Chapter 555 Physiology of Puberty

Between early childhood and approximately 8-9 yr of age (prepubertal stage), the hypothalamic-pituitary-gonadal axis is dormant, as reflected by undetectable serum concentrations of luteinizing hormone (LH) and sex hormones (estradiol in girls, testosterone in boys). One to 3 yr before the onset of clinically evident puberty, low serum levels of LH during sleep become demonstrable (peripubertal period). This sleep-entrained LH secretion occurs in a pulsatile fashion and reflects endogenous episodic discharge of hypothalamic gonadotropin-releasing hormone (GnRH). Nocturnal pulses of LH continue to increase in amplitude and, to a lesser extent, in frequency as clinical puberty approaches. This pulsatile secretion of gonadotropins is responsible for enlargement and maturation of the gonads and the secretion of sex hormones. The appearance of the secondary sex characteristics in early puberty is the visible culmination of the sustained, active interaction occurring among hypothalamus, pituitary, and gonads in the peripubertal period. By mid-puberty, LH pulses become evident even during the daytime and occur at about 90- to 120-min intervals. A second critical event occurs in middle or late adolescence in girls, in whom cyclicity and ovulation occur. A positive feedback mechanism develops whereby increasing levels of estrogen in midcycle cause a distinct increase of LH.

The increasing secretion of hypothalamic GnRH in a pulsatile fashion thus underlies the onset of pubertal development. The resulting “GnRH pulse generator” is regulated by multiple neurotransmitters, including glutamic acid and kisspeptin (both stimulatory) and γ-aminobutyric acid and pre-proenkephalin (both inhibitory). GnRH secretion is also regulated by factors produced by the glial cells, such as transforming growth factor β (TGF-β). The role of GnRH is fundamental; its pulsed administration can reproduce pubertal development in sexually immature or gonadotropin-deficient animals and humans. Mutations of the GPR54 gene (a G protein–coupled receptor gene whose ligand is kisspeptin) cause an autosomal recessive form of hypogonadotropic hypogonadism. Defects of this receptor-ligand system do not affect GnRH neuronal migration, in contrast to the X-linked hypogonadotropic hypogonadism of Kallmann syndrome; rather they impair the activity of GnRH-secreting neurons in the hypothalamus. Conversely, TGF-β signaling has been associated with the occurrence of central precocious puberty in patients with hypothalamic hamartoma.

The interpretation of the hormonal changes of puberty is complex. Issues in interpreting gonadotropin (LH and follicle stimulating hormone [FSH]) measurements include the presence of multiple isoforms, immunoassay-related variability, and problems inherent to their pulsatile secretion, which mandates serial sampling in plasma or urine. Important sex differences exist in the maturation of the hypothalamus and pituitary gland, and serum LH concentrations increase earlier in the course of the pubertal process in boys than in girls. Adrenocortical androgens also have a role in sexual maturation. Serum levels of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) begin to increase at approximately 6-8 yr of age, before any increase in LH or sex hormones and before the earliest physical changes of puberty are apparent; this process has been called adrenarche. DHEAS is the most abundant adrenal C-19 steroid in the blood, and its serum concentration remains fairly stable over 24 hr. A single measurement of this hormone is commonly used as a marker of adrenal androgen secretion. Although adrenarche typically antedates the onset of gonadal activity (gonadarche) by a few years, the 2 processes do not seem to be causally related, because adrenarche and gonadarche are dissociated in conditions such as central precocious puberty and adrenocortical failure.

The effects of gonadal steroids (testosterone in boys, estradiol in girls) on bone growth and osseous maturation are critical. Both aromatase deficiency and estrogen receptor defects result in delayed epiphyseal fusion and tall stature in affected boys. These observations suggest that estrogens, rather than androgens, are responsible for the process of bone maturation that ultimately leads to epiphyseal fusion and cessation of growth. Estrogens also mediate the increased production of growth hormone, which, along with a direct effect of sex steroids on bone growth, is responsible for the pubertal growth spurt.

The age of onset of puberty varies and is more closely correlated with osseous maturation than with chronological age (Chapter 12). In girls, the breast bud (thelarche) is usually the first sign of puberty (10-11 yr), followed by the appearance of pubic hair (pubarche) 6-12 mo later. The interval to the onset of menstrual activity (menarche) is usually 2-2.5 yr but may be as long as 6 yr. In the United States, at least 1 sign of puberty is present in approximately 95% of girls by 12 yr of age and in 99% of girls by 13 yr of age. Peak height velocity occurs early (at breast stage II-III, typically between 11 and 12 yr of age) in girls and always precedes menarche. The mean age of menarche is about 12.75 yr. There are, however, wide variations in the sequence of changes involving growth spurt, breast bud, pubic hair, and maturation of the internal and external genitalia.

In boys, growth of the testes (≥4 mL in volume or 2.5 cm in longest diameter) and thinning of the scrotum are the first signs of puberty (11-12 yr). These are followed by pigmentation of the scrotum and growth of the penis (Chapter 12) and by pubarche. Appearance of axillary hair usually occurs in mid-puberty. In boys, unlike in girls, acceleration of growth begins after puberty is well under way and is maximal at genital stage IV-V (typically between 13 and 14 yr of age). In boys, the growth spurt occurs approximately 2 yr later than in girls, and growth can continue beyond 18 yr of age.

Genetic and environmental factors affect the onset of puberty. Despite the debate raised by population-based studies in the USA suggesting a secular trend for slightly earlier (by 2.5 to 4 months) ages at menarche, the latter has generally been considered stable over the last 30-40 yr. This period of relative stability follows a significant decrease over the previous century, a result of major changes in nutritional and health conditions. African American girls may be more advanced in development of secondary sex characteristics for age than Caucasian girls. A positive correlation between the degree of adiposity and early pubertal development in girls has been reported. Conversely, ballet dancers, gymnasts, and other female athletes in whom leanness and strenuous physical activity have coexisted from early childhood often exhibit a marked delay in puberty or menarche, and they often have oligomenorrhea or amenorrhea as adults (Chapter 682). Pubertal delay is also prevalent in boys who are physically very active. These observations support the thesis that the energy balance is closely related to the activity of the GnRH pulse generator and the mechanisms initiating and sustaining puberty, perhaps via hormonal signals, which can include adipokines.