Neuroendocrine control of the onset of puberty

Abstract

This chapter is based on the Geoffrey Harris Memorial Lecture presented at the 8th International Congress of Neuroendocrinology, which was held in Sydney, August 2014. It provides the development of our understanding of the neuroendocrine control of puberty since Harris proposed in his 1955 monograph (Harris, 1955) that "a major factor responsible for puberty is an increased rate of release of pituitary gonadotrophin" and posited "that a neural (hypothalamic) stimulus, via the hypophysial portal vessels, may be involved." Emphasis is placed on the neurobiological mechanisms governing puberty in highly evolved primates, although an attempt is made to reverse translate a model for the timing of puberty in man and monkey to non-primate species.

Keywords: GnRH pulse generation; GnRH surge generation; Human; Kisspeptin; Puberty; Rat; Rhesus monkey; Sheep.

Figure 1

Ovulatory ovarian cycles in two premenarcheal rhesus monkeys induced by a chronic intermittent intravenous infusion of GnRH (1 pulse/hr) initiated on day 0. Note that the pituitary-ovarian axis reverted to a prepubertal state following termination of GnRH treatment on days 92 and 111, respectively, and subsequent administration of estradiol (indicated by the open bar labeled E2) failed to induce a gonadotropin surge. The occurrence of menstruation is indicated by M. (Reprinted with permission from AAAS from Ref. 20).

Figure 2

Premature activation of the hypothalamic GnRH-pituitary-Leydig cell axis of a prepubertal male rhesus monkeys by repetitive neurochemical stimulation with NMDA administered iv once every 3 h for 8 weeks. NMDA stimulation was initiated at week 0 when the animal was between 15 – 16 months of age: 1.5 – 2 years before the expected age of puberty. Although intermittent stimulation with NMDA was maintained without interruption, circulating LH and testosterone concentrations were only monitored during a 6 h window at weekly or biweekly intervals. The right hand panel shows pulsatile profiles of plasma LH and testosterone levels in a male monkey during spontaneous puberty. Reprinted from Ref. . Testicular sperm and motile epididymal sperm are typically observed in juvenile monkeys after 16–26 weeks of NMDA stimulation [25].

Figure 3

LH responses in agonadal GnRH primed juvenile male rhesus monkeys (N=4) during the last two priming infusions of GnRH (administered on Day 1 at 0900 and 1000 h, open arrows) and during brief hourly intravenous infusions of either kisspeptin or vehicle (black arrows) initiated on Day 1 at 1100 h and maintained for 48 h. The LH response to kisspeptin is shown by black data points. Note that although the kisspeptin and vehicle injections were administered without interruption for 48 h, only those injections to which the LH response was monitored are indicated. The LH response to the first 2 re-priming pulses of GnRH are shown for the kisspeptin experiment (administered on Day 3 at 1100 and 1200 h, open arrow). The GnRH priming infusions before and after kisspeptin administration produced a pulsatile discharge of LH comparable to that observed spontaneously in pubertal animals. The response to repetitive kisspeptin administration was abolished by concomitant treatment with a GnRH receptor antagonist (data not shown), indicating the intermittent kisspeptin infusion provides the GnRH neuronal network of the juvenile hypothalamus with a stimulus similar to that produced endogenously by the GnRH pulse generator in pubertal animals. Vertical lines above data points indicate SEM. Reprinted with approval from Ref. .

Figure 4

Time courses of circulating LH (top panel) and FSH (bottom panel) concentrations (means±SE) determined in blood samples collected in the morning from birth until 142–166 weeks of age in rhesus monkeys ovariectomized (●, N = 6) and orchidectomized (stippled area, N = 4) at 1 week of age. Note that the prepubertal hiatus in the secretion of FSH, and LH to a lesser extent, in agonadal females is truncated in comparison to that in castrated males. This difference between agonadal males and females, which presumably underlies the earlier onset of female puberty, is further exaggerated when nighttime concentrations of LH and FSH are examined (not shown). (The data for males are redrawn with approval, from Ref. 64).

Figure 5

Time courses of circulating LH concentrations (mean±SE) in male guinea pigs bilaterally orchidectomized at 2 days of age (closed data points) and in intact controls (open data points). LH secretion increased dramatically immediately after castration to plateau in the adult range by 44 days of age. Also, note the unremarkable changes in circulating LH concentrations in intact males during the period of study (birth to 98 days of age). Reprinted with approval from Ref. .

Figure 6

A model for the control of GnRH pulse generator activity and the resulting drive to the pituitary-gonadal-axis in primates. Kisspeptin (KP, green) signaling is posited to be a critical component of the neural machinery essential for generation of pulsatile GnRH (red) release in the hypothalamus. In this model, the GnRH pulse generating mechanism resides in the arcuate nucleus (ARC) and the output of this signaling is relayed to GnRH terminals in the median eminence (ME) by KP projections arising from perikarya in the ARC. During infancy (left panel), ARC GnRH pulse generating activity is robust leading to intermittent release of KP in the ME, resulting in a corresponding pattern of GnRH release into the portal circulation. This, in turn, drives pulsatile gonadotropin (LH and FSH) secretion. In the transition from infancy to the juvenile phase of development (middle panel), a neurobiological brake holds the ARC GnRH pulse generating mechanism in check and pulsatile release of KP in the ME is markedly suppressed. This leads to reduced GnRH release and to a hypogonadotropic state in the juvenile period. The onset of puberty is initiated when the brake is removed and GnRH pulse generation with robust intermittent release of KP in the ME is reactivated (right panel). According to this model, the mystery of primate puberty lies in the molecular basis of the neurobiological brake, and the mechanism that times the application of the brake during infancy and its release at the end of the juvenile phase of development. Two possible timing models are proposed. The first is based on the idea of a pubertal clock resident in the primate brain (represented by the clock face in the hypothalamus at the stages of development). The second, posits that a growth tracking device in the brain, termed a somatometer (SM, indicated by the grey boxes) is able to monitor a circulating signal of somatic development (perhaps skeletal, as shown in this model) and thereby co-ordinates the reactivation of the GnRH pulse generator with the impending attainment of adult somatic size. The thickness of the blue (T, testosterone) and gold (E, estradiol) arrows indicating negative feedback by the testis and ovary, respectively, reflect the degree of gonadal steroid inhibition exerted on LH secretion at these three stages of primate development. It should be noted that the ability of the post natal gonad to respond fully to gonadotropin stimulation is not acquired until the juvenile stage of development by which time the hypothalamic GnRH pulse generator has been brought into check and a hypogonadotropic state prevails. AC, anterior commissure; AP, anterior pituitary gland, ARC, arcuate nucleus; OC, optic chiasm; ME, median eminence; MMB, mammillary body. Modified from Ref. .