Puberty

Department of Anthropology, Peabody Museum, Harvard University, Boston introduction

Puberty refers to the onset of adult reproductive capacity. As a milestone in human development, puberty is quite dramatic, involving a rapid transformation of anatomy, physiology, and behavior. Other than pregnancy, it is probably the most abrupt and encompassing developmental transition that human beings undergo between birth and death. It is also a transition of deep cultural significance in most societies around the world, often marked by special rituals and ceremonies.1 As dramatic as it is, however, puberty is not an instantaneous threshold or a discrete state but a process integrated more or less smoothly with the antecedent and consequent developmental phases of immaturity and adulthood. As a result it is, in fact, quite difficult to clearly identify either the beginning or the end of the puber-tal period. Unlike the metamorphosis of an insect through discrete morphological stages, the human organism is transformed from its immature to its mature state through a rapid and profound, but essentially continuous, trajectory of change.

The central feature of human puberty is the maturation of the primary reproductive endocrine axis, composed of the hypothalamus, pituitary gland, and gonad. This three-part system—referred to in general as the hypothalamic-pituitary-gonadal (HPG) axis, or specifically as the hypothalamic-pituitary-ovarian (HPO) axis in females and the hypothalamic-pituitary-testicular (HPT) axis in males—controls the reproductive functions of the organism, including the production and maturation of gametes and the activity of the other components of the reproductive tract necessary for reproduction in both sexes. The secondary features of human puberty include the development of secondary sexual characteristics, the development of sexually dimorphic anatomical features, the acceleration and ultimate cessation of linear growth, quantitative changes in the function of many other endocrine systems

(particularly those involved in the partitioning of metabolic effort), and changes in behavior and its substrates, including the libido. Virtually all the secondary changes of puberty are downstream consequences of the primary maturation of the HPG axis. In particular, the actions of the steroid hormones produced by the ovaries and testes are directly involved in most aspects of pubertal development. A few physiological changes associated with puberty precede HPG axis activation, although their status as releasers or causes of the primary events of puberty is uncertain.

An understanding of human puberty, therefore, begins with an understanding of the functioning of the HPG axis and its developmental trajectory.2-5 Secondary features of puberty can then be viewed as consequences of this central developmental transformation. While this approach can successfully integrate much of what we know about human puberty—its normal course and variability, its mechanisms, and its associated pathologies—it also highlights areas of ongoing controversy, contemporary research, and lingering ignorance.

hpg axis

The hormonal signals that flow between the components of the HPG axis coordinate the central processes of reproductive biology and integrate them with other features of the organism's anatomy, physiology, and behavior. The central features of this regulatory system can be sketched out in rather simple terms, but the student should be aware the details are far more complex and convoluted than implied by such summaries (Figure 4-1).

The hypothalamus serves as the main enabling center for the rest of the HPG axis. Its primary signal is a small peptide hormone variously known as gonadotropin-releasing hormone (GnRH) and luteinizing-hormone-releasing hormone (LHRH).6,7 It is secreted by the median eminence of the hypothalamus into the tiny portal vascular system that connects this region of the brain to the anterior pituitary gland.8 The effect of GnRH is to stimulate production and release of two protein hormones from the pituitary, follicle-stimulating hormone (FSH) and luteinizing hormone (LH).9,10 GnRH must be released in a pulsatile fashion to have its ordinary stimulatory effect on the pituitary. In adults, the hypothalamus releases GnRH pulses about once an hour, controlled by a pulse generator located in the region of the arcuate nucleus.11 Surgical manipulation of rhesus monkeys has demonstrated that pulse frequencies much faster or slower than this result in a suppression of gonadotropin release by the pituitary.12,13 On the other hand, a constant regime of exogenously administered hourly GnRH pulses is sufficient to sustain normal functioning of the axis both in experimental animals and humans suffering pathological disruptions of hypothalamic function. In particular, it is notable that a constant regime of circhoral GnRH pulses is sufficient to maintain full ovarian cyclicity in both rhesus monkeys and women.14-17 These observations give rise to the concept

figure 4-1 The hypothalamic-pituitary-gonadal axis (hypothalamic-pituitary-testicular axis in males, hypothalamic-pituitary-ovarian axis in females) and its principal hormones.

of the hypothalamus as the primary on-off switch controlling reproductive function.18 The hypothalamus receives many inputs from other neural centers, allowing the discrete control of reproductive function to be susceptible to a broad range of influences. Olfactory, photoperiod, and tactile stimuli are known to modify hypothalamic function in many mammals. More complex influences on central nervous system activity may also be able to modify patterns of GnRH release and so affect reproductive function. However, hypothalamic control of HPG axis activity is primarily discrete and qualitative. Quantitative variation in the activity of the axis is regulated by steroid feedback and linkages to general metabolism.

The pituitary responds to GnRH from the hypothalamus by synthesizing and releasing FSH and LH. These hormones are also released in a pulsatile fashion in adults, although the pattern of gonadotropin secretion does not directly reflect the pattern of GnRH secretion. In women in particular, the frequency and amplitude of gonadotropin pulses is greatly modified by the levels of circulating steroid hormones.19,20

The testes and ovaries respond to stimulation by the gonadotropins in broadly analogous ways. In the testis, LH stimulates production of testosterone by the Ley-dig cells clustered outside the basement membrane that surrounds the seminiferous tubules. FSH stimulates the Sertoli cells inside the tubules. The Sertoli cells respond by nurturing the development of the spermatocytes as well as by secreting a protein hormone, inhibin, that differentially suppresses pituitary production of FSH. Testosterone also stimulates Sertoli function while suppressing pituitary release of both gonadotropins. As a result of these feedback controls, gamete production in a normal man is self-sustaining, with gonadotropins maintained at a low level. Interruptions of gamete production, however, are followed by rises in the gonadotropins that reinitiate the process.21

In the ovary, LH stimulates testosterone production by the cells clustered around the outside of the basement membrane surrounding a developing follicle. FSH stimulates the granulosa cells inside the follicle to convert testosterone to estradiol and support the development of the oocyte. The granulosa cells also secrete inhibin with a suppressive effect on FSH. After ovulation, the follicle is transformed into a corpus luteum, secreting progesterone and inhibin. Among the important peripheral targets for ovarian steroids is the endometrial lining of the uterus. Estradiol production in the follicular phase of the menstrual cycle stimulates endometrial proliferation. Progesterone production in the luteal phase following ovulation stimulates secretory activity by the endometrium and maintains its viability. In the absence of progesterone, a developed endometrium will soon be sloughed off in menstruation. Menstrual blood loss thus implies estradiol production but not necessarily progesterone production. Nor, by extension, does menstruation necessarily imply ovulation.22

The combined effect on the pituitary of steroid and inhibin production by the gonads is primarily inhibitory. Gonadectomy in either sex and menopause in women are characterized by high and unrestrained levels of pituitary gonadotropins. In men, the HPG axis normally functions at a sustained level, although acute variations as well as age-related changes occur. In women, the waves of follicular maturation that characterize ovarian cycles cause cyclic variation in both ovarian and pituitary hormones. The interaction of ovarian and pituitary signals is elegantly designed to produce key events of the ovarian cycle, such as the selection of the dominant follicle and ovulation.

Gonadal function is also subject to regulation by factors outside the HPG axis. Several major regulators of metabolism affect gonadal function, including insulin, cortisol, growth hormone, and insulinlike growth factor-1 (IGF-I).23,24 In addition, the adrenal cortex represents a significant source of steroid production that is not under the control of the HPG axis but may nevertheless affect its activity. These sources of regulation are likely to have quantitative effects on the activity of the HPG axis rather than discrete, qualitative effects.

Maturation of the HPG Axis

The feedback relationships governing the HPG axis become established during gestation. After birth, the withdrawal of placental steroids results in a period of high gonadotropin secretion in the neonate. Over a period of months, the sensitivity of the axis to negative feedback appears to increase, leading to a decline in gonadotropin secretion to the very low levels characteristic of early childhood.25,26 Pulsatile gonadotropin secretion is observable in prepubertal children but at very low amplitudes. Pulse frequency in prepubertal boys is comparable to that in adults while the frequency observed in girls is considerably slower.27 The first evidence of a change in HPG axis activity is the appearance of sleep-associated increased LH pulse amplitude in both sexes and an associated increase in pulse frequency in girls, occurring in girls about 8-9 years old and in boys 1-2 years later.28,29 Changes in FSH activity also are likely during this period but are more difficult to document, given the lower circulating levels of FSH than LH. Over time, the pulsatile pattern of LH secretion extends to characterize the entire 24-hour period.

These early elevations of gonadotropins are associated with gonadal maturation in both sexes. Testis volume begins to increase from childhood values of some 2 ml to adult values of 12-25 ml. This increase is associated with growth of the seminiferous tubules, appearance of Sertoli cells, and proliferation of spermato-cytes. Pulsatile LH secretion leads to Leydig cell stimulation and increases in circulating testosterone levels. Rising testosterone levels stimulate a host of other pubertal changes, including the appearance of pubic, axillary, and facial hair, voice changes, accelerated linear growth, and increases in muscle mass. The differential responsiveness of these target tissues to androgenic stimulation is largely responsible for the variations in timing of these pubertal changes among individuals.30-32

In girls ovarian growth occurs throughout childhood.33 Increased LH stimulation at the beginning of puberty leads to increases in ovarian steroid production, with estradiol levels approaching those characteristic of women in the follicular phase.34 Testosterone levels also rise and the ratio of testosterone to estradiol is somewhat higher in puberty than adulthood.35 The development of pubic and axillary hair, breast enlargement, linear growth acceleration, pelvic remodeling, and increases in adiposity are all characteristic consequences of increasing steroid pro-duction.32 The first appearance of menstrual bleeding, known as menarche, is also a reflection of increasing estradiol levels. It tokens a level of estrogenic stimulation sufficient to cause endometrial proliferation. Although the first menstrual period is a discrete event in the life of an individual, it should be noted that is merely the first outward manifestation of a continuously changing level of endometrial stimulation.

The ability of the gonads to produce gametes also matures during the pubertal period. In boys, the first appearance of sperm in urine occurs in association with the early increases in gonadotropin secretion, but regular sperm production is not established until several years later.36 In girls, ovulation is extremely unlikely before menarche and may lag behind menarche by many months. Both longitudinal and cross-sectional studies indicate that the frequency of ovulation increases steadily after menarche and may not reach adult rates for many years.37 In men, androgen levels reach a peak by the late teens to early twenties, at about the time that linear growth is completed. In women, gonadal steroid levels and frequencies of ovulation may continue to increase for several years after the cessation of linear growth, accompanied by continuing changes in body composition.

LH Surge in Females

It is often claimed that the maturation of the HPO axis in females includes the development of a positive feedback response to estradiol as part of the mechanism of ovulation.38,39 This conclusion derives from the fact that an LH surge can be elicited in mature women by supplying large increments of exogenous estradiol, whereas the same response cannot be elicited in prepubertal girls. However, the mechanism of positive feedback itself and its role in stimulating the normal mid-cycle LH surge has recently been challenged. Levran et al.40 demonstrated that the LH surge in mature women is a consequence of a leveling-off or decline in estra-diol levels after a preceding rise and is not triggered by the attainment of any threshold level of estradiol. They argue that the withdrawal of the negative feedback of estradiol on LH release precipitates the dramatic surge of accumulated gonadotropins and that it is not necessary to postulate a separate positive feedback mechanism. Notably, however, to effectively produce an LH surge, a drop in estradiol must follow a sustained rise and must also occur in an individual with adult levels of baseline LH production. The reason why an LH surge is not produced in a prepubertal girl by the same estradiol treatment that is effective in an adult, in this view, is that baseline LH production is too low for appreciable amounts to accumulate in the releasable pool. Hence, the appearance of the LH surge late in female puberty does not necessarily token the initiation of a new, positive feedback relationship.

causes and correlates of hpg axis maturation

Early experiments involving transplants of pituitary and gonadal tissue between immature and mature animals led to the conclusion that changes in hypothalamic function must be responsible for pubertal activation of the HPG axis.41 This conclusion has been elegantly confirmed by experiments on immature rhesus monkeys where exogenous administration of pulsatile GnRH led to rapid and premature establishment of adult HPG axis function.42 Humans who lack endogenous capacity for GnRH production ordinarily fail to undergo normal pubertal development but can be induced to do so through exogenous administration of pulsatile GnRH.17 Conversely, precocious puberty can be caused by premature appearance of a pulsatile GnRH pattern and can often be arrested by exogenous administration of long-acting GnRH agonists that swamp the endogenous pulsatile signal.43,44 Thus, puberty does not seem to be limited by the maturational status of either the pituitary or the gonad. Rather it is assumed that some process leads to the establishment of a mature pattern of circhoral GnRH production by the hypothalamus. The elucidation of this process represents a continuing challenge. Controversy exists both over the nature of the functional change that occurs in the hypothalamus and the factors that cause the change.

Two leading hypotheses have been advanced to describe the functional changes in the HPG axis at puberty. According to the first, initially applied to humans by Kulin, Grumbach, and Kaplan,45 a decrease in the sensitivity of the hypothalamus to the negative feedback effects of gonadal steroids occurs in puberty, leading to a progressive rise in the circulating levels of gonadotropins and steroids. This hypothesis has been referred to as the gonadostat hypothesis, evoking an analogy between the HPG axis and the thermostat regulating heat production by a furnace. Puberty, in this analogy, is caused by a resetting of the "gonadostat" to a higher level, so that more circulating steroid is necessary to turn off the flow of gonadotropins, in the same way that setting a thermostat higher requires more heat to turn off the stimulating signal to the furnace. Support for this hypothesis comes from demonstrations of the suppression of gonadotropin levels in prepubertal children by low levels of exogenous steroids that are ineffective in adults.

Plant27 criticized this hypothesis and suggested an alternative based on changes in the positive stimulation of gonadotropin production. He noted that the gona-dostat hypothesis implies that the castration of a prepubertal individual should lead to a dramatic rise in gonadotropins, a phenomenon that does not, in fact, occur. Instead, prepubertal castration of male or female rhesus monkeys leads to only small increases in gonadotropin levels, much smaller than observed following the castration of adult animals. Rather than being held in check by an extreme sensitivity to the low, prepubertal levels of circulating steroids, Plant argued that gonadotropin production in the prepubertal animal is subject to weak positive stimulation. Puberty, in his view, results from an increase in this positive "hypophys-iotropic drive."

Neither of these hypotheses resolves the issue of the proximate causes of HPG axis maturation. It is suspected that changes in neurotransmitter or neuromodula-tor activity are involved in the maturational changes of the hypothalamus,46 but whether these changes arise on an endogenous developmental schedule or are coupled to other somatic or endocrine maturational events remains an area of ongoing investigation. In considering this question, it is important to adequately distinguish potential causes of HPG axis maturation from correlated and consequent events.

Adrenarche

Humans share with the other African apes a characteristic of adrenal development known as adrenarche, which usually precedes recognizable pubertal changes in the HPG axis by 1 or 2 years.2,47-49 During this period, the adrenal cortex acquires a third secretory zone, the zona reticularis, functionally analogous to the zona fetalis of the fetal adrenal (Figure 4-2). During gestation, the zona fetalis produces androgens that serve as precursors for placental estrogen synthesis. Like the zona fetalis, the zona reticularis produces large quantities of the C-19 steroid hormones dehy-droepiandrosterone (DHEA) and androstenedione (A). Circulating levels of these hormones rise in prepubertal children, together with levels of their sulfate conjugates, before detectable increases in gonadotropins and gonadal steroids. These adrenal androgens have weak potency at androgen receptors and may also serve as substrates for conversion to estrogens in peripheral tissues and the hypothalamus itself. It has been suggested by some that adrenal androgens may contribute to the maturation of the HPG axis, perhaps by desensitizing the hypothalamus through exposure to rising steroid levels outside its own regulatory control.50

The potential for adrenal androgen production to influence pubertal development is most clearly demonstrated in cases of untreated congenital adrenal hyperplasia.51,52 Uncontrolled overproduction of adrenal androgens in childhood, which can result from specific enzyme deficiencies, can precipitate precocious puberty, including HPG axis activation, in both boys and girls. Whether adrenarche has a significant influence on the timing or pace of puberty in nonpathological situations is less clear. Some data suggest that early adrenarche is associated with an advancement of subsequent pubertal events within the normal range of variation.53 The relationship may be stronger in girls, where adrenal androgen levels may contribute significantly to the adolescent growth spurt and to the development of pubic hair.

The factors that control the timing of adrenarche remain obscure, however. There is no evidence of a rise in pituitary adrenocorticotropic hormone levels and no concomitant rise in cortisol production at the time of adrenarche. Increased androgen production involves alteration in the enzyme activity of the steroid synthetic pathway, including a suppression of 3-beta-hydroxysteroid dehydrogenase (3-beta-HSD) and an induction of 17,20-lyase activity.54,55 Estradiol has been shown to have a suppressive effect on 3-beta HSD, and girls with precocious adrenarche have been

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