Delayed Puberty Physiological Aspects

Increase in the pulsatile release of LHRH is a necessary condition for puberty onset, as demonstrated 22 years ago by Knobil et al. in rhesus monkeys. Appropriate intermittent pulsatile secretion of LHRH stimulates the pituitary-ovarian axis and controls and maintains the menstrual cycle, allowing ovarian sex-steroid secretion and follicular maturation.

The LHRH neurosecretory system already works in the neonatal period, leading to gonadotropin stimulation and estrogenic secretion during the first 6 months of life. It then enters a dormant state during childhood with reduced LHRH pulses, low secretion of gonadotropins, and very low estrogenic secretion. The nocturnal increase in pulse frequency, pulse amplitude and baseline level of LHRH will initiate pubertal maturation, followed by prominent nocturnal increasing amplitude in mid-puberty until the time of the first ovulation. Then, in late puberty, the circadian fluctuation and pulse amplitude will decrease to the adult level.

During the early pubertal period, maturation of the LHRH neurosecretory system allows an increase in mean FSH levels, followed by an increase in mean LH levels. Basal levels of LH and amplitude and frequency of LH pulses increase with circadian fluctuations with an increasing ratio of basal LH/FSH.

The increase in gonadotropins stimulates ovarian estrogen secretion, which induces peripheral sexual changes and FSH suppression by a negative feedback effect. Periodic changes in the increasing secretion of estrogen will lead to the first vaginal bleeding (menarche) before any LH surge or ovulation. Regular adult ovulatory cycles will occur more than 1 year after menarche. The adult type of pulsatile LHRH release is mandatory for the positive feedback effect of estrogen after a priming effect of the gonadotropic cells by both pulsatile LHRH and increasing levels of estrogen, as illustrated in the model of anorexia nervosa.

Increase in pulsatile LHRH release clearly triggers puberty. However, the precise neuronal mechanisms of the reactivation of the LHRH pulse generator and the establishment of the adult type of pulsatile LHRH release remain incompletely elucidated. A classical hypothesis known as the 'gonadostat theory' has proposed that a differential sensitivity of the hypothalamus to the ovarian steroid negative feedback could explain the onset. However, even though the estrogen-dependent suppression of gonadotropin secretion is stronger in prepubertal girls than in adults, it cannot explain why children with ovarian dysgenesis or total ovarian destruction have very low levels of FSH and LH during infancy until the prepubertal period. In fact, one has to consider the hypothesis that sexual quiescence before the onset of puberty is the consequence of a central inhibition of LHRH release, independent of estrogen negative feedback, and that an autonomous increase in pulsatile LHRH release triggers puberty.

Several studies in female monkeys support the evidence that γ-aminobutyric acid (GABA) is the predominant inhibiting neurotransmitter during prepuberty that acts directly or indirectly on LHRH neurons through GABAA receptors. These receptors are present on LHRH neurons and also on glutamate neurons. Maturation of the hypothalamus and the neurosecretory LHRH system during development and puberty may involve decrease of GABA synthesis and secretion, allowing decrease in the direct inhibition on LHRH neurons and the liberation of the glutamate pathway able to stimulate indirectly LHRH release.