Differential Response of the Primate HPG Axis to N-Methyl-d, l-aspartate, but not to Kisspeptin Challenge under Euglycemic and Hypoglycemic Conditions

F. Wahab; W-uz. Zaman; M. Shahab

doi:10.1055/s-0032-1306309

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2012; 44(06): 451-457
DOI: 10.1055/s-0032-1306309

Original Basic

Differential Response of the Primate HPG Axis to N-Methyl-d, l-aspartate, but not to Kisspeptin Challenge under Euglycemic and Hypoglycemic Conditions

F. Wahab^*

¹ Laboratory of Reproductive Neuroendocrinology, Department of Animal Sciences, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan

² Department of Physiology, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, KPK, Pakistan

,

W-uz. Zaman^*

¹ Laboratory of Reproductive Neuroendocrinology, Department of Animal Sciences, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan

,

M. Shahab

¹ Laboratory of Reproductive Neuroendocrinology, Department of Animal Sciences, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan

› Author Affiliations

Abstract

Hypoglycemia inhibits the hypothalamic-pituitary-gonadal (HPG) axis by still incompletely deciphered mechanisms. Many evidences suggest that the hypoglycemia-induced inhibition of the HPG axis involves alteration of the hypothalamic gonadotropin-releasing hormone (GnRH) release, but neuroendocrine factors responsible for this alteration are yet to be completely elucidated. The current study was carried out to ascertain whether insulin-induced hypoglycemic suppression of the HPG axis involves modulation of responsiveness of the GnRH neuron to kisspeptin and excitatory amino acids (EAA) drives. Five intact chair-restraint habituated adult male rhesus monkeys (Macaca mulatta) were given intravenous boli of GnRH, hCG, human kisspeptin-10 (KP10), NMDA (N-methyl-d, l-aspartate, an EAA analogue), and vehicle in both insulin (1 IU/kg)-induced hypoglycemic (IIH) and normal euglycemic conditions. Specific RIAs were used for measuring plasma cortisol and T concentrations. KP10 and NMDA administration stimulated significantly (p<0.005) T secretion in both euglycemic and hypoglycemic monkeys. Mean post-KP10 T concentrations and AUC were comparable between euglycemic and hypoglycemic monkeys. However, mean post-NMDA T levels and AUC in hypoglycemic animals were significantly lower (p<0.01–0.005) as compared to the corresponding values in euglycemic animals. T response to GnRH and hCG was similar between hypoglycemic and euglycemic monkeys. Vehicle did not affect plasma T concentrations in all conditions. Our results demonstrate that while the primate HPG axis response to kisspeptin stimulation remains intact that to EAA excitation is attenuated in hypoglycemic conditions, suggesting that hypogonadism in IIH is contributed, in part, by reduced sensitivity of the GnRH neurons to EAA signaling in the primate hypothalamus.

Key words

hypoglycemia - kisspeptin - GPR54 - NMDA - EAA - GnRH - testosterone

Full Text

References

References
1 Clarke IJ, Horton RJE, Doughton BW. Investigation of the mechanism by which insulin-induced hypoglycemia decreases luteinizing hormone secretion in ovariectomized ewes. Endocrinology 1990; 127: 1470-1476
2 Goubillon ML, Thalabard JC. Insulin-induced hypoglycemia decreases luteinizing hormone secretion in the castrated male rat: involvement of opiate peptides. Neuroendocrinology 1996; 64: 49-56
3 Cagampang FR, Cates PS, Sandhu S, Strutton PH, McGarvey C, Coen CW, O’Byrne KT. Hypoglycemia-induced inhibition of pulsatile luteinizing hormone secretion in female rats: role of oestradiol, endogenous opioids and the adrenal medulla. J Neuroendocrinol 1997; 9: 867-872
4 Adam CL, Findlay PA. Inhibition of luteinizing hormone secretion and expression of C-fos and corticotrophin-releasing factor genes in the paraventricular nucleus during insulin induced hypoglycemia in sheep. J Neuroendocrinol 1998; 10: 777-783
5 Cates PS, O’Byrne KT. The area postrema mediates insulin hypoglycemia-induced suppression of pulsatile LH secretion in the female rat. Brain Res 2000; 853: 151-155
6 Chen MD, O’Byrne KT, Chiappini SE, Hotchkiss J, Knobil E. Hypoglycemic stress and gonadotropin-releasing hormone pulse generator activity in the rhesus monkey: role of the ovary. Neuroendocrinology 1992; 56: 666-673
7 Chen MD, Ordog T, O’Byrne KT, Goldsmith JR, Connaughton MA, Knobil E. The insulin hypoglycemia-induced inhibition of gonadotropin-releasing hormone pulse generator activity in the rhesus monkey: role of vasopressin and corticotrophin-releasing factor. Endocrinology 1996; 137: 2012-2021
8 Heisler LE, Pallotta CM, Reid RL, Van-Vugt DA. Hypoglycemia-induced inhibition of luteinizing hormone secretion in the rhesus monkey is not mediated by endogenous opioid peptides. J Clin Endocrinol Metab 1993; 76: 1280-1285
9 Heisler LE, Tumber AJ, Reid RL, Van-Vugt DA. Vasopressin mediates hypoglycemia-induced inhibitioin of luteinizing hormone secretion in the ovariectomized rhesus monkey. Neuroendocrinology 1994; 60: 297-304
10 Van-Vugt DA, Washburn DL, Farley AE, Reid RL. Hypoglycemia-induced inhibition of LH and stimulation of ACTH secretion in the rhesus monkey is blocked by alprazolam. Neuroendocrinology 1997; 65: 344-352
11 Lado-Abeal J, Clapper JA, Norman RL. Antagonism of central vasopressin receptors blocks hypoglycemic stress induced inhibition of luteinizing hormone release in male rhesus macaques. J Neuroendocrinol 2001; 13: 650-655
12 Lado-Abeal J, Clapper JA, Chen Zhu B, Hough CM, Syapin PJ, Norman RL. Hypoglycemia-induced suppression of luteinizing hormone (LH) secretion in intact female rhesus macaques: role of vasopressin and endogenous opioids. Stress 2002; 5: 113-119
13 Oltmanns KM, Fruehwald-Schultes B, Kern W, Born J, Fehm HL, Peters A. Hypoglycemia, but not insulin, acutely decreases LH and T secretion in men. J Clin Endocrinol Metab 2001; 86: 4913-4919
14 He D, Funabashi T, Sano A, Uemura T, Minaguchi H, Kimura F. Effects of glucose and related substrates on the recovery of the electrical activity of gonadotropin-releasing hormone pulse generator which is decreased by insulin-induced hypoglycemia in the estrogen-primed ovariectomized rat. Brain Res 1999; 820: 71-76
15 Lujan ME, Krzemien AA, Van Vugt DA. Hypoglycemia does not affect gonadotroph responsiveness to gonadotropin-releasing hormone in rhesus monkeys. Endocrine 2003; 21: 109-114
16 Knobil E, Plant TM, Wildt L, Belchetz PE, Marshall G. Control of the rhesus monkey menstrual cycle: permissive role of hypothalamic gonadotropin-releasing hormone. Science 1980; 207: 1371-1373
17 Lincoln DW, Fraser HM, Lincoln GA, Martin GB, McNeilly AS. Hypothalamic pulse generators. Recent Prog Horm Res 1985; 41: 369-419
18 Terasawa E, Fernandez DL. Neurobiological mechanisms of the onset of puberty in primates. Endocrine Rev 2001; 22: 111-151
19 Plant TM, Shahab M. Neuroendocrine mechanisms that delay and initiate puberty in higher primates. Physiol Behav 2002; 77: 717-722
20 Ebling FJ. The neuroendocrine timing of puberty. Reproduction 2005; 129: 675-683
21 Raff H, Papanek PE, Crowley Jr AW. ACTH and Vasopressin responses to insulin-induced hypoglycemia in intact and neurohypophysectomized conscious dogs. Neuroendocrinology 1991; 53: 85-90
22 Shahab M, Zaman W, Bashir K, Arslan M. Fasting-induced suppression of hypothalamic-pituitary-gonadal axis in the adult rhesus monkey: evidence for involvement of excitatory amino acid neurotransmitters. Life Sci 1997; 61: 1293-1300
23 Wahab F, Aziz F, Irfan S, Zaman W, Shahab M. Short-term fasting attenuates the response of the HPG axis to kisspeptin challenge in the adult male rhesus monkey (Macaca mulatta). Life Sci 2008; 83: 633-637
24 Seminara SB. Metastin and its G protein-coupled receptor, GPR54: critical pathway modulating GnRH secretion. Front Neuroendocrinol 2005; 26: 131-138
25 Plant TM. Hypothalamic control of the pituitary-gonadal axis in higher primates: key advances over the last two decades. J Neuroendocrinol 2008; 20: 719-726
26 Roa J, Aguilar E, Dieguez C, Pinilla L, Tena-Sempere M. New frontiers in kisspeptin/GPR54 physiology as fundamental gatekeepers of reproductive function. Front Neuroendocrinol 2008; 29: 48-69
27 Wahab F, Quinton R, Seminara SB. The kisspeptin signaling pathway and its role in human isolated GnRH deficiency. Mol Cell Endocrinol 2011; 346: 29-36
28 Han SK, Gottsch ML, Lee KJ, Popa SM, Smith JT, Jakawich SK, Clifton DK, Steiner RA, Herbison AE. Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of Puberty. J Neurosci 2005; 25: 11349-11356
29 Shahab M, Mastronardi C, Seminara SB, Crowley WF, Ojeda SR, Plant TM. Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. PNAS 2005; 102: 2129-2134
30 Dhillo WS, Chaudhri OB, Patterson M, Thompson EL, Murphy KG, Badman MK, McGowan BM, Amber V, Patel S, Ghatei MA, Bloom SR. Kisspeptin-54 stimulates the hypothalamic-pituitary-gonadal axis in human males. J Clin Endocrinol Metab 2005; 90: 6609-6615
31 Ramaswamy S, Seminara SB, Pohl CR, DiPietro MJ, Crowley WF, Plant TM. Effect of continuous intravenous administration of human metastin 45-54 on the neuroendocrine activity of the hypothalamic-pituitary-testicular axis in the adult male rhesus monkey (Macaca mulatta). Endocrinology 2007; 148: 3364-3370
32 Wahab F, Bano R, Jabeen S, Irfan S, Shahab M. Effect of peripheral kisspeptin administration on adiponectin, leptin, and resistin secretion under fed and fasting condition in the adult male rhesus monkey (Macaca mulatta). Horm Metab Res 2010; 42: 570-574
33 Wahab F, Tanzeela R, Shahab M. Study of the effect of peripheral kisspeptin administration on basal and glucose-induced insulin secretion under fed and fasting conditions in the adult male rhesus monkey (Macaca mulatta). Horm Metab Res 2011; 43: 37-42
34 Wahab F, Ullah F, Chan YM, Seminara SB, Shahab M. Decrease in hypothalamic Kiss1 and Kiss1r expression: a potential mechanism for fasting-induced suppression of the HPG axis in the adult male rhesus monkey (Macaca mulatta). Horm Metab Res 2011; 43: 81-85
35 Abbud R, Smith MS. Altered luteinizing hormone and prolactin responses to excitatory amino acids during lactation. Neuroendocrinology 1993; 58: 454-464
36 Meeker RB, Greenwood RS, Hayward JN. Glutamate receptors in the rat hypothalamus and pituitary. Endocrinology 1994; 134: 621-629
37 Brann DW, Mahesh VB. Excitatory amino acids: evidence for a role in the control of reproduction and anterior pituitary hormone secretion. Endocr Rev 1997; 18: 678-700
38 d’Anglemont de Tassigny X, Chatzidaki EE, Colledge WH. Kisspeptin-GPR54 signaling is essential for NMDA-induced luteinizing hormone secretion in the mouse. 1^st World Conference on Kisspeptin Signaling in the Brain. Cordoba; Spain: 2008. Oral-2: 45
39 d’Anglemont de Tassigny X, Ackroyd KJ, Chatzidaki EE, Colledge WH. Kisspeptin signaling is required for peripheral but not central stimulation of gonadotropin-releasing hormone neurons by NMDA. J Neurosci 2010; 30: 8581-8590
40 Gambacciani M, Yen SS, Rasmussen DD. GnRH release from the mediobasal hypothalamus: in vitro inhibition by corticotrophin releasing factor. Neuroendocrinology 1986; 43: 533-536
41 Olster DH, Ferin M. Corticotropin-releasing hormone inhibits gonadotropin secretion in the ovariectomized rhesus monkeys. J Clin Endocrinol Metab 1987; 65: 262-267
42 Ellis MJ, Schmidli RS, Donald RA, Livesey JH, Espiner EA. Plasma corticotrophin-releasing factor and vasopressin responses to hypoglycemia in normal man. Clin Endrocrinol (Oxf) 1990; 32: 93-100
43 Nagatani S, Thompson RC, Foster DL. Prevention of glucoprivic stimulation of corticosterone secretion by leptin does not restore high frequency luteinizing hormone pulses in rats. J Neuroendocrinol 2001; 13: 371-377
44 Kinoshita M, Moriyama R, Tsukamura H, Maeda KI. A rat model for the energetic regulation of gonadotropin secretion: role of the glucose-sensing mechanism in the brain. Domest Anim Endocrinol 2003; 25: 109-120
45 Dubey AK, Plant TM. A suppression of gonadotropin secretion by cortisol in castrated male rhesus monkeys (Macaca mulatta) mediated by the interruption of hypothalamic gonadotropin-releasing hormone release. Biol Reprod 1985; 33: 423-431
46 Williams CL, Nishihara M, Thalabard JC, Grosser PM, Hotchkiss J, Knobil E. Corticotropin-releasing factor and gonadotropin releasing hormone pulse generator activity in the rhesus monkey. Neuroendocrinology 1990; 52: 133-137