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Puberty is the transitional process leading to reproductive maturity. Proper diagnosis and management of pubertal disorders requires understanding of: (1) basic endocrinology of the hypothalamic-pituitary-gonadal axis; (2) developmental changes that occur at different points throughout childhood; and (3) the wide variability in timing of physical changes of puberty seen in normal children.


The three anatomic sites most pertinent to pubertal development are the hypothalamus, the anterior pituitary gland, and the gonads (ovaries or testes), known collectively as the hypothalamic-pituitary-gonadal (HPG) axis (Figure 7-1). Also shown in this figure are the critical hormones and feedback loops of the HPG axis.

Figure 7-1
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Schematic diagram of the hypothalamic-pituitary-gonadal axis.


Kisspeptins are peptides secreted by neurons in the arcuate and anteroventral periventricular nucleus of the hypothalamus.1 These peptides bind to a G protein-coupled receptor called GPR54 on hypothalamic neurons that secrete gonadotropin-releasing hormone (GnRH). The resulting pulses of GnRH in turn induce pulsatile secretion of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). LH and FSH working in concert lead to germ cell (spermatozoa or ova) maturation and also stimulation of sex steroid (androgen or estrogen) secretion by the gonads, along with gonadal peptides such as inhibins. The sex steroids exert a negative feedback effect at both hypothalamic and pituitary levels, reducing the secretion of kisspeptin, GnRH, and LH, while inhibins control FSH secretion via a separate negative feedback loop at the pituitary level. Later in life, once menstrual cycles begin, women also develop a positive feedback cycle whereby estrogens stimulate gonadotropin release during phases of the cycle critical for ovulation.


These basic hormonal pathways are modulated by many different central nervous system (CNS) inputs, including stimulatory effects of glutaminergic neural systems, inhibitory effects of gamma-aminobutyric acid (GABA)-ergic systems, and direct interactions between glial cells and hypothalamic neurons. The CNS in turn integrates the effects of many external factors such as nutrient availability, exercise, stress, social/psychological factors, and indirect effects of chronic disease.


Fetal Period


Four critical developmental steps during fetal life establish the required anatomy for the HPG axis and normal pubertal development. First, GnRH-producing neurons must migrate from the olfactory region to proper positions in the hypothalamus, with dependence on products of the KAL-1 (Kallmann syndrome 1) and FGFR1 (fibroblast growth factor receptor-1) genes for normal anatomic development. Second, the mechanism for pulsatile GnRH secretion and responsiveness must be established, with dependence upon genes such as KISS-1 (producing kisspeptin) and GnRHR (GnRH receptor). Third, normal development of the hypothalamus and gonadotropin-secreting cells of the pituitary depends upon genes such as NR5A1 (SF-1), NROB1 (DAX-1), PROP1, HESX1, LHX, LH-β, LHR (LH receptor), FSH-β, and FSHR (FSH receptor) among others.2 Fourth, the gonads must form properly, with differentiation of Leydig and Sertoli cells in the testis, and granulosa ...

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