Disorders of Pubertal Development: Precocious Puberty

Nirupama Kakarla, MD; Karen D. Bradshaw, MD

Disclosures

Semin Reprod Med. 2003;21(4) 

In This Article

Physiology of Normal Puberty

Puberty is a period during which many dramatic hormonal changes occur. Of these, it is clear that changes in the axes controlling the secretion of growth hormone and gonadal steroids play central roles.

Growth hormone (GH) is produced by the somatotropes of the anterior pituitary gland. Although its control is complex, its synthesis and release is under the principal control of growth hormone-releasing hormone (GHRH), which is released by the nerve endings of the hypothalamic GHRH neurons into the hypophyseal portal circulation. In response to pulses of GHRH, the pituitary releases pulses of GH into the systemic circulation. GH exerts its effects by binding to high affinity receptors on the surfaces of responsive cells. Although GH certainly modulates some biological processes directly, in many tissues the actions of GH are modulated indirectly through the action of growth factors that are produced in response to the action of GH, specifically insulin-like growth factor-1 (IGF-1) and its complex series of binding proteins. Serum levels of IGF-1 rise with age in concert with age-related increases in mean GH levels.[1]

At the onset of puberty, increased activity of the GnRH pulse generator causes a progressive rise in mean concentrations of gonadotropins, resulting from an increase in the frequency and amplitude of GnRH pulses (see below). These increases are first detected as nocturnal gonadotropin pulses, but as puberty progresses gonadotropin pulses also increase during daytime until adult mean gonadotropin levels are achieved. Fig. 2 depicts pulsatile LH release throughout the pubertal stages.

Figure 2.

Serum LH levels throughout the pubertal stages. Note nocturnal release initially in early puberty.

Although several lines of evidence indicate that there are complex hormonal interactions that mediate the somatic changes of puberty, the interplay between the sex steroid and growth hormone axes can be seen most clearly in studies of the patterns of growth of individuals with genetic defects that alter the function of one or both of these axes. Boys with absent gonadal function at the time of puberty and a normal growth hormone axis (e.g., patients with an isolated deficiency of gonadotropins) manifest normal growth rates when treated with testosterone alone.[3] Administration of androgens alone to subjects with combined defects of the gonadal and growth hormone axes (e.g., patients with panhypopituitarism) does not reestablish a normal rate of growth. Normal growth rates are observed only when such patients are treated with both growth hormone and gonadal steroids.[3]

A variety of other hormones are also modulated and change with onset and progression of puberty. As a result of increased sex steroid concentrations, sex hormone-binding globulin is lower during puberty than in childhood. The gonadal peptide inhibin, structurally related to transforming growth factor-β (TGF-β), is regulated by and involved in regulation of FSH. This product of Sertoli and granulosa cells shows a progressive increase in mean concentration with advancing puberty in both sexes.[1] Concentrations of the glycoprotein anti-müllerian hormone (AMH) show marked sexual dimorphism. AMH is produced in Sertoli cells and the levels are relatively high in newborn boys but are undetectable in girls. In contrast, the hormone becomes very low in boys during puberty, at which time AMH concentrations increase in girls.[2]

The role of estrogens in the process of skeletal maturation in both boys and girls has been postulated for some time. As an example, effective suppression of the rapid skeletal maturation seen in boys with gonadotropin-independent forms of precocious puberty requires inhibition of aromatase activity to reduce serum estradiol concentrations in addition to antiandrogens to interfere with androgen action.[4] Furthermore, a female patient with a genetic deficiency of aromatase activity had no pubertal growth spurt and exhibited delayed skeletal maturation, indicating that estrogen, not androgen, is required for these events.[2]

Inferences drawn from such cases regarding the importance of estrogen in promoting skeletal maturation in both sexes are reinforced by contrasting the patterns of pubertal development in syndromes of androgen and estrogen resistance. Studies of patients with complete androgen insensitivity have documented that normal pubertal growth spurt is observed with the onset of pubertal gonadal function.[5] In males with estrogen resistance, an inactivating mutation of the estrogen receptor, the epiphyseal growth plates demonstrate no evidence of epiphyseal fusion and bone mineralization is markedly decreased. Such findings suggest that the effects of gonadal steroids in male pubertal development are not mediated via the androgen receptor but are instead exerted indirectly following the conversion of testosterone to estrogen.[6]

These considerations emphasize the complex hormonal interactions that characterize the process of normal puberty. It is clear that the normal functioning of each of these components is necessary for normal pubertal development to occur. As described below, abnormalities at many levels can disrupt normal pubertal growth, development and maturation.

Maturation of the Hypothalamic-Pituitary-Gonadal Axis

Maturation of the reproductive system occurs in a phasic manner in humans and higher primates and can be viewed as occurring in several distinct stages.

The first stage, which begins during fetal life and lasts until late infancy, is characterized by development of the neuroendocrine systems responsible for regulation of the reproductive system. GnRH neurons develop in the rostral forebrain associated with the olfactory placode. These neurons migrate to an area in the arcuate nucleus of the hypothalamus destined to become the GnRH pulse generator. These neural cells develop intrinsic and unregulated pulsatile activity by ~11 weeks of gestation. During this stage the reproductive system appears to be fully active, with gonadotropin and sex steroid hormone concentrations being measurable in fetal plasma. Concentrations of LH and FSH peak at ~4 to 5 months' gestational age. Later in gestation, negative feedback from gonadal steroids begins to regulate the pulse generator and by term, gonadotropin levels (and by inference the activity of the GnRH pulse generator) are low.[7]

At the time of delivery the infant is separated from the dominant source of estrogenic sex steroids, the placenta, and owing to the withdrawal of this negative feedback, the levels of gonadotropins rise. This increase is responsible for a transient secondary gonadal stimulation occurring in the first months following birth. Although occurring in both boys and girls, this is observed most readily in female infants in whom there may be prolonged neonatal breast budding.

By six months of postnatal age, gonadotropin and sex steroid concentrations in plasma have again declined to low levels and the third stage of maturation begins. This stage lasts throughout childhood and is characterized by low plasma concentrations of LH, FSH, and sex steroids. From a physiological perspective, the prepubertal stage of development presents apparent contradictions. Measurements of gonadotropins and sex steroids during fetal development suggest that the hypothalamic-gonadal axis has completely developed in utero and that it is regulated by steroid hormones during the latter stages of pregnancy. Despite this, during the prepubertal period, gonadotropins remain low even when sex steroids concentrations are extremely low, such as in patients with Turner syndrome or in castrated children.[2] That serum gonadotropin concentrations remain low under such conditions suggests that additional inhibitory mechanisms in the central nervous system (CNS)/hypothalamus have developed. Early studies to explain these different regulatory behaviors focused on examining the sensitivity of the hypothalamus and pituitary to feedback inhibition by gonadal steroids. Such investigations demonstrated that the levels of estrogen and androgen required to inhibit LH and FSH secretion in young prepubertal animals and in humans are consistently lower than those required to suppress gonadotropin levels to an equivalent extent in adult castrated animals.[1] Such differences in the sensitivity of regulation of gonadotropin secretion in young prepubertal and adult animals have been described in several different species. Although such observations have substantial power in explaining the prepubertal quiescence of gonadotropin secretion, other observations suggest that additional mechanisms might also be operative. Although mean serum concentrations of gonadotropins are low during the prepubertal period, the reproductive system is not completely inhibited as small spontaneous LH pulses occur at a low frequency in normal children.

The fourth stage, puberty itself, occurs as the result of reactivation of the reproductive axis. There is a reemergence of GnRH secretion from its relative quiescence during childhood, activating the cascade of pituitary-gonadal maturation.[8] Although a great deal of effort has been expended to identify the signals that control the onset of puberty, it appears that the mechanisms responsible for the initiation of pubertal events are extremely complex. They likely involve the integration of numerous different signals including attainment of a certain body mass or composition, which is likely linked with leptin levels. The effect of increased leptin levels on the initiation of puberty appears to be secondary to the suppression of the neuropeptide Y by leptin, thus releasing its inhibition of the pituitary gonadotropin axis. Neural signals derived from centers within the central nervous system that serve as a biological clock are also likely involved.

The onset of puberty is heralded by striking increases in nocturnal LH secretion, manifested by an increase in amplitude and frequency of LH pulses. These increases of LH precede rises of sex steroid concentrations and the development of secondary sex characteristics. As pubertal maturation progresses, the amplitude and frequency of gonadotropin pulses also increases during the day in a pattern similar to that seen at night, until the final stage of sexual maturation, adulthood, is reached. In this period, regular pulses of GnRH establish the mature pattern of gonadal steroid secretion. The mechanism underlying the relative suppression and subsequent pubertal activation of hypothalamic GnRH is unknown. In females, this results in the regular cyclical variations of gonadotropins, estrogen, and progesterone characteristic of the menstrual cycle. Pulsatile GnRH stimulates pituitary FSH and LH secretion, ultimately stimulating gonadal steroid production and gametogenesis in males and females (Fig. 3). In the ovary, FSH stimulates follicular maturation and estrogen production through aromatization of androgens, whereas LH stimulates production by theca cells, triggers ovulation, and maintains progesterone production by the corpus luteum. In males, the same regular pulses of GnRH establish a pattern characterized by relatively constant levels of testosterone and gonadotropins, with minimal diurnal variation. In the testis, FSH acts on Sertoli-Leydig cells to initiate spermatogenesis and LH acts on the Leydig cells to stimulate testosterone production.[9]

The changes in sensitivity of the hypothalamic gonodostat. In the prepubertal state, the concentration of sex steroids and gonadotropins is low; the hypothalamic gonadostat is functional but highly sensitive to low levels of sex steroids. With the onset of puberty there is decreased sensitivity of the hypothalamus to negative feedback by sex steroids, increased release of GnRH, and enhanced secretion of gonadotropins. In adults, the negative feedback mechanism in the hypothalamus is less sensitive to feedback by sex steroids (adult set point), and adult levels of gonadotropins and sex steroids are present. (© The University of Texas Southwestern Medical Center at Dallas and Karen Bradshaw, M.D., 2000. Reprinted with permission.)

The hypothalamic-pituitary-adrenal (HPA) axis also has some minor input into the physiologic process of puberty through the secretion of adrenal androgens (adrenarche). However, the major involvement of the HPA axis in puberty is its potential pathologic influence, primarily in accelerating its onset and/or progress.[9]

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