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GENERAL INTRODUCTORY COMMENTS

Puberty is the transitional process leading to reproductive maturity. Proper diagnosis and management of pubertal disorders requires understanding of (1) the basic endocrinology of the hypothalamic-pituitary-gonadal (HPG) 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.

BASIC ENDOCRINOLOGY OF PUBERTY

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 HPG axis (Figure 3-1). Also shown in this figure are the critical hormones and feedback loops of the HPG axis.

FIGURE 3-1

Schematic diagram of the hypothalamic-pituitary-gonadal axis.

Kisspeptin is a peptide secreted by neurons in the hypothalamus.1 Through the kisspeptin receptor (KiSS1R), also known as GPR54, a G-protein-coupled receptor, located on hypothalamic neurons that secrete gonadotropin-releasing hormone (GnRH) in a pulsatile manner, kisspeptin appears to be part of the key pulse generator that determines onset and control of puberty.2 Makorin ring finger protein 3 (MKRN3), also produced in the hypothalamus, appears to function as a pubertal "brake", with circulating levels low during the mini-puberty of infancy, higher during the prepubertal years, and again low with the start of puberty during the adolescent years.

GnRH binds to G-protein-coupled receptors on pituitary gonadotropes to control secretion of the peptide gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Of note, the pulsatility of GnRH release is important for LH and FSH secretion since continuous (non-pulsatile) GnRH administration will inhibit, rather than stimulate, gonadotropin release.

LH and FSH bind to gonadal G-protein-coupled receptors working in concert which lead to maturation of germ cells (spermatozoa or ova) and also secretion of sex steroids (androgen or estrogen) along with gonadal peptides such as the inhibins and anti-Müllerian hormone (AMH) (also known as Müllerian-inhibiting hormone [MIH] or Müllerian-inhibiting substance [MIS]). Both LH and FSH are surprisingly complex glycoproteins, with many differentially glycosylated isoforms that differ in potency and circulating half-life.3 Such structural complexity leads to difficulty in standardizing the measurement of gonadotropins and provides many opportunities for mutations affecting gonadotropin function.

Gonadal steroids and peptides are part of a negative feedback cycle that affects gonadotropin release. Sex steroids act at both the hypothalamic and pituitary levels to control (usually inhibit) the secretion of GnRH and LH. Inhibin A from ovarian follicles and inhibin B from granulosa cells in girls and from Sertoli cells in boys act at the pituitary level to inhibit FSH secretion. Later in life, once menstrual cycles begin, women also develop a positive feedback loop whereby high concentrations of estrogens stimulate gonadotropin release during phases of the cycle leading up to ovulation.

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