Puberty and Disorders of Pubertal Development

Fetal and Newborn Period

The fetal hypothalamic–pituitary–gonadal axis is capable of producing adult levels of gonadotropins and sex steroids. By 20 weeks' gestation, levels of gonadotropins —follicle-stimulating hormone (FSH) and luteinizing hormone (LH)— rise dramatically in both male and female fetuses ( Figure 32-1 ). Late in gestation, a surge in levels of glucocorticoids in the fetal circulation occurs. This is essential for normal maturation of fetal lungs and critical for the development of the fetal thyroid, kidney, brain, and pituitary. Recently, it has been suggested that excessive exposure of the developing fetus to glucocorticoids or exposure at the wrong time may lead to lifelong alterations in the function of the hypothalamic–pituitary–adrenal axis.

The female fetus acquires the lifetime peak number of oocytes (in utero) by mid-gestation and also has a brief period of follicular maturation and sex steroid production in response to elevated gonadotropin levels in utero. This transient increase in serum estradiol (a sex steroid) acts on the fetal hypothalamic-pituitary unit, resulting in a reduction of gonadotropin secretion (a negative feedback effect), which in turn reduces estradiol production. This indicates that the inhibitory effect of sex steroids on gonadotropin release is operative before birth.

In both male and female fetuses, serum estradiol is primarily of maternal and placental origin. With birth and the acute loss of maternal and placental sex steroids, the negative feedback action on the hypothalamic-pituitary axis is lost, and gonadotropins are once again released from the pituitary gland, reaching adult or near-adult concentrations in the early neonatal period. In the female infant, peak serum levels of gonadotropins are generally seen by 3 months of age, then they slowly decline until a nadir is reached by the age of 4 years. In contrast to gonadotropin levels, sex steroid concentrations decrease rapidly to prepubertal values within 1 week of birth and remain low until the onset of puberty.

During fetal development, the adrenal glands are large in proportion to their size in adult life (similar to the fetal kidneys). Early in gestation, the fetal adrenal gland produces abundant dehydroepiandrosterone sulfate (DHEA-S), which serves as a precursor for estrogen production by the placenta and is also able to convert placental progesterone into cortisol. It is not until about 23 weeks' gestation that the fetal adrenal cortex expresses the enzyme to directly synthesize cortisol from cholesterol or pregnenolone. In the first few months of postnatal life, the innermost part of the adrenal cortex (the fetal zone) largely regresses, and there is a rapid decrease in the production of DHEA-S.

Childhood

The hypothalamic–pituitary–gonadal axis in the young child is suppressed between the ages of 4 and 10 years. The hypothalamic–pituitary system regulating gonadotropin release has been termed the gonadostat . Low levels of gonadotropins and sex steroids during this prepubertal period are a function of two mechanisms: (1) maximal sensitivity of the gonadostat to the negative feedback effect of the low circulating levels of estradiol present in prepubertal children, and (2) intrinsic central nervous system inhibition of hypothalamic gonadotropin-releasing hormone (GnRH) secretion. These mechanisms occur independently of the presence of functional gonadal tissue. This is clearly demonstrated in children with gonadal dysgenesis. Agonadal children display elevated gonadotropin concentrations during the first 2 to 4 years of life, followed by a decline in circulating FSH and LH levels by 6 to 8 years of age. By 10 to 12 years of age, gonadotropin concentrations spontaneously rise once again, eventually achieving castration levels. This pattern of gonadotropin secretion in early childhood is similar to that of children with normal gonadal function. These data suggest that an intrinsic central nervous system regulator of GnRH release is the principal inhibitor of gonadotropin secretion from 4 years of age until the peripubertal period. Furthermore, after regression of the fetal zone of the adrenal gland (a few months after birth), very low concentrations of adrenal androgen precursors are available, resulting in decreased adrenal androgen production in early childhood.

Late Prepubertal Period

In general, androgen production and differentiation by the zona reticularis of the adrenal cortex are the initial endocrine changes associated with puberty. Serum concentrations of DHEA, DHEA-S, and androstenedione rise between the ages of 8 and 11 years. This rise in adrenal androgens induces the growth of both axillary and pubic hair and is known as adrenarche or pubarche. This increase in adrenal androgen production occurs independently of gonadotropin secretion or gonadal steroid levels, and the mechanism of its initiation is not understood at this time. Some studies have suggested that the morphologic and functional changes in the zona reticularis are induced by increasing cortisol levels. In cellular studies, human fetal adrenal cells exposed to cortisol in high concentrations produce DHEA, whereas in human studies, infants treated with high-dose adrenocorticotropic hormone for infantile spasms have been noted to have adrenal androgen production.

Recent studies indicate that girls who undergo premature pubarche are more likely than other girls to develop polycystic ovarian syndrome (PCOS) as adults (see Chapter 33 ).

Pubertal Onset

By approximately the 11th year of life, there is a gradual loss of sensitivity by the gonadostat to the negative feedback of sex steroids ( Figure 32-2 ). As a consequence, GnRH pulses (with their mirroring pulses of FSH and LH) increase in amplitude and frequency. The factors that reduce the sensitivity of the gonadostat are incompletely understood. Some studies indicate that a rise in the concentration of leptin, a hormone produced by adipocytes (fat cells) that mediates appetite satiety, precedes and is necessary for this change. This, in turn, supports the association between minimum weight or total body fat and the onset of puberty. The Frisch hypothesis suggests that a critical body weight is necessary for pubertal onset. Further investigations support the concept that fat stores might influence pubertal onset through several mechanisms. First, adipocytes secrete adipokines such as leptin. Leptin appears to serve as a signal to the hypothalamic GnRH pulse generator that there are sufficient energy stores for fertility to commence. Studies have shown that every 1-kg gain in body weight lowers the onset of menarche by 13 days and that every increase of 1 ng/ml in serum leptin lowers the age of menarche by 1 month. Second, aromatase activity in adipocytes is dependent on fat mass, and obesity results in greater peripheral conversion of androstenedione to estrone and of testosterone to estradiol. Last, increasing adipose tissue is related to increasing insulin resistance, which decreases serum levels of sex hormone binding globulin. This leads to an increased level of bioavailable sex hormones.

A further decrease in sensitivity of the gonadostat combined with the loss of intrinsic central nervous system inhibition of hypothalamic GnRH release is heralded by sleep-associated increases in GnRH secretion. This nocturnal dominant pattern gradually shifts into an adult-type secretory pattern, with GnRH pulses occurring every 90 to 120 minutes throughout the 24-hour day.

The increase in gonadotropin release promotes ovarian follicular maturation and sex steroid production, which induces the development of secondary sexual characteristics. By middle to late puberty, maturation of the positive feedback mechanism of estradiol on LH release from the anterior pituitary gland is complete, and ovulatory cycles are established.

Stages of Pubertal Development

The first physical sign of puberty is usually breast budding (thelarche), followed by the appearance of axillary or pubic hair (adrenarche/pubarche). Unilateral breast development is not uncommon in early puberty and may last up to 6 months before the development of the contralateral breast. Maximal growth or peak height velocity is usually the next stage, followed by menarche (the onset of menstrual periods). The final somatic changes are the appearance of adult pubic hair distribution and adult-type breasts. In approximately 15% of normally developing girls, the development of pubic hair occurs before breast development. The sequence of pubertal changes generally occurs over a period of 4.5 years, with a normal range of 1.5 to 6 years ( Figure 32-5 ).

Race plays a role in determining the age of the onset of puberty. African American girls begin puberty earlier than girls in other racial groups (on average between the ages of 8 and 9 years), followed by Mexican Americans and whites ( Table 32-1 ). In African American girls, thelarche and adrenarche can occur as early as 6 years of age, whereas in whites, they can occur as early 7 years of age.