Molecular and Environmental Mechanisms Regulating Puberty Initiation: An Integrated Approach

Abstract

The mechanisms underlying the initiation of puberty, one of the cornerstones of human evolution, have not been fully elucidated as yet. However, recently, an accumulating body of evidence has helped unravel several critical aspects of the process. It is clear that a change in the pattern of pituitary gonadotropin secretion serves as a hormonal trigger for puberty induction. This change is directly guided by the hypothalamic GnRH pulse generation, a phenomenon regulated by the Kisspeptin-Neurokinin-Dynorphin (KNDy) system also in the hypothalamus. This represents the kisspeptin molecule, which is crucial in augmenting GnRH secretion at puberty, whose secretion is fine-tuned by the opposing signals neurokinin B and dynorphin. Recently, the novel kisspeptin inhibitory signal MKRN3 was described, whose role in puberty initiation provided further insight into the mechanistic aspects of pubertal onset. Furthermore, the description of higher inhibitory and stimulatory signals acting upstream of the KNDy neurons suggested that the trigger point of puberty is located upstream of the KNDy system and the GnRH pulse generator. However, the mechanism of pubertal onset should not be considered as an isolated closed loop system. On the contrary, it is influenced by such factors as adipose tissue, gastrointestinal function, adrenal androgen production, energy sensing, and physical and psychosocial stress. Also, fetal and early life stressful events, as well as exposure to endocrine disruptors, may play important roles in pubertal initiation, the latter primarily through epigenetic modifications. Here we present the available data in the field and attempt to provide an integrated view of this unique and crucial phenomenon.

Has the Frequency of Precocious Puberty and Rapidly Progressive Early Puberty Increased in Girls During the COVID-19 Pandemic?

“…Activation of the gonadotropin-releasing hormone (GnRH) pulse generator occurs with the interaction of kisspeptin and kisspeptin 1 receptor, synchronized operation of neurokinin-B, glutamate, leptin, and androgens. Inhibitory systems are endogenous opioid peptides, such as dynorphin A, gamma-aminobutyric acid (GABA), and macorin ring finger protein-3 (MKRN3) ( 1 ). While various hypothalamic genes including KISS1, KISS1R, MKRN3, DLK1 regulate the rate of puberty, micro RNAs provide epigenetic control of puberty by regulating GnRH gene transcription.…”

Endocrine Disrupting Chemicals’ Effects in Children: What We Know and What We Need to Learn?

“…Early puberty occurs in both genders, resulting in a progressive trend towards an earlier age of appearance for first pubertal signs and towards an older age of puberty completion [ 175 ] and in recent decades, a progressive shortening of the time of puberty in girls and a consequent increased incidence of precocious puberty and premature thelarche was observed worldwide [ 176 ]. Variation of the timing and the progression of puberty is not only genetically dependent, so other key factors are involved in its regulation, and concerns raised on the potential role of EDCs [ 4 , 177 ].…”

Disorders of Puberty in Girls

“…These genes play roles in the birth and migration of GnRH neurons, the hypothalamic regulation of the KNDy and GnRH neurons, and pituitary development. 23 Inheritance patterns are autosomal recessive, autosomal dominant, X-linked, and oligogenic. Clinical investigation accompanied by validation in animal models has identified proteins involved in transcriptional regulation of the puberty genes.…”

“…11 Both leptin and ghrelin may partially explain the link between adiposity, energy intake, and pubertal onset. 23…”

“…These neurons have been designated as the kisspeptin-NKB-dynorphin (KNDy) neurons. 23,24 Both kisspeptin and NKB promote GnRH secretion, whereas dynorphin is an inhibitory factor. The GnRH pulse generator is responsible for promoting basal or "tonic" gonadotropin secretion that governs ovarian maturation, folliculogenesis, and corpus luteum function.…”