Posts Tagged ‘GH’

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

It is well established that food restriction delays pubertal onset, whereas refeeding abolishes this delay. In addition, murine and human genetic models of leptin deficiency fail to enter puberty, and treatment with leptin can establish a pulsatile secretory pattern of gonadotropins that is characteristic of early puberty. The female transgenic skinny mouse, which is an in vivo model of chronic hyperleptinemia in the absence of adipose tissue, enters puberty precociously. Data regarding the effects of leptin administration on pubertal onset are controversial. It has been shown that intracerebroventricular leptin administration prevents the delay in vaginal opening induced by chronic food restriction in the rat. By contrast, it has been found that artificially raised leptin levels are not sufficient to abolish the delay of pubertal onset caused by food deprivation. Thus, the question arises whether leptin might be a ‘permissive factor’ (tonic mediator), whose concentration above a certain threshold is required for pubertal onset, or a ‘trigger’ (phasic mediator) that determines the pubertal spurt through a rise in serum concentration at an appropriate time of development.

The temporal correlation between increases in leptin concentration and the initiation of LH pulsatility over the peripubertal period has been studied in several species. In men it has been shown that leptin levels rise by 50% before the onset of puberty, and decrease to baseline after the initiation of puberty. Other cross-sectional studies showed that age has a significant effect on serum leptin concentrations through prepuberty into early puberty. It has been reported repeatedly that there are no significant changes in leptin levels over the peripubertal period in male rhesus macaques; however, more recent studies performed in castrated male monkeys showed that nocturnal levels of leptin increase just before the nocturnal prepubertal increase in pulsatile LH release.

A possible explanation for such contrasting reports in monkeys could be the sampling of nocturnal rather than diurnal blood. Indeed, in primates, prepubertal changes in nocturnal LH release occur approximately five months before diurnal variations. Another reason might be the use of different models: agonadal monkeys were treated with intermittent exogenous GnRH to sensitize the pituitary to endogenous GnRH, thus magnifying the LH release independently from gonadal influences. In the same study, the leptin rise was accompanied by a sustained increase in nocturnal GH and IGF-I concentrations before the onset of puberty, which is defined as the increase in nocturnal pulsatile LH secretion. It is not clear whether one of the two metabolic signals has a predominant role or whether both act in concert. Indeed, it has been reported that the maximum increase in GH and leptin occurs simultaneously, about 10–30 days before the onset of puberty. However, these conclusions were based on results from a study that used castrated animals, which in the strictest sense do not undergo puberty. Thus, it remains to be clarified whether the same mechanisms that result in the onset of the pubertal rise in LH secretion in castrated animals are also responsible for the reactivation of the HPG axis in intact animals.

The sexual dimorphism in leptin concentrations becomes evident after puberty. In males, leptin levels rise throughout childhood, reach a peak in the early stages of puberty and then decline, whereas they increase steadily during pubertal development in females. Consequently, leptin levels are three to four times higher in females than in males. The reason for this postpubertal sexual dimorphism in leptin levels is not clear. After puberty, serum testosterone and testicular volume are inversely related to leptin levels in males, whereas in females, when adjusted for adiposity indexes, estradiol is directly correlated with leptin levels. These observations indicate that androgens and estradiol might account, at least in part, for the gender differences in circulating leptin levels. This is also supported by in vitro studies which show that androgens and estrogens inhibit and stimulate leptin expression and release from human adipocytes in culture, respectively.

Thus, puberty represents a turning point in the sexual dimorphic relationships between the HPG axis and leptin by determining the steroid milieu that leads to a different regulation of leptin secretion in the sexes.

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