The current view is that central inhibition of GnRH release results in a prepubertal "quiescence" of gonadotropin secretion, and the onset of puberty results from the removal of this central restraint (28). Mechanisms related to the control of the onset of puberty have been extensively studied in various rodent models. However, in rodents, the interval between infancy and puberty is condensed, and these two developmental phases cannot be separated by a clearly demarcated juvenile phase of quiescence of the hypothalamic-pituitary-gonadal axis (29,30). Therefore, some of the neurobiological mechanisms responsible for restraining the GnRH pulse generator in late infancy and for holding it in check during the prepubertal period, as well as those pathways that reaugment pulsatile GnRH release, all of which are aspects with significant relevance to human puberty, can be studied only in primate models.
y-Aminobutyric acid (GABA) is the dominant inhibitory neurotransmitter in the hypothalamus, but in primates, direct innervation of GnRH neurons by GABA neurons has not been demonstrated. It is possible that the inhibition of GnRH neurons by GABA is mediated via glutamergic neurons, because a reciprocal innervation between GABA-ergic and glutamatergic neurons has been found (31). During development, the GABA concentration and the number of GABA-ergic neurons increase from embryonic day 13 to the second postnatal week, which is then followed by a decline in the third postnatal week (32). Before the onset of puberty, GABA release in the preoptic area decreases in female rats (33), and in the rhesus monkey, GABA release in the median eminence decreases concomitant with the pubertal increase of GnRH secretion (34).
The major excitatory amino acid neurotransmitter involved in the regulation of GnRH release is glutamate. Glutamatergic neurons provide axodendritic synaptic input to the hypothalamic GnRH neuronal network (31). GnRH pulsatile release is regulated via two amino acid receptors: (1) inotropic receptors, which are coupled to ion channels (including receptor for N-methyl-D-aspartate, NMDA), and (2) metabotropic receptors, which are coupled to G proteins (for review see ref. 35). The pubertal increase in GnRH secretion possibly results from increased glutaminase activity, the enzyme responsible for converting glutamine to glutamate. Furthermore, in male rats, an increase in NMDA receptor activity is seen before the onset of puberty, probably reflecting increased glutamate activity (36). These peripubertal changes suggest that the neurotransmitter glutamate has a significant role in stimulation of GnRH release at the onset of puberty.
Neuropeptide Y (NPY) is involved in many CNS functions, including appetite control and reproduction. Infusion of NPY into the median eminence stimulates GnRH release in pubertal, but not in prepubertal, female monkeys, suggesting that NPY contributes to the pubertal process (37). Furthermore, in male rhesus monkeys, the postnatal pattern of GnRH pulse generator activity is inversely related to that of NPY gene and protein expression in the mediobasal hypothalamus, and central administration of an NPY Y1 receptor antagonist to juvenile animals elicits precocious GnRH release (38), suggesting a central role for NPY in the break restraining the onset of puberty in primates.
The peptide leptin exerts it effects in the CNS through NPY neurons by decreasing NPY-ergic signaling (39,40). Absence of leptin signaling results in obesity and infertility, whereas leptin treatment decreases food intake and restores reproductive functions. Thus, in fasting, leptin levels decrease and gonadotropin secretion is suppressed. These findings imply that nutrition, especially fat tissue and leptin, could contribute to puber-tal development. Clinical observations have further supported a role for leptin signaling in the onset of puberty, e.g., leptin or leptin receptor gene mutations result in the delay or absence of pubertal development on boys and girls (41,42) and, in a 12-yr-old girl with congenital leptin deficiency, treatment with recombinant leptin was followed by a pubertal pattern of LH release (43). These observations have led to the speculation that leptin could serve as the somatic signal that inhibits hypothalamic NPY tone at the termination of prepuberty and, thereby, triggers the pubertal reaugmentation of the GnRH pulse generator activity. However, leptin is probably not an important metabolic trigger for the onset of puberty, because leptin levels remain constant in the prepubertal and postpubertal stages of development in primates (44,45) and, further, leptin gene expression in the hypothalamus is unchanged during development in the rat (46,47). However, this conclusion does not detract from the hypothesis, derived from rat studies, that leptin serves as a permissive signal that allows a developmental program in GnRH pulse generator activity to unfold (47).
Several growth factors secreted by glial cells regulate GnRH release, implying that the glial tissue may be involved in the regulation of GnRH release. However, the role of glia in triggering puberty remains uncertain. Of these growth factors, transforming growth factor-a (TGF-a) stimulates GnRH release and stimulates glial cells to produce bioactive substances, such as prostaglandin E2 (PgE2), which, in turn, stimulate the release of GnRH (48). A role for TGF-a has also been postulated in the pathogenesis of precocious puberty associated with hypothalamic lesions: lesion-induced astrogliosis may be responsible for increased TGF-a in the hypothalamus.
The opioidergic system also plays a role in the control of GnRH secretion, because in humans, opioid peptides decrease gonadotropin levels (49). Furthermore, the opiate receptor antagonist, naloxone, increases LH secretion after estradiol suppression in normal adult men and women, but it does not have this effect in prepubertal boys (25). Thus, the opioidergic system becomes operative during pubertal development and possibly mediates, in part, the negative feedback action of sex steroids on GnRH.
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