1. Puberty in Non-human Primates and Man
Chapter 32
Puberty in Non-human Primates and Man
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2. FIGURE 32.1 Moment-to-moment changes in circulating LH concentrationsf at 4–7 weeks of age in six infantile female (top three panels) and two infantile male (lower panel) rhesus monkeys that were bilaterally gonadectomized at 1 week of age. Arrows indicate increments in LH identified as pulses by PULSAR. Note that the frequency of LH pulses, and presumably therefore of GnRH discharges, in agonadal infantile females is markedly slower than that in agonadal males of similar age. Source: Reprinted with permission from Ref. 210.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

3. FIGURE 32.2 Ovulatory ovarian cycles in two premenarcheal rhesus monkeys induced by a chronic intermittent intravenous infusion of GnRH (1 pulse/h) 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 unshaded bar labeled E2) failed to induce a gonadotropin surge. The occurrence of menstruation is indicated by M. Source: Reprinted with permission from AAAS from Ref. 21.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

4. FIGURE 32.3 Peripubertal developmental changes in GnRH pulse generator activity, as reflected by nocturnal frequency of LH secretory episodes, obtained by aligning data for five agonadal male monkeys to the onset of the pubertal resurgence in pulsatile GnRH release (day 0). Heightened pituitary responsiveness to GnRH stimulation was maintained by a “priming” infusion of pulsatile GnRH between assessment windows. Ages of animals at day 0 ranged from 24 to 29 months. PRE, values for the earliest assessment window examined in each monkey, which ranged from 14 to 22 months of age; asterisk, significantly different from PRE (P < 0.05). N for each time point varies from 3 to 5. Source: Reprinted with permission from Ref. 221.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

5. FIGURE 32.4 A model of the impact of the neurobiological brake on pulsatile GnRH release during juvenile development in males (above) and females (below). Insets indicate frequency of pulsatile GnRH release at respective stages of development. Source: From Plant TM. Control of onset of puberty in primates. Top Endocrinol 2002; 20 Chapterhouse Codex Ltd.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

6. FIGURE 32.5 Time courses of circulating mean LH (top panel) and FSH (bottom panel) concentrations 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). Vertical bars above data points indicate SEMs. Source: The data for males are redrawn with permission, from Ref. 49.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

7. FIGURE 32.6 This figure is reproduced in color in the color plate section. Confocal images illustrating developmental changes in GnRH (top panels) and kisspeptin (middle panels) neurons (immunopositive perikarya and fibers) in the MBH at the mid-tuberal level during postnatal development in the agonadal male rhesus monkey. The lower panels show the merged images. A hemi-hypothalamic section is shown for an infant (left-hand panels), juvenile (center panels), and adult (right-hand panels) animal; stages of postnatal development corresponding to the onoff- on pattern of GnRH pulse generator activity in primates. Note that kisspeptin immunoactivity is reduced in the juvenile MBH at a time when GnRH pulsatility is arrested but GnRH immunoactivity in the median eminence is maintained during this phase of development. In most cases the ependymal lining of the third ventricle is visible on the right-hand boundary of each hemi-section. Arrow indicates kisspeptin neurons in the arcuate nucleus. Scale bar, 100 μm. Source: Parts of this montage have been reprinted with permission from Refs 170,266.
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8. FIGURE 32.7 The hypogonadotropic state of the agonadal juvenile male monkey in comparison with that of the infant and pubertal state (panel A) is associated with a correspondingly low pituitary LH protein and LHβ mRNA content (panels B and C, respectively) but, interestingly, the content of GnRH peptide and mRNA in the MBH at this stage of development is maintained (panels D and E, respectively). Two histograms are shown for the juvenile stage of development because two separate groups of animals at this stage of development were studied: one was used in a study comparing infants and juveniles267 (closed histogram) and one was used to compare juvenile and pubertal monkeys250 (gray histogram). Means and SE are shown. Source: Data for serum LH concentration, pituitary LH content, MBH GnRH peptide, and mRNA content redrawn from Refs 250, 259, 267. Data for LHβ; Winters SJ, Plant TM, unpublished observations.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

9. FIGURE 32.8 Pulsatile kisspeptin release in the region of the pituitary stalk and median eminence of ovarian intact prepubertal (panels (A) and (B)) and pubertal (panels (E) and (F)) monkeys, and ovariectomized animals at similar stages of development (panels (C) and (D), and (G) and (H), respectively) as assessed by microdialysis. Note that the scale on the y-axis in panels (E)–(H) (pubertal monkeys) is 10-fold higher than that in panels (A)–(D) (prepubertal monkeys). The dark phase of the light–dark cycle is indicated on the top of each of the eight panels with a dark solid line. Asterisks indicate increments in kisspeptin identified as pulses by PULSAR. Source: Modified with permission from Ref. 273.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

10. FIGURE 32.9 The number of kisspeptin neurons per hemi crosssection throughout the arcuate nucleus of the agonadal infant male monkey (closed histograms) is greater than that in juveniles monkeys of similar gonadal stature (open histograms). Section number indicates distance posterior from the optic chiasm with section 1, the first retrochiasmatic section. The distance between two sequentially numbered sections was 250 μm. * p < Source: Reprinted with permission from Ref. 266.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

11. FIGURE 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 response to the experiment in which kisspeptin was administered is shown by the 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 two repriming pulses of GnRH are shown for the kisspeptin experiment (administered on Day 3 at 1100 and 1200 h, open arrow). The priming infusion before and after the kisspeptin infusion produces 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 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. Source: Reprinted with permission from Ref. 276.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

12. FIGURE 32. 11 A model for the control of the timing of puberty
FIGURE A model for the control of the timing of puberty. The role of kisspeptin signaling is posited to be a critical component of the neural machinery that generates pulsatile gonadotropin-releasing hormone (GnRH) release from the hypothalamus (the hypothalamic GnRH pulse generator). In this model, the hypothalamic GnRH pulse generator resides in the arcuate nucleus (ARC) and the output of the pulse generator is relayed to GnRH terminals in the median eminence (ME) by kisspeptin projections arising from KNDy neurons in the ARC. During infancy (left panel), GnRH pulse generator activity is robust, leading to intermittent release of kisspeptin in the ME, resulting in a corresponding pattern of GnRH release into the portal circulation. This, in turn, drives pulsatile gonadotropin secretion. In the transition from infancy to the juvenile phase of development (middle panel), a neurobiological brake restrains the GnRH pulse generator and pulsatile release of kisspeptin in the ME is markedly suppressed. This leads to reduced GnRH release and to a hypogonadotropic state in the juvenile period. Puberty is triggered when the neural brake is released and GnRH pulse generator activity with robust intermittent release of kisspeptin in the ME is reactivated (right panel). According to this model, the mystery of primate puberty lies in the nature of the neurobiological brake and in the mechanism that times its application during infancy and its release at the end of the juvenile phase of development. It should be noted that the ability of the postnatal gonad to respond fully to gonadotropin stimulation is not acquired until the juvenile stage of development, by which time luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion is low as a result of the GnRH pulse generator being brought into check. The thickness of the arrows (T, testosterone and E, estradiol) from gonad to ARC indicating negative feedback by the testis and ovary, respectively, reflects the degree of gonadal steroid inhibition exerted on LH secretion at these three stages of development. AC, anterior commissure; AP, anterior pituitary gland, ARC, arcuate nucleus; OC, optic chiasm; ME, median eminence; MMB, mammillary body. Source: Reprinted from Ref. 168.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

13. FIGURE Release of GnRH (A) and (D), GABA (B) glutamate (C), and kisspeptin (E) in the stalk–median eminence of ovariectomized pre-, early- and mid-pubertal female rhesus monkeys, as measured in hypothalamic perfusates. GnRH (A), GABA (B), and glutamate (C) were measured in the same samples obtained in one study280 and GnRH (D) and kisspeptin (E) were measured in the same samples obtained in another study.272 In the first study (A)–(C), samples were collected in the morning only, whereas in the second study (D and E), samples were collected in the morning (open bars) and evening (closed bars). *p < 0.05 versus prepubertal; **p < 0.01 versus prepubertal; ***p < versus early pubertal; +p < 0.05 versus prepubertal; ++p < 0.01 versus early pubertal; +++p < versus early pubertal; a p < 0.05 versus AM; aa p < 0.01 versus Am, aaa p < versus AM. N = 5–25 (see individual bars). Source: Reproduced with permission from Refs 272,280.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

14. FIGURE Panel (A): A brief 10 min infusion of the GABAA antagonist, bicuculline (BM) into the stalk–median eminence region (dark shaded vertical bar) stimulates kisspeptin release in a prepubertal female monkey. Panel (B): Coinfusion of the kisspeptin receptor antagonist, peptide 234 (P234), and BM (light shaded vertical bar) blocks the action of the GABAA antagonist and elicits GnRH release. Source: Reprinted with permission from Ref. 286.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

15. FIGURE Developmental changes in serum LH concentrations (solid circles) in four female monkeys ovariectomized at approximately 13 months of age: two served as control (top two panels) and two were treated with IGF-1 (60–300 μg/ day) from 16 to 18 months of age (bottom two panels). All four animals were replaced with estradiol starting at approximately 25 months of age (week 0). For this purpose, steroid-containing pellets were implanted subcutaneously every 6 weeks and resulted in “spikes” of circulating estradiol (continuous line) lasting approximately 3 weeks. The doses of estradiol used (low, intermediate, and high) are shown for each monkey. Reproduced by permission from Ref © Society for Endocrinology 2005.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

16. FIGURE Failure of pinealectomy to induce a precocious pubertal reactivation of the GnRH pulse generator (as reflected by circulating LH concentrations) in agonadal male rhesus monkeys. Data for pinealectomized animals (•- •, N = 3) are compared to those from a similar group of pineal-intact monkeys (O–O, N = 3). Arrows indicate the age at pinealectomy. The time courses of FSH secretion in the two groups of animals (not shown) were similar to that of LH. Redrawn with permission from Ref. 208.
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17. FIGURE Time courses of circulating mean LH (top panel) and FSH (bottom panel) concentrations from birth until 166–180 weeks of age in a group of rhesus monkeys orchidectomized at 1 week of age (stippled area, N = 4) and in a group of similar agonadal males adrenalectomized at 4 weeks of age (•: N = 3, birth to 40 weeks; N = 5, 41–180 weeks). The apparent earlier initiation of the pubertal mode of open-loop gonadotropin secretion in adrenalectomized animals is attributable to one animal. In the remaining four adrenalectomized animals, the pubertal rise in FSH secretion was not observed until 136 weeks of age or later. Vertical lines above data points indicate SEMs. The data for castrated males are redrawn with permission from Ref. 49, and those for castrated/adrenalectomized males are, in part, redrawn with permission from Ref. 252.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition