Mechanisms underlying episodic gonadotropin-releasing hormone secretion

The episodic secretion of gonadotropin-releasing hormone (GnRH) is crucial for fertility, but the cellular mechanisms and network properties generating GnRH pulses are not well understood. We will explore three primary aspects of this intermittent hormonal signal: the source of rhythm(s), the possible mechanisms comprising oscillator(s), and how GnRH neurons are synchronized to produce a pulse of hormone release into the pituitary portal blood. Current knowledge will be reviewed, and hypotheses and working models proposed for future studies.

[1]  Y. Mori,et al.  Electrophysiological approach to the hypothalamic GnRH pulse generator. , 2019, Journal of reproduction and fertility. Supplement.

[2]  S. Wray,et al.  In Situ GABAergic Modulation of Synchronous Gonadotropin Releasing Hormone-1 Neuronal Activity , 2002, The Journal of Neuroscience.

[3]  S. Moenter,et al.  Estradiol feedback alters potassium currents and firing properties of gonadotropin-releasing hormone neurons. , 2002, Molecular endocrinology.

[4]  J. Levine,et al.  Progesterone Receptors as Neuroendocrine Integrators , 2001, Frontiers in Neuroendocrinology.

[5]  Immortalized gonadotropin‐releasing hormone neurons secrete γ‐aminobutyric acid – evidence for an autocrine regulation , 1998, The European journal of neuroscience.

[6]  W. S. Lee,et al.  Luteinizing hormone-releasing hormone neurons express Fos protein during the proestrous surge of luteinizing hormone. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[7]  H. Hiruma,et al.  Naloxone increases the frequency of the electrical activity of luteinizing hormone-releasing hormone pulse generator in long-term ovariectomized rats. , 1991, Neuroendocrinology.

[8]  T. Hökfelt,et al.  Immunohistochemical mapping of nitric oxide synthase in the rat hypothalamus and colocalization with neuropeptides , 1996, Journal of Chemical Neuroanatomy.

[9]  J. Roberts,et al.  Gonadotropin-Releasing Hormone and NMDA Receptor Gene Expression and Colocalization Change during Puberty in Female Rats , 1996, The Journal of Neuroscience.

[10]  D. Pfaff,et al.  The Physiology of Reproduction, Second Edition , 1995 .

[11]  K. Parker,et al.  The nuclear receptor steroidogenic factor 1 is essential for the formation of the ventromedial hypothalamic nucleus. , 1995, Molecular endocrinology.

[12]  K. Catt,et al.  Control of action potential-driven calcium influx in GT1 neurons by the activation status of sodium and calcium channels. , 1999, Molecular endocrinology.

[13]  F. Dudek,et al.  Genetic targeting of green fluorescent protein to gonadotropin-releasing hormone neurons: characterization of whole-cell electrophysiological properties and morphology. , 2000, Endocrinology.

[14]  A. Gorman,et al.  Intracellular calcium and the control of neuronal pacemaker activity. , 1981, Federation proceedings.

[15]  F. Wondisford,et al.  Migratory arrest of gonadotropin-releasing hormone neurons in transgenic mice. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[16]  A. R. Midgley,et al.  Dynamics of gonadotropin-releasing hormone release during a pulse. , 1992, Endocrinology.

[17]  T. Uemura,et al.  Neuronal Synchronization and Ionic Mechanisms for Propagation of Excitation in the Functional Network of Immortalized GT1–7 Neurons: Optical Imaging with a Voltage‐Sensitive Dye , 1997, Journal of neuroendocrinology.

[18]  J. Marshall,et al.  The role of changing pulse frequency in the regulation of ovulation. , 1993, Human reproduction.

[19]  F. Ashcroft,et al.  ATP-sensitive K+ channels: a link between B-cell metabolism and insulin secretion. , 1990, Biochemical Society transactions.

[20]  K. Aguan,et al.  Histochemical localization of nitric oxide neurons in the hypothalamus: association with gonadotropin-releasing hormone neurons and co-localization with N-methyl-D-aspartate receptors. , 1995, Neuroendocrinology.

[21]  Martin Straume,et al.  Gonadotropin-releasing hormone neurons generate interacting rhythms in multiple time domains. , 2003, Endocrinology.

[22]  J. Pelletier,et al.  Multiunit activity in the anterior median eminence and adjacent areas of the hypothalamus of the ewe in relation to LH secretion. , 1981, Neuroendocrinology.

[23]  K. Catt,et al.  Coordinate regulation of gonadotropin-releasing hormone neuronal firing patterns by cytosolic calcium and store depletion. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[24]  T. Plant,et al.  Hypophysial responses to continuous and intermittent delivery of hypopthalamic gonadotropin-releasing hormone , 1978 .

[25]  A. Gore,et al.  Post‐Transcriptional Regulation of the Gonadotropin‐Releasing Hormone Gene in GT1–7 Cells , 1997, Journal of neuroendocrinology.

[26]  K. Catt,et al.  Expression of gonadotropin-releasing hormone receptors and autocrine regulation of neuropeptide release in immortalized hypothalamic neurons. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[27]  J. Costantin,et al.  cAMP modulates the excitability of immortalized H=hypothalamic (GT1) neurons via a cyclic nucleotide gated channel. , 2001, Molecular endocrinology.

[28]  Ernest Lawrence Rossi,et al.  Ultradian Rhythms in Life Processes , 2011, Springer London.

[29]  F. Dudek,et al.  Burst discharge in mammalian neuroendocrine cells involves an intrinsic regenerative mechanism. , 1983, Science.

[30]  L. Núñez,et al.  Episodic gonadotropin-releasing hormone gene expression revealed by dynamic monitoring of luciferase reporter activity in single, living neurons. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[31]  D. McCormick,et al.  A model of the electrophysiological properties of thalamocortical relay neurons. , 1992, Journal of neurophysiology.

[32]  R. Gallo,et al.  The influence of progesterone and estradiol on the acute changes in pulsatile luteinizing hormone release induced by ovariectomy on diestrus day 1 in the rat. , 1984, Endocrinology.

[33]  A. Jakubowiak,et al.  Printed in U.S.A. Copyright © 1997 by The Endocrine Society Differential Effects of Gonadotropin-Releasing Hormone (GnRH) Pulse Frequency on Gonadotropin Subunit and GnRH Receptor Messenger Ribonucleic Acid Levels in Vitro* , 2022 .

[34]  R. Dyball,et al.  Phasic firing enhances vasopressin release from the rat neurohypophysis , 1979, The Journal of physiology.

[35]  K Kusano,et al.  Electrical and synaptic properties of embryonic luteinizing hormone-releasing hormone neurons in explant cultures. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[36]  O. Rønnekleiv,et al.  Estradiol-17 beta and mu-opioid peptides rapidly hyperpolarize GnRH neurons: a cellular mechanism of negative feedback? , 1995, Endocrinology.

[37]  D. Sarkar,et al.  Gonadotropin-releasing hormone (GnRH) in pituitary stalk blood from proestrous rats: effects of anesthetics and relationship between stored and released GnRH and luteinizing hormone. , 1980, Endocrinology.

[38]  S. Tobet,et al.  Disruption of the gene encoding SF‐1 alters the distribution of hypothalamic neuronal phenotypes , 2000 .

[39]  J. Witkin,et al.  Novel associations among gonadotropin-releasing hormone neurons. , 1995, Endocrinology.

[40]  E. Rojas,et al.  Immortalized GnRH neurons express large-conductance calcium-activated potassium channels. , 1996, Neuroendocrinology.

[41]  C. Villalobos,et al.  The Relationship between Pulsatile Secretion and Calcium Dynamics in Single, Living Gonadotropin-Releasing Hormone Neurons. , 2000, Endocrinology.

[42]  E. Herzog,et al.  Long-term recordings of networks of immortalized GnRH neurons reveal episodic patterns of electrical activity. , 2001, Journal of neurophysiology.

[43]  S. Moenter,et al.  Pattern of gonadotropin-releasing hormone (GnRH) secretion leading up to ovulation in the ewe: existence of a preovulatory GnRH surge. , 1991, Endocrinology.

[44]  V. Padmanabhan,et al.  Neuroendocrine Control of Follicle-Stimulating Hormone (FSH) Secretion. I. Direct Evidence for Separate Episodic and Basal Components of FSH Secretion1. , 1997, Endocrinology.

[45]  K. Catt,et al.  Autocrine regulation of calcium influx and gonadotropin-releasing hormone secretion in hypothalamic neurons. , 2000, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[46]  J. Levine,et al.  Luteinizing hormone-releasing hormone release during the rat estrous cycle and after ovariectomy, as estimated with push-pull cannulae. , 1982, Endocrinology.

[47]  M. Conti,et al.  Phosphodiesterase expression targeted to gonadotropin-releasing hormone neurons inhibits luteinizing hormone pulses in transgenic rats , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[48]  M. Lehman,et al.  Fos expression during the estradiol-induced gonadotropin-releasing hormone (GnRH) surge of the ewe: induction in GnRH and other neurons. , 1993, Endocrinology.

[49]  I. Clarke,et al.  Negative Feedback Regulation of the Secretion and Actions of Gonadotropin-Releasing Hormone in Males , 2001, Biology of reproduction.

[50]  W. L. Dees,et al.  Role of nitric oxide in the control of luteinizing hormone-releasing hormone release in vivo and in vitro. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[51]  J. D. Neill,et al.  The Physiology of reproduction , 1988 .

[52]  A. Caraty,et al.  Effect of time after castration on secretion of LHRH and LH in the ram. , 1988, Journal of reproduction and fertility.

[53]  T. Herdendorf,et al.  Release of luteinizing hormone-releasing hormone from enzymatically dispersed rat hypothalamic explants is pulsatile. , 1998, Biology of reproduction.

[54]  S. Moenter,et al.  Dynamics of gonadotropin-releasing hormone (GnRH) secretion during the GnRH surge: insights into the mechanism of GnRH surge induction. , 1992, Endocrinology.

[55]  D. Rasmussen,et al.  Episodic gonadotropin-releasing hormone release from the rat isolated median eminence in vitro. , 1993, Neuroendocrinology.

[56]  L. Jennes,et al.  Kainate Receptor Subunit-Positive Gonadotropin-Releasing Hormone Neurons Express c-Fos during the Steroid-Induced Luteinizing Hormone Surge in the Female Rat1. , 2000, Endocrinology.

[57]  A. Charles,et al.  Mechanisms of spontaneous calcium oscillations and action potentials in immortalized hypothalamic (GT1-7) neurons. , 1995, Journal of neurophysiology.

[58]  K. Pau,et al.  Preovulatory gonadotropin-releasing hormone surge in ovarian-intact rhesus macaques. , 1993, Endocrinology.

[59]  S. Wray,et al.  LHRH cells migrate on peripherin fibers in embryonic olfactory explant cultures: an in vitro model for neurophilic neuronal migration. , 1994, Developmental biology.

[60]  W. Wetsel,et al.  Intrinsic pulsatile secretory activity of immortalized luteinizing hormone-releasing hormone-secreting neurons. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[61]  D. Haisenleder,et al.  A pulsatile gonadotropin-releasing hormone stimulus is required to increase transcription of the gonadotropin subunit genes: evidence for differential regulation of transcription by pulse frequency in vivo. , 1991, Endocrinology.

[62]  C. Knauf,et al.  Evidence for a Spontaneous Nitric Oxide Release from the Rat Median Eminence: Influence on Gonadotropin-Releasing Hormone Release. , 2001, Endocrinology.

[63]  M. Lehman,et al.  Role of the thyroid gland in seasonal reproduction. III. Thyroidectomy blocks seasonal suppression of gonadotropin-releasing hormone secretion in sheep. , 1991, Endocrinology.

[64]  A. Herbison,et al.  Heterogeneity in the Basic Membrane Properties of Postnatal Gonadotropin-Releasing Hormone Neurons in the Mouse , 2001, The Journal of Neuroscience.

[65]  B. Hille.  Ionic channels of excitable membranes , 2001 .

[66]  F. Edward Dudek,et al.  Episodic Bursting Activity and Response to Excitatory Amino Acids in Acutely Dissociated Gonadotropin-Releasing Hormone Neurons Genetically Targeted with Green Fluorescent Protein , 2002, The Journal of Neuroscience.

[67]  J. Takahashi,et al.  Neuropeptide Y stimulates luteinizing hormone-releasing hormone release from superfused hypothalamic GT1-7 cells. , 1994, Endocrinology.

[68]  D. Cook,et al.  Intracellular ATP directly blocks K+ channels in pancreatic B-cells , 1984, Nature.

[69]  F. Maekawa,et al.  Morphological characterization of relationship between gap junctions and gonadotropin releasing hormone nerve terminals in the rat median eminence , 1999, Neuroscience Letters.

[70]  S. Moenter,et al.  Estradiol-sensitive afferents modulate long-term episodic firing patterns of GnRH neurons. , 2002, Endocrinology.

[71]  J. Costantin,et al.  Modulation of Ca(2+) signaling by K(+) channels in a hypothalamic neuronal cell line (GT1-1). , 2001, Journal of neurophysiology.

[72]  K. Mogi,et al.  Pulsatile release of luteinizing hormone-releasing hormone (LHRH) in cultured LHRH neurons derived from the embryonic olfactory placode of the rhesus monkey. , 1999, Endocrinology.

[73]  D. Brann,et al.  Excitatory Amino Acids: Function and Significance in Reproduction and Neuroendocrine Regulation , 1994, Frontiers in Neuroendocrinology.

[74]  J. E. Schneider,et al.  Control of fertility by metabolic cues. , 1996, The American journal of physiology.

[75]  C. Hölscher.  Nitric oxide, the enigmatic neuronal messenger: its role in synaptic plasticity , 1997, Trends in Neurosciences.

[76]  F. Dudek,et al.  Printed in U.S.A. Copyright © 2000 by The Endocrine Society Whole-Cell Recordings from Preoptic/Hypothalamic Slices Reveal Burst Firing in Gonadotropin-Releasing Hormone Neurons Identified with Green Fluorescent Protein in Transgenic Mice* , 2022 .

[77]  D. Sarkar,et al.  Gonadotropin-releasing hormone surge in pro-oestrous rats , 1976, Nature.

[78]  F. Hirahara,et al.  Immortalized Gonadotropin-Releasing Hormone Neurons (GT1-7 Cells) Exhibit Synchronous Bursts of Action Potentials , 2001, Neuroendocrinology.

[79]  S. Shorte,et al.  Pulsatile exocytosis is functionally associated with GnRH gene expression in immortalized GnRH-expressing cells. , 2001, Endocrinology.

[80]  Daniel F. Hanley,et al.  GABA- and Glutamate-Activated Channels in Green Fluorescent Protein-Tagged Gonadotropin-Releasing Hormone Neurons in Transgenic Mice , 1999, The Journal of Neuroscience.

[81]  J. Witkin,et al.  Synaptology of luteinizing hormone-releasing hormone neurons in rat preoptic area , 1985, Peptides.

[82]  R. Weiner,et al.  Generation and synchronization of gonadotropin-releasing hormone (GnRH) pulses: intrinsic properties of the GT1-1 GnRH neuronal cell line. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[83]  L. Lubbers,et al.  Influence of Testosterone on LHRH Release, LHRH mRNA and Proopiomelanocortin mRNA in Male Sheep 1 , 1996, Journal of neuroendocrinology.

[84]  Y. Oka,et al.  Gonadotropin-releasing hormone (GnRH)-immunoreactive terminal nerve cells have intrinsic rhythmicity and project widely in the brain , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[85]  S. Rivest,et al.  The role of corticotropin-releasing factor and interleukin-1 in the regulation of neurons controlling reproductive functions. , 1995, Endocrine reviews.

[86]  A. Herbison,et al.  Promoter Transgenics Reveal Multiple Gonadotropin-Releasing Hormone-I-Expressing Cell Populations of Different Embryological Origin in Mouse Brain , 1999, The Journal of Neuroscience.

[87]  P. Claude,et al.  A primary cell culture system of luteinizing hormone releasing hormone neurons derived from embryonic olfactory placode in the rhesus monkey. , 1993, Endocrinology.

[88]  J. Bourguignon,et al.  Pulsatile secretion of gonadotropin-releasing hormone by rat hypothalamic explants without cell bodies of GnRH neurons [corrected]. , 1997, Neuroendocrinology.

[89]  J. Vincent,et al.  Control of Action Potential Timing by Intrinsic Subthreshold Oscillations in Olfactory Bulb Output Neurons , 1999, The Journal of Neuroscience.

[90]  Y. Mori,et al.  Chronic recording of electrophysiological manifestation of the hypothalamic gonadotropin-releasing hormone pulse generator activity in the goat. , 1991, Neuroendocrinology.

[91]  Elizabeth A. Vitalis,et al.  Role of the cAMP signaling pathway in the regulation of gonadotropin-releasing hormone secretion in GT1 cells. , 2000 .

[92]  N. Wayne,et al.  Characteristics of the melatonin signal that provide the photoperiodic code for timing seasonal reproduction in the ewe. , 1988, Reproduction, nutrition, developpement.

[93]  I. Clarke,et al.  Effects of stress on reproduction in non-rodent mammals: the role of glucocorticoids and sex differences. , 2000, Reviews of reproduction.

[94]  S. Moenter,et al.  Cycles of transcription and translation do not comprise the gonadotropin-releasing hormone pulse generator in GT1 cells. , 2001, Endocrinology.

[95]  Suzanne M. Moenter,et al.  Activation of A-type gamma-aminobutyric acid receptors excites gonadotropin-releasing hormone neurons. , 2002, Molecular endocrinology.

[96]  I. Clarke,et al.  THE TEMPORAL RELATIONSHIP BETWEEN GONADOTROPIN RELEASING HORMONE (GnRH) AND LUTEINIZING HORMONE (LH) SECRETION IN OVARIECTOMIZED EWES1 , 1982 .

[97]  J. Windle,et al.  Immortalization of hypothalamic GnRH by genetically targeted tumorigenesis , 1990, Neuron.

[98]  J. Lisman.  Bursts as a unit of neural information: making unreliable synapses reliable , 1997, Trends in Neurosciences.

[99]  J L Costantin,et al.  Spontaneous action potentials initiate rhythmic intercellular calcium waves in immortalized hypothalamic (GT1-1) neurons. , 1999, Journal of neurophysiology.

[100]  L. Wildt,et al.  Frequency and amplitude of gonadotropin-releasing hormone stimulation and gonadotropin secretion in the rhesus monkey. , 1981, Endocrinology.

[101]  S. Shorte,et al.  Synchronized exocytotic bursts from gonadotropin-releasing hormone-expressing cells: dual control by intrinsic cellular pulsatility and gap junctional communication. , 2001, Endocrinology.

[102]  D T Mauger,et al.  Does estradiol induce the preovulatory gonadotropin-releasing hormone (GnRH) surge in the ewe by inducing a progressive change in the mode of operation of the GnRH neurosecretory system. , 1995, Endocrinology.

[103]  R. Llinás,et al.  Electrophysiological properties of in vitro Purkinje cell dendrites in mammalian cerebellar slices. , 1980, The Journal of physiology.

[104]  P. Guyenet,et al.  Autoactivity of A5 neurons: role of subthreshold oscillations and persistent Na+current. , 1997, American journal of physiology. Heart and circulatory physiology.

[105]  GnRH neurons and episodic bursting activity , 2002, Trends in Endocrinology & Metabolism.

[106]  K. Catt,et al.  Autocrine regulation of gonadotropin-releasing hormone secretion in cultured hypothalamic neurons. , 1999, Endocrinology.

[107]  G. Martin,et al.  Hypothalamic multiunit activity and LH secretion in conscious sheep , 2004, Experimental Brain Research.

[108]  D. Matesic,et al.  Immortalized hypothalamic luteinizing hormone-releasing hormone neurons express a connexin 26-like protein and display functional gap junction coupling assayed by fluorescence recovery after photobleaching. , 1993, Neuroendocrinology.

[109]  W. Fujimoto,et al.  Lowering of pHi inhibits Ca2+-activated K+ channels in pancreatic B-cells , 1984, Nature.

[110]  M L Johnson,et al.  Cluster analysis: a simple, versatile, and robust algorithm for endocrine pulse detection. , 1986, The American journal of physiology.

[111]  W. Stumpf,et al.  Ultrastructural characterization of gonadotropin‐releasing hormone (GnRH)‐producing neurons , 1985, The Journal of comparative neurology.

[112]  F. Karsch,et al.  Feedback actions of estradiol on GnRH secretion during the follicular phase of the estrous cycle. , 1996, Acta neurobiologiae experimentalis.

[113]  T. A. Richter,et al.  Synchronization of Ca(2+) oscillations among primate LHRH neurons and nonneuronal cells in vitro. , 2002, Journal of neurophysiology.

[114]  Suzanne M. Moenter,et al.  Calcium Current Subtypes in GnRH Neurons1 , 2003, Biology of reproduction.

[115]  H. Jarry,et al.  Evidence to suggest that gonadotropin-releasing hormone inhibits its own secretion by affecting hypothalamic amino acid neurotransmitter release. , 1996, Neuroendocrinology.

[116]  G. Dayanithi,et al.  The role of patterned burst and interburst interval on the excitation‐coupling mechanism in the isolated rat neural lobe. , 1985, The Journal of physiology.

[117]  A. Herbison,et al.  Multimodal influence of estrogen upon gonadotropin-releasing hormone neurons. , 1998, Endocrine reviews.

[118]  J. Kaufman,et al.  Central electrophysiologic correlates of pulsatile luteinizing hormone secretion in the rhesus monkey. , 1984, Neuroendocrinology.

[119]  J. Rawson,et al.  Projections from the arcuate/ventromedial region of the hypothalamus to the preoptic area and bed nucleus of stria terminalis in the brain of the ewe; lack of direct input to gonadotropin-releasing hormone neurons , 2001, Brain Research.

[120]  E. Terasawa,et al.  Intracellular Ca2+ Oscillations in Luteinizing Hormone-Releasing Hormone Neurons Derived from the Embryonic Olfactory Placode of the Rhesus Monkey , 1999, The Journal of Neuroscience.

[121]  M. Bosma,et al.  Ion channel properties and episodic activity in isolated immortalized gonadotropin-releasing hormone (GnRH) neurons , 1993, The Journal of Membrane Biology.

[122]  P. Emson,et al.  Relationship of Neuronal Nitric Oxide Synthase Immunoreactivity to GnRH Neurons in the Ovariectomized and Intact Female Rat , 1996, Journal of neuroendocrinology.