMC6179991.6. Dauber A, Cunha-Silva M, Macedo DB, Brito VN, Abreu AP, Roberts SA, Montenegro LR, Andrew M, Kirby A, Weirauch MT, Labilloy G, Bessa DS, Carroll RS, Jacobs DC, Chappell PE, Mendonca BB, Haig D, Kaiser UB, Latronico AC. Paternally Inherited DLK1 Deletion Associated With Familial Central Precocious Puberty. J Clin Endocrinol Metab. 2017 May 1;102(5):1557-1567. doi: 10.1210/jc.2016-3677. PMID: 28324015; PMCID: PMC5443333.7. Lam BYH, Williamson A, Finer S, Day FR, Tadross JA, Gonçalves Soares A, Wade K, Sweeney P, Bedenbaugh MN, Porter DT, Melvin A, Ellacott KLJ, Lippert RN, Buller S, Rosmaninho-Salgado J, Dowsett GKC, Ridley KE, Xu Z, Cimino I, Rimmington D, Rainbow K, Duckett K, Holmqvist S, Khan A, Dai X, Bochukova EG; Genes & Health Research Team; Trembath RC, Martin HC, Coll AP, Rowitch DH, Wareham NJ, van Heel DA, Timpson N, Simerly RB, Ong KK, Cone RD, Langenberg C, Perry JRB, Yeo GS, O’Rahilly S. MC3R links nutritional state to childhood growth and the timing of puberty. Nature. 2021; 599(7885):436-441. doi: 10.1038/s41586-021-04088-9. PMID: 34732894; PMCID: PMC8819628.