60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-pituitary–gonadal axis

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   Figure 1

   Model proposed by Harris in his 1955 monograph to illustrate the relationship between the external environment and the reproductive organs. Reproduced from Harris GW (1955) Neural Control of the Pituitary Gland. London, UK: Edward Arnold.
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   Figure 2

   Demonstration of the need of intermittent GnRH stimulation of the pituitary for sustained secretion of LH (closed data points) and FSH (open data points). A monkey rendered hypogonadotropic by a hypothalamic lesion was treated initially with an intermittent i.v. infusion of GnRH (1 μg/min for 6 min every h). On day 0 the pulsatile regimen was terminated and replaced with a continuous GnRH infusion (1 μg/min). On day 20 the pulsatile mode of GnRH stimulation was re-instituted. Reproduced, with permission, from Belchetz PE, Plant TM, Nakai Y, Keogh EJ & Knobil E (1978) Hypophysial responses to continuous and intermittent delivery of hypopthalamic gonadotropin-releasing hormone. Science 202 631–633. Copyright 1978, American Association for the Advancement of Science.
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   Figure 3

   Relationship between pulsatile secretion of GnRH (open data points) into hypophysial portal blood and corresponding episodes of pituitary LH secretion (closed data points) into the systemic circulation in an ovariectomized ewe. The arrow indicates the time at which the portal vessels were cut; arrow heads identify an episode (pulse) of LH or GnRH secretion. Reproduced with permission of Association for the Study of Internal Secretions, from Clarke IJ & Cummins JT (1982) The temporal relationship between gonadotropin releasing hormone (GnRH) and luteinizing hormone (LH) secretion in ovariectomized ewes. Endocrinology 111 1737–1739. Permission conveyed through Copyright Clearance Center, Inc.
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   Figure 4

   (A and B) Typical morphology of mouse GnRH neurons revealed by immunohistochemistry. (C) Two GnRH neurons in sheep. (D) A GnRH neuron from an adult mouse has been filled in situ with the dye, biocytin, in order to facilitate visualization of the entire length of the dendrites, which in the case of the lower process is seen to extend more than 500 μm. The two higher magnification insets on the right reveal a high density of dendritic spines. Reproduced, with permission, from Herbison AE (2015) Physiology of the adult gonadotropin-releasing hormone neuronal network. In Knobil and Neill's Physiology of Reproduction, 4th edn, pp 399–467. Eds TM Plant & AJ Zeleznik. San Diego, CA, USA. Copyright Elsevier (2015).
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   Figure 5

   The KNDy neuron model of the GnRH pulse generator proposed by Lehman, Coolen and Goodman. KNDy neurons reside within the arcuate nucleus (dotted purple circle) and express kisspeptin (Ks, green), neurokinin B (NKB, purple) and dynorphin (dyn, red). The model proposes that pulse generation by the network of KNDy neurons in the arcuate nucleus is achieved by a poorly understood reciprocating interplay of stimulatory NKB and inhibitory dyn inputs and an unidentified interneuron (gray). The output of the pulse generator is relayed to the GnRH neuronal network (blue) by a brief kisspeptin signal that evokes a discharge of GnRH into the hypophysial–portal circulation (shown in the lower portion of the figure). Note that the phenotype of each terminal indicates biologically relevant peptide and not selective transport of that peptide to the terminal. Similarly, the triple colored KNDy neurons indicate co-expression of the three peptides and not location within the cell body. R_Ks, Ks receptor; R_NKB, NKB receptor, R_DYN, dyn receptor. Reproduced, with permission, from Goodman RL & Inskeep EK (2015) Control of the ovarian cycle of the sheep. In Knobil and Neill's Physiology of Reproduction, 4th edn, pp 1259–1305. Eds TM Plant & AJ Zeleznik. San Diego, CA, USA. Copyright Elsevier (2015).
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   Figure 6

   Chronic intermittent neurochemical stimulation of juvenile male monkeys with N-methyl-dl-aspartate (NMDA) readily induces a precocious pubertal pattern of pulsatile GnRH release as reflected by the emergence of corresponding discharges of LH (open data points) and testicular testosterone (closed data points) secretion. Testicular and motile epididymal sperm were typically observed after 16–26 weeks of NMDA stimulation. Means±s.e.m. (n=4) are shown. Arrows indicate time of i.v. injections of NMDA. Reproduced, with permission, from Plant TM, Gay VL, Marshall GR & Arslan M (1989) Puberty in monkeys is triggered by chemical stimulation of the hypothalamus. PNAS 86 2506–2510. Copyright (1989) National Academy of Sciences, USA.
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   Figure 7

   Ovarian tissue transplanted subcutaneous to the abdomen of an adult male rhesus monkey (#7082) castrated post-pubertally and receiving anti rejection therapy with cyclosporine A exhibits regular cycles of folliculogenesis and ovulation followed by a normal luteal phase. Numbers on the peaks in LH indicate maximum concentration of the gonadotropin on that day. Reproduced, with permission of Association for the Study of Internal Secretions, from Norman RL & Spies HG 1986 Cyclic ovarian function in a male macaque: additional evidence for a lack of sexual differentiation in the physiological mechanisms that regulate the cyclic release of gonadotropins in primates. Endocrinology 118 2608–2610. Permission conveyed through Copyright Clearance Center, Inc.
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   Figure 8

   A model for the seasonal control of pulsatile GnRH release. The duration of the photoperiod is relayed by melatonin to melatonin receptors (MT1) in the thyrotrophs of the pars tuberalis (PT), and further relayed by thyrotropin (TSH) to the mediobasal hypothalamus, where the arcuate nucleus KNDy neurons are located. TSH upregulates the expression of the genes encoding deiodinases 2 and 3 (DIO2 and DIO3), in specialized ependymal cells (tanycytes) lining the base of the third ventricle (3v). The deiodinase enzymes convert thyroid hormone (T₄) into the active metabolite, tri-iodothyronine (T₃), and the increase in thyroid hormone activity dictates the level of GnRH pulsatility, which in turn governs the gonadotropin output from the gonadotrophs in the pars distalis (PD). TSH is considered to reach the MBH via the 3v and/or from brain capillaries (Cp). Reproduced, with permission, from Hazlerigg D & Simonneaux V (2015) Seasonal reproduction in mammals. In Knobil and Neill's Physiology of Reproduction, 4th edn, pp 1575–1604. Eds TM Plant & AJ Zeleznik. San Diego, CA, USA. Copyright Elsevier (2015).

• © 2015 Society for Endocrinology