Adrenal Androgens

(ANDROSTENEDIONE, 1 DHEA)

figure 4-2 The layers of the adult adrenal cortex and the principal steroids produced by each layer.

observed to have elevated estradiol levels. These observations led some to suggest that as yet undetectable increases in ovarian estradiol production early in puberty may trigger adrenarche in girls.56 This possibility has not yet been discriminated from the alternative, that elevated estradiol is a consequence and not a cause of precocious adrenarche, nor does it provide an explanation of the timing of adrenal development in boys. Insulinlike growth factor I has also been observed to induce 17,20-lyase activity and promote adrenal androgen production in both the zona fetalis and the zona reticularis, and insulin sensitivity has been observed to be negatively correlated with adrenal androgen production by the zona reticularis.57,58 Therefore, it may be that developmental changes in either the somatotropic axis or insulin sensitivity in late childhood play a role in initiating adrenarche in both sexes.

Somatotropic Axis

The somatotropic axis exerts pronounced effects on the proliferation and maintenance of many tissues, including the stimulation of skeletal growth and protein anabolism. Both stimulatory and inhibitory hormones are secreted by the hypothalamus into the hypophyseal portal system, where they control the release of growth hormone (GH) from the anterior pituitary. GH is secreted in a pulsatile fashion, much like the gonadotropins. Although GH has direct effects on some cells, many of its effects are mediated by the local production of insulinlike growth factors (IGFs) in target tissues.

Increased activity of the somatotropic axis is a normal part of pubertal development, stimulating both the linear acceleration in skeletal growth and the accumulation of lean body mass.59,60 The increase in somatotropic axis activity appears to be a consequence of increased gonadal steroid production.61-63 Both estradiol and testosterone affect GH production by augmenting GH pulse amplitude, although testosterone may achieve this effect after aromatization to estradiol within the hypothalamus. Increases in IGF-I, the major mediator of GH action on skeletal growth, are correlated with Tanner stages of pubertal development and gonadal steroid levels. GH and IGF-I also have stimulatory effects on gonadal steroid production, and gonadal steroids have independent effects on skeletal growth not mediated by the somatotropic axis.24,64-66 Thus, the somatotropic axis and the HPG axis function synergistically in promoting the adolescent growth spurt. The initial stimulation, however, comes from maturation of the HPG axis.

Insulin Sensitivity

Insulin levels rise during puberty as a consequence of a transient decrease in insulin sensitivity.67,68 In euglycemic clamp studies, the insulin response to a glucose challenge is observed to be two- to threefold greater during puberty than in either prepubescent children or postpubescent adults.69 The change in insulin sensitivity is closely correlated with Tanner stages of pubertal development, decreasing simultaneously with the initiation of pubertal development (Tanner stage 2) and returning to normal by the end of puberty (Tanner stage 5). The pubertal decrease in insulin sensitivity is also closely correlated with increases in GH and body mass index (BMI), even after correction for sex, age, and pubertal stage.70 Increases in GH may contribute to decreases in insulin sensitivity by increasing the rate of glucose uptake by anabolic tissues, but increased insulin levels may potentiate GH effects as well. Insulin has a suppressive effect on IGF-binding proteins, thus raising free levels of IGF-1.68 Insulin has also been shown to increase gonadotropin-stimulated gonadal steroid production in the ovary.23 69 Hyperinsu-linemic states are often associated with advanced pubertal progression while hypoinsulinemic states are often associated with pubertal delay. Whether developmental changes in insulin resistance independently contribute to normal HPG axis maturation via effects on gonadal steroid production has not been thoroughly explored.

Body Composition

Frisch and colleagues suggested, in the 1970s, that changes in body composition had an important causal influence on HPO axis maturation in females.71,72 Although it has been extensively criticized on empirical and theoretical grounds (see the review in Ellison73), this hypothesis continues to be widely cited. Significant changes in body composition occur during puberty in both sexes, with males increasing in lean body mass percentage and females increasing in fat mass percentage. In both cases, however, these changes are consequences of increased production of gonadal steroids rather than causes or even antecedents.74 Longitudinal studies of pubertal maturation in girls have clearly documented that increases in gonadal estrogen production precede any change in body composition, with significant increases in fat percentage occurring after menarche.75,76 In boys, the increases in muscle mass that accompany puberty are direct consequences of the anabolic effects of gonadal testosterone.77 Thus, in both sexes, changes in body composition must be viewed as downstream consequences of the maturation of the HPG axis and not contributing causes.

Leptin

Considerable confusion and controversy surrounds the role of leptin in human physiology generally and pubertal development in particular.78-82 Leptin is a 16-KDa cytokine of the tumor necrosis factor group coded by the ob gene. In rodents, leptin appears to affect hypothalamic centers, regulating food intake and energy expenditure. Deficiency in either leptin (ob mutants) or its receptor (db mutants) leads to hyperphagia and inactivity. Exogenous leptin administration in ob mutants leads to reductions in food intake and increases in energy expenditure.83 In humans, defects in leptin signaling (both leptin deficiency and leptin receptor defects) have also been associated with massive, early onset obesity.84,85 However, administra tion of exogenous leptin to human subjects has no significant effect on weight change, energy intake, or energy expenditure.86 Thus, the relationship of leptin to energy metabolism appears to be different in rodents and humans.87

In humans, leptin is primarily produced in adipocytes of subcutaneous fat tissue.88 Leptin receptors occur in the hypothalamus, although not on GnRH-producing cells, and in various peripheral tissues, including the ovary.89,90 In adults, circulating levels of leptin are positively correlated with fat mass. The relationship is highly sexually dimorphic, however, with women typically having threefold higher leptin levels per fat mass than men. This dimorphism is a result of the effects of gonadal steroids, testosterone suppressing, and estradiol enhancing leptin production.74,91 In addition to fat mass and gender, leptin levels reflect energy balance and energy flux. Weight loss is associated with low levels of leptin per fat mass, and weight gain with high levels. Maintenance of a lower than normal weight through caloric intake restriction is also associated with low leptin levels per fat mass, indicating a suppressive effect of low energy flux.92,93

The effects of energy balance and energy flux on leptin levels may reflect the control of leptin production by factors regulating energy metabolism.94,95 The control of leptin production by insulin has been particularly well demonstrated by recent studies. Leptin levels are more strongly correlated with insulin levels than with adiposity.96,97 Children with new-onset type I (insulin-deficiency) diabetes have abnormally low leptin levels for their fat mass, but those levels quickly rise to the normal range with insulin therapy.98 Similarly, biliopancreatic diversion in obese subjects produces a reduction in both insulin and leptin levels and a dissociation between leptin and fat mass.99 The regulation of leptin production by insulin may underlie the relationship with energy balance and energy flux and may also contribute to reported population differences in leptin levels scaled for fat mass.100-102 In women, the stimulatory effect of estradiol on leptin production produces menstrual cycle variation in leptin levels and decreases in leptin production per fat mass in postmenopausal women.74,103,104 Since ovarian function is known to respond to changes in energy balance, variation in ovarian steroid production may contribute to the relationship between energy balance and leptin production, a relationship somewhat stronger in women than men.92

In addition to defects in metabolic regulation, ob mutant mice are infertile with subnormal gonadotropin levels. Administration of leptin not only leads to weight reduction in these animals but raises gonadotropin levels and restores fertility.105 These observations suggested a potential relationship between leptin and the HPG axis. It has been hypothesized that leptin levels may also trigger puberty in rodents. In mice, ob mutant females normally fail to undergo puberty but do so if treated with exogenous leptin. Wild-type female mice injected prepubertally with leptin grow more slowly but display vaginal opening and estrus behavior earlier than untreated controls.106 In rats, leptin administration only partially reverses the delay in pubertal maturation caused by food restriction, leading to the suggestion that leptin levels may have a permissive, rather than a triggering, effect on puberty in that species.107 In rhesus monkeys, there is no increase in leptin preceding the initiation of HPG axis maturation, leading to further doubt regarding the general-izability of the rodent model.108

There has been speculation that leptin may in some way contribute to the control of puberty in humans as well. Clinical evidence on this issue is somewhat ambiguous but on the whole does not support a direct effect of leptin on the timing of human puberty. Genetic mutations in leptin and its receptor have each been associated in human subjects with massive obesity and the failure of normal pubertal progression.84,85 However, profound alterations of metabolism and pituitary function, including defects in growth hormone and thyrotropin production, also occur in these individuals, making the role of leptin in the failure of pubertal maturation uncertain. Precocious maturation of the HPG axis, on the other hand, is not associated with any change in leptin levels.109,110 Andrelli et al.111 report on two female patients, both of whom experienced complete atrophy of subcutaneous and visceral adipose tissue that occurred during childhood. Leptin levels in both women were well below the normal range, yet both experienced menarche between 11 and 12 years of age with regular menstrual cycles thereafter. Gonadotropin and gonadal steroid levels were normal for both women, one of whom had been pregnant and given birth three times.

Longitudinal and cross-sectional studies of leptin levels during puberty indicate a sustained increase in leptin levels in girls in association with increasing adi-posity.112-114 As noted previously, however, the increase in female adiposity is primarily a consequence of HPG axis maturation, not a cause. Hence, the puber-tal increase in leptin production, correlated with the increases in fat mass, must be seen as a pubertal consequence as well. Sexual dimorphism in leptin production also develops during puberty but similarly is best understood as a downstream consequence of gonadal steroid production. In boys, early puberty is marked by a transient rise in leptin levels, which then decline to prepubertal levels as puberty progresses.115,116 The transient rise may well be a consequence of the transient rise in insulin levels, which occurs at the same time, with the subsequent decline in leptin resulting both from a decline in insulin and a rise in testosterone.

In summary, there is little evidence that an elevation in leptin is either necessary or sufficient for the initiation of HPG axis maturation in humans. Pubertal changes in leptin concentrations are instead most easily understood as consequences of gonadal activity and insulin production. Rather than playing an important role in regulating reproductive maturation or mature reproductive function, leptin appears to be more closely associated with metabolic regulation and insulin dynamics in particular.

Skeletal Maturation

While the proximate causes of the initiation of pubertal maturation remain obscure, the synchronization of reproductive and physical maturation in humans is striking. Gonadal steroid production plays an important role in the accelerating and decelerating phases of the adolescent growth spurt, with androgens more impor tant in the acceleration phase and estrogens more important in the deceleration phase.117 Estrogen receptor defects can be associated with prolongation of the acceleration phase even in men.118 It has been noted that in females variation in skeletal maturity and height decreases as menarche is approached with a close correlation between menarche and the attainment of adult pelvic dimensions.119121 The correlation between age at menarche and the attainment of adult pelvic size is demonstrable both within and between populations. Pelvic remodeling and the enlargement of the female birth canal are among the last events in skeletal growth and maturation, occurring as a consequence of gonadal estrogen production.122 Because early and late-maturing women converge on similar adult internal pelvic dimensions, it has been suggested that the timing of puberty is coordinated to ensure the attainment of an appropriate physical scale for successful reproduction.73,120 This perspective recognizes that physical constraints on successful female reproduction must be overcome before energetic constraints become salient. Therefore, it would make sense, from an adaptive perspective, for the timing of reproductive maturation to be conditioned on signals related to overall size and for shifts in metabolic energy allocation (such as increasing fat storage) to be consequences of puberty rather than causes.

The association of puberty with skeletal growth and maturation is also reflected in the close correlation between secular trends in height and age at menarche.123 Considerable evidence now documents the historical trend toward increasing height and decreasing menarcheal age in northern and western European populations during the nineteenth and twentieth centuries. Both height at menarche and final adult height in women increased during this period while weight for height at menar-che declined. The advance in pubertal timing thus seems to have been correlated with accelerated skeletal development, not with accelerated accumulation of adipose tissue.

end of puberty

The completion of pubertal development receives much less attention than its initiation. Conventionally, the pubertal phase of development is considered to end with the attainment of final adult height. There is considerable evidence that ovarian function continues to mature in women, however, long after this point.37,124 126 The frequency of ovulation and levels of gonadal hormones continue to rise in European and American women until the early to midtwenties. There is also evidence that the tempo of this later phase of reproductive maturation is correlated with the tempo of earlier maturation, so that women with late menarcheal ages take longer after menarche to attain their fully mature levels of ovarian function.37,127 This late phase of reproductive maturation in women is also associated with ovulation from smaller follicles and lower levels of fecundity.128 Although males typically take longer to initiate puberty and reach final adult height, there does not appear to be as prolonged a phase of reproductive maturation after adult height is attained. Adult sperm counts and concentrations are usually attained by that time and testosterone levels and muscle mass peak soon after. Whether the later phase of female reproductive maturation is properly understood as a part of pubertal development or as a different trajectory of adult reproductive function deserves fuller consideration.

Puberty, the process of reproductive maturation, is primarily a process of neuroendocrine maturation of the HPG axis. Some of the principal hormones of puberty and their relationships with each other and with parameters of physical maturation are summarized in Figure 4-3. After a long period of functional quiescence, the hypothalamus begins to secrete GnRH in an adult, pulsatile pattern, leading to increased production of pituitary gonadotropins, which in turn stimulate gonadal production of steroid hormones and gametes. Increasing gonadal steroid production leads to a broad array of developmental effects, including the stimulation of the adolescent growth spurt, the development of secondary sex characteristics, and sexual dimorphism in body composition and leptin production. The mechanisms that initially stimulate this reawakening of the HPG axis remain obscure but may normally be linked to signals reflecting physical size and skeletal maturity. In women, reproductive maturation, reflected in increasing indices of ovarian function and fecundity, continues for several years after the attainment of final adult height, while in men, reproductive maturation is largely complete at that time.

conclusion

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