Puberty presents remarkable individual differences in timing reaching over 5 years in humans. We put emphasis on the two edges of the age distribution of pubertal signs in humans and point to an extended distribution towards earliness for initial pubertal stages and towards lateness for final pubertal stages. Such distortion of distribution is a recent phenomenon. This suggests changing environmental influences including the possible role of nutrition, stress and endocrine disruptors. Our ability to assess neuroendocrine effects and mechanisms is very limited in humans. Using the rodent as a model, we examine the impact of environmental factors on the individual variations in pubertal timing and the possible underlying mechanisms. The capacity of environmental factors to shape functioning of the neuroendocrine system is thought to be maximal during fetal and early postnatal life and possibly less important when approaching the time of onset of puberty.

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The aim of this chapter is to revise some common views on changes in pubertal timing. This revision is based on recent epidemiological findings on the clinical indicators of pubertal timing and data on environmental factor effects and underlying mechanisms. A current advancement in timing of female puberty is usually emphasized. It appears, however, that timing is also changing in males. Moreover, the changes are towards earliness for initial pubertal stages and towards lateness for final stages in both sexes. Such observations indicate the complexity of environmental influences on pubertal timing. The mechanisms of changes in pubertal timing may involve both the central neuroendocrine control and peripheral effects at tissues targeted by gonadal steroids. While sufficient energy availability is a clue to the mechanism of pubertal development, changes in the control of both energy balance and reproduction may vary under the influence of common determinants such as endocrine-disrupting chemicals (EDCs). These effects can take place right before puberty as well as much earlier, during fetal and neonatal life. Finally, environmental factors can interact with genetic factors in determining changes in pubertal timing. Therefore, the variance in pubertal timing is no longer to be considered under absolutely separate control by environmental and genetic determinants. Some recommendations are provided for evaluation of EDC impact in the management of pubertal disorders and for possible reduction of EDC exposure along the precautionary principle.

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Debate makes science progress. In the field of endocrine disruption, endocrinology has brought up findings that substantiate a specific perspective on the definition of endocrine disrupting chemicals (EDCs), the role of the endocrine system and the endpoints of hormone and EDC actions among other issues. This paper aims at discussing the relevance of the endocrine perspective with regard to EDC effects on pubertal timing. Puberty involves particular sensitivity to environmental conditions. Reports about the advancing onset of puberty in several countries have led to the hypothesis that the increasing burden of EDCs could be an explanation. In fact, pubertal timing currently shows complex changes since advancement of some manifestations of puberty (e.g. breast development) and no change or delay of others (e.g. menarche, pubic hair development) can be observed. In a human setting with exposure to low doses of tenths or hundreds of chemicals since prenatal life, causation is most difficult to demonstrate and justifies a translational approach using animal models. Studies in rodents indicate an exquisite sensitivity of neuroendocrine endpoints to EDCs. Altogether, the data from both human and animal studies support the importance of concepts derived from endocrinology in the evaluation of EDC effects on puberty.

Testosterone production by the fetal testis depends on a functional relationship between hCG and the LH/chorionic gonadotropin receptor (LHCGR). Failure of the receptor to correctly respond to its ligand leads to impaired sexual differentiation in males. A phenotypically female patient with pubertal delay had a 46,XY karyotype and was diagnosed with 46,XY disorder of sex development (DSD). Novel compound heterozygous LHCGR mutations were found in the signal peptide: a duplication p.L10_Q17dup of maternal origin, and a deletion (p.K12_L15del) and a p.L16Q missense mutation of paternal origin. cAMP production was very low for both the deletion and duplication mutations and was halved for the missense mutant. The duplication and missense mutations were both expressed intracellularly, but at very low levels at the cell membrane; they were most likely retained in the endoplasmic reticulum. The deletion mutant had a very limited intracellular expression, indicating impaired biosynthesis. There was reduced expression of all three mutants, which was most marked for the deletion mutation. There was also decreased protein expression of all three mutant receptors. In the deletion mutation, the presence of a lower-molecular-weight band corresponding to LHCGR monomer, probably due to lack of glycosylation, and a lack of bands corresponding to dimers/oligomers suggests absent ER entry. This novel case of 46,XY DSD illustrates how different LHCGR signal peptide mutations led to complete receptor inactivation by separate mechanisms. The study underlines the importance of specific regions of signal peptides and expands the spectrum of LHCGR mutations.

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