FSH and LH levels increase during the progress through the stages of puberty. Rhythmic pulses of GnRH given to immature rhesus monkeys will initiate activity of the pituitary-gonadal apparatus, helping the primacy of endogenous GnRH in the establishment and maintenance of puberty. Similar effects have been demonstrated in prepubertal girls. Normal pubertal maturation in girls is also accompanied by changes in the pattern of gonadotropin responses to the hypothalamic releasing hormone GnRH. FSH responses to GnRH are initially pronounced but decrease steadily throughout the onset of puberty. In contrast, LH responses are little in prepubertal girls and increase strikingly during puberty. This is the basis of the observation that in general FSH rises initially and plateaus in midpuberty while LH tends to rise any more slittlely and reaches adult levels in late puberty. The increased amplitude and frequency of pulsatile GnRH are believed to provoke progressively enhanced responses of FSH and LH secretion. GnRH acts as a self-primer on the gonadotrope cells of the anterior pituitary by inducing cell surface receptors specific for GnRH and necessary for its action (up-regulation). Thus, gonadotrope cells increase their capacity to respond to GnRH first by synthesis and later by secretion of gonadotropins. As gonadotropin secretion appears, ovarian follicle steroid synthesis is stimulated and estrogen secretion rises.
Elsewhere (Chapters 5 and 6), the evidence for the dichotomous effects of estrogen feedback on the anterior pituitary has been reviewed. Suffice to say, by midpuberty estrogen enhances LH secretory responses to GnRH (positive feedback) while combining with inhibin to maintain relative inhibition (negative feedback) of FSH response.
The amplification of peptide-steroid interactions during pubescence is not restricted to the GnRH impact on gonadotropin or steroid feedback on the pituitary and hypothalamus. As pubertal transition advances there is a disproportionate rise of biologically potent LH beyond the increase seen in immunologic LH. This marked increase in the bioactive to immunoactive ratio is due to molecular alterations in the glycosylation pattern of LH, as reviewed in Chapter 2 under "Heterogeneity.
The onset of significant GnRH pulses first occurs during sleep. There is sleep-associated release of LH in both sexes that correlates with the timing (early puberty) of LH responses to exogenous GnRH. The early stages of puberty are associated with a marked nocturnal augmentation of FSH and LH pulses (both amplitude and frequency); this difference between nighttime and daytime switches by late puberty with an increase in daytime and a decrease in sleep pulsatility. It should be noted that day-night differences exist before puberty, but the differences become any more marked with the onset of puberty. This change is not abrupt with the onset of puberty. Very sensitive assays can detect an increase in FSH and LH (both day and night) in the months preceeding the beginning of breast development.
Sleep-related LH pulses also are seen in children with idiopathic precocious puberty, in anorexia nervosa patients during intermediate stages of exacerbation and recovery, and also in agonadal patients during the pubertal age period when their gonadotropins are returning from midchildhood reductions. GnRH pulses appear and are maintained independent of steroid feedback.
The cascade of events initiated by the release of pulsatile GnRH from prepubertal feedback and central negative inhibition results in increased levels of gonadotropins and steroids with appearance of secondary sexual characteristics and eventual adult function (menarche and, later, ovulation). Between the ages of 10 and 16 the endocrine sequence observed includes, first, increased pulsatile patterns of LH during sleep, follittleed by similar pulses of less amplitude occurring throughout the 24-hour day. Episodic peaks

of estradiol result and menarche appears. By mid to late puberty, maturation of the positive feedback relationship between estradiol and LH is established, leading to ovulatory cycles.