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.

Though opioids do not have any inhibiting action on LHRH release before puberty -  as they do in the adult during stress -  the importance of other inhibitory neurotransmitters before and at the onset of puberty are still under discussion. For example, neuropeptide Y (NPY) plays several important roles in regulating brain function, including food intake behaviors. It seems to have an inhibitory action on LHRH release before puberty and this inhibiting effect decreases during and after puberty.

Quantitative or qualitative undernutrition can delay puberty and induce functional amenorrhea. Metabolic factors such as glucose and/or amino acids may act directly by modulating neurons involved in the control of LHRH release. Frisch and McArthur have postulated that a minimal weight, body mass index -  or even better, body fat mass -  is necessary for the onset of puberty in girls. Actually, leptin, which is the product of the Ob gene and is secreted by adipose tissue, increases in girls during the pubertal stages. Leptin receptors are present in the hypothalamic centers especially on NPY neurons. Leptin could serve as a link between the reproductive function and the energetic balance and participate in puberty onset and the maintenance of the adult hypothalamo-pituitary-ovarian axis. Leptin deficiency is associated with primitive IHH, while puberty can be induced by recombinant leptin. However, this induction cannot be obtained before a critical age, which suggests that leptin has to be considered more as a permissive factor not critical for the timing of puberty, rather than as a trigger of onset. Nevertheless, it seems useful to evaluate leptin blood level in girls in all situations of functional delay of puberty associated with negative energetic balance consecutive to general diseases or undernutrition, whether intentional or not.

The hypothalamic- somatotropic- insulin-like growth factor I axis and the hypothalamic-gonadotropic-ovarian axis present striking similarities and interactions during puberty. Both are controlled by a neurosecretory system, which includes pulsatile intermittent secretion (LHRH/GHRH), that will present developmental changes during puberty resulting in an amplification of pulsatile neurohormone secretion.

Both are controlled by multiple neural, hormonal and metabolic influences. Interactions between both endocrine systems are not yet well understood but puberty needs a functional growth hormone (GH) axis for full gonadal activation and onset of puberty is associated with a dramatic increase in linear height velocity. In girls, but probably also in boys, estrogens are responsible for the amplifying secretory activity of the GH axis during puberty. Estrogens will induce the height velocity spurt and then influence epiphyseal maturation. Estrogens have in fact a biphasic action on longitudinal growth. At first, very low levels of estrogens may stimulate bone growth indirectly through stimulation of the GH-IGF-1 axis, without affecting sexual maturation, and then higher levels of estrogens stimulate secondary sexual characteristics and epiphyseal fusion. Furthermore, GH secretion will contribute through IGF-1 action to complete ovarian development.