Semin Reprod Med 2001; 19(1): 103-110
DOI: 10.1055/s-2001-13917
Copyright © 2001 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Neural Actions of Luteinizing Hormone and Human Chorionic Gonadotropin

Z. M. Lei, Ch. V. Rao
  • Department of Obstetrics and Gynecology, Division of Basic Science Research, University of Louisville Health Sciences Center, Louisville, Kentucky
Further Information

Publication History

Publication Date:
31 December 2001 (online)

ABSTRACT

Luteinizing hormone (LH) and its homologue, human chorionic gonadotropin (hCG), are able to elicit multiple effects in the central nervous system (CNS) through binding to their receptors. Specific receptors for LH/hCG have been identified in the hippocampus, dentate gyrus, hypothalamus, cortex, brain stem, area postrema, cerebellum, choroid plexus, ependymal cells, glial cells, neural retina, pituitary gland, and neuron processes of the spinal cord. Neurotropic effects of LH and hCG have been demonstrated in fetal rat brain, where the expression of LH/hCG receptors is developmentally regulated. Administration of hCG has been found to be beneficial in restoration of transected spinal cord function in rats. In adult rat brain, LH and hCG are involved in the feedback regulation of synthesis and secretion of gonadotropin-releasing hormone (GnRH) in the hypothalamus and LH in the pituitary gland. LH and hCG also induce several behavioral and other changes that are associated with the hippocampus, which contains the highest density of LH/hCG receptors. Many of the behavioral changes induced by hCG in rats parallel those in pregnant women. Some of these behavioral effects are correlated with changes of eicosanoid metabolism induced by LH and hCG in the brain. The LH/hCG receptors present in the choroid plexus, brain vessels, and perihypophyseal vascular complex may be involved in the modulation of transport of LH, hCG, and GnRH into the CNS. Thus, the CNS is one of the specific target tissues for LH and hCG, by which LH/hCG act as pleiotropic hormones that regulate several reproduction-related as well as reproduction-nonrelated functions in the CNS.

REFERENCES

  • 1 McEwen B S, Alves S E. Estrogen actions in the central nervous system.  Endocr Rev . 1999;  20 279-307
  • 2 Croxatto H, Arrau J, Croxatto H. Luteinizing hormone-like activity in human median eminence extracts.  Nature . 1964;  204 584-585
  • 3 Bagshawe K D, Orr A H, Rushworth A G. Relationship between concentrations of human chorionic gonadotropin in plasma and cerebrospinal fluid.  Nature . 1968;  217 950-951
  • 4 Antunes J L, Carmel P W, Zimmerman E A, Ferin M. The pars tuberalis of the rhesus monkey secretes luteinizing hormone.  Brain Res . 1979;  166 49-55
  • 5 Gross D S, Page R B. Luteinizing hormone and follicle-stimulating hormone production in the pars tuberalis of hypophysectomized rats.  Am J Anat . 1979;  156 285-291
  • 6 Hostetter G, Gallo R V, Brownfield M S. Presence of immunoreactive luteinizing hormone in the rat forebrain.  Neuroendocrinology . 1981;  33 241-245
  • 7 Emanuele N, Connick E, Howell T. Hypothalamic luteinizing hormone (LH): characteristics and response to hypophysectomy.  Biol Reprod . 1981;  25 321-326
  • 8 Emanuele N V, Anderson J, Andersen E. Extrahypothalamic brain luteinizing hormone: characterization by radioimmunoassay, chromatography, radioligand assay and bioassay.  Neuroendocrinology . 1983;  36 254-260
  • 9 Balasinor N, Gill-Sharma M K, Parte P, Juneja H S. Cerebrospinal fluid and blood concentrations of luteinizing hormone, follicle stimulating hormone and prolactin following castration of adult male rats.  Acta Endocrinol (Copenh) . 1992;  127 58-65
  • 10 Bowen D J. Taste and food preference changes across the course of pregnancy.  Appetite . 1992;  19 233-242
  • 11 Reeves N, Potempa K, Gallo A. Fatigue in early pregnancy: an exploratory study.  J Nurse Midwifery . 1991;  36 303-309
  • 12 Rofe Y, Blittner M, Lewin I. Emotional experiences during the three trimesters of pregnancy.  J Clin Psychol . 1993;  49 3-12
  • 13 Utian W H. Menopause and Hormone Replacement Therapy.  Boston: Blackwell Scientific Publications; 1993
  • 14 Keye W R. Premenstrual Syndrome.  Boston: Blackwell Scientific Publications; 1993
  • 15 Miyake A, Tanizawa O, Aono T, Yasuda M, Kurachi K. Suppression of luteinizing hormone in castrated women by the administration of human chorionic gonadotropin.  J Clin Endocrinol Metab . 1976;  43 928-932
  • 16 Masson G M, Anthony F, Chau E. Serum chorionic gonadotrophin (hCG), schwangerschaftsprotein 1 (SP1), progesterone and oestradiol levels in patients with nausea and vomiting in early pregnancy.  Br J Obstet Gynaecol . 1985;  92 211-215
  • 17 David M A, Fraschini F, Martini L. Control of LH secretion: role of a ``short'' feedback mechanism.  Endocrinology . 1966;  78 55-60
  • 18 Gallo R V, Johnson J H, Kalra S P, Whitmoyer D I, Sawyer C H. Effects of luteinizing hormone on multiple-unit activity in the rat hippocampus.  Neuroendocrinology . 1972;  9 149-157
  • 19 Terasawa E, Whitmoyer D I, Sawyer C H. Effects of luteinizing hormone on multiple-unit activity in the rat hypothalamus.  Am J Physiol . 1969;  217 1119-1126
  • 20 Kuhl H, Taubert H D. Short-loop feedback mechanism of luteinizing hormone: LH stimulated hypothalamic L-cystine arylamidase to inactivate LH-RH in the rat hypothalamus.  Acta Endocrinol (Copenh) . 1975;  78 649-663
  • 21 Molitch M, Edmonds M, Jones E E, Odell W D. Short-loop feedback control of luteinizing hormone in the rabbit.  Am J Physiol . 1976;  230 907-910
  • 22 Lei Z M, Rao C V, Kornyei J L, Licht P, Hiatt E S. Novel expression of human chorionic gonadotropin/luteinizing hormone receptor gene in brain.  Endocrinology . 1993;  132 2262-2270
  • 23 Harvev S, Render C L, Hull K L, Nutley M. Gonadotropin receptor expression in brain and pituitary tissue. Endocrine Society annual meeting, Anaheim, CA, 1994, abstract 448
  • 24 Reiter E, Sente B, McNamara M, Thunus S, Hennuy B, Hennen G. Ubiquitous expression of human chorionic gonadotropin/luteinizing hormone receptor in the rat organs. Endocrine Society annual meeting, Anaheim, CA, 1994, abstract 1174
  • 25 Reiter E, McNamara M, Closset J, Hennen G. Expression and functionality of luteinizing hormone/chorionic gonadotropin receptor in the rat prostate.  Endocrinology . 1995;  136 917-923
  • 26 Al-Hader A A, Tao Y X, Lei Z M, Rao C V. Fetal rat brains contain luteinizing hormone/human chorionic gonadotropin receptors.  Early Pregnancy . 1997;  3 323-329
  • 27 Thompson D A, Othman M I, Lei Z. Localization of receptors for luteinizing hormone/chorionic gonadotropin in neural retina.  Life Sci . 1998;  63 1057-1064
  • 28 Petrusz P. Localization and Sites of Action of Gonadotropins in Brain.  Basel: Karger 1975
  • 29 Lei Z M, Rao C V. Novel presence of luteinizing hormone/ human chorionic gonadotropin (hCG) receptors and the down-regulating action of hCG on gonadotropin- releasing hormone gene expression in immortalized hypothalamic GT1-7 neurons.  Mol Endocrinol . 1994;  8 1111-1121
  • 30 Zhang W, Lei Z M, Rao C V. Immortalized hippocampal cells contain functional luteinizing hormone/human chorionic gonadotropin receptors.  Life Sci . 1999;  65 2083-2098
  • 31 Huang Z H, Lei Z M, Rao C V. Immortalized anterior pituitary alpha T3 gonadotropes contain functional luteinizing hormone/human chorionic gonadotropin receptors.  Mol Cell Endocrinol . 1995;  114 217-222
  • 32 Hu Y L, Lei Z M, Rao C V. Analysis of the promoter of the luteinizing hormone/human chorionic gonadotropin receptor gene in neuroendocrine cells.  Life Sci . 1998;  63 2157-2165
  • 33 Al-Hader A A, Lei Z M, Rao C V. Novel expression of functional luteinizing hormone/chorionic gonadotropin receptors in cultured glial cells from neonatal rat brains.  Biol Reprod . 1997;  56 501-507
  • 34 Al-Hader A A, Lei Z M, Rao C V. Neurons from fetal rat brains contain functional luteinizing hormone/chorionic gonadotropin receptors.  Biol Reprod . 1997;  56 1071-1076
  • 35 Carmichael D N, Morgan N G, Scarpello J HB. Human chorionic gonadotropin stimulates the growth of retinal vascular cells.  Diabetologia . 1995;  38(suppl) A275
  • 36 Corbin A. Pituitary and plasma LH of ovariectomized rats with median emince implants of LH.  Endocrinology . 1966;  84 786-797
  • 37 Ojeda S R, Ramirez V D. Automatic control of LH and FSH secretion by short feedback circuits in immature rats.  Endocrinology . 1969;  84 786-797
  • 38 Hirono M, Igarashi M, Matsumoto S. The direct effect of HCG upon pituitary gonadotrophin secretion.  Endocrinology . 1972;  90 1214-1219
  • 39 Kawakami M, Sakuma Y. Responses of hypothalamic neurons to the microiontophoresis of LH-RH, LH and FSH under various levels of circulating ovarian hormones.  Neuroendocrinology . 1974;  15 290-307
  • 40 Sanghera M, Harris M C, Morgan R A. Effects of microiontophoretic and intravenous application of gonadotrophic hormones on the discharge of medial-basal hypothalamic neurones in rats.  Brain Res . 1978;  140 63-74
  • 41 Melrose P A. In vitro evidence for short-loop gonadotropin feedback on gonadotropin-releasing hormone neurons harvested from adult male rats.  Endocrinology . 1987;  121 200-204
  • 42 Nakazawa K, Marubayashi U, McCann S M. Mediation of the short-loop negative feedback of luteinizing hormone (LH) on LH-releasing hormone release by melatonin-induced inhibition of LH release from the pars tuberalis.  Proc Natl Acad Sci U S A . 1991;  88 7576-7579
  • 43 Lukacs H, Hiatt E S, Lei Z M, Rao C V. Peripheral and intracerebroventricular administration of human chorionic gonadotropin alters several hippocampus-associated behaviors in cycling female rats.  Horm Behav . 1995;  29 42-58
  • 44 Lei Z M, Toth P, Rao C V, Pridham D. Novel coexpression of human chorionic gonadotropin (hCG)/human luteinizing hormone receptors and their ligand hCG in human fallopian tubes.  J Clin Endocrinol Metab . 1993;  77 863-872
  • 45 Mores N, Krsmanovic L Z, Catt K J. Activation of LH receptors expressed in GnRH neurons stimulates cyclic AMP production and inhibits pulsatile neuropeptide release.  Endocrinology . 1996;  137 5731-5734
  • 46 Li X, Lei Z M, Rao C V. Human chorionic gonadotropin down-regulates the expression of gonadotropin-releasing hormone receptor gene in GT1-7 neurons.  Endocrinology . 1996;  137 899-904
  • 47 Lei Z M, Rao C V. Signaling and transacting factors in the transcriptional inhibition of gonadotropin releasing hormone gene by human chorionic gonadotropin in immortalized hypothalamic GT1-7 neurons.  Mol Cell Endocrinol . 1995;  109 151-157
  • 48 Lei Z M, Rao C V. Cis-acting elements and trans-acting proteins in the transcriptional inhibition of gonadotropin-releasing hormone gene by human chorionic gonadotropin in immortalized hypothalamic GT1-7 neurons.  J Biol Chem . 1997;  272 14365-14371
  • 49 Lei Z M, Rao C V. Inhibition of transcription of rat gonadotropin releasing hormone (GnRH) gene by luteinizing hormone and human chorionic gonadotropin (LH/hCG) in GT1-7 neurons involves a homeodomain transcription factor. Endocrine Society annual meeting, New Orleans, 1998, abstract P3-638
  • 50 Skipor J, Bao S, Grzegorzewski W, Wasowska B, Rao C V. The inhibitory effect of hCG on counter current transfer of GnRH and the presence of LH/hCG receptors in the perihypophyseal cavernous sinus-carotid rete vascular complex of ewes.  Theriogenology . 1999;  51 899-910
  • 51 Grzegorzewski W, Skipor J, Wasowska B, Krzymowski T. Counter current transfer of oxytocin from the venous blood of the perihypophyseal cavernous sinus to the arterial blood of carotid rete supplying the hypophysis and brain depends on the phase of the estrous cycle in pigs.  Biol Reprod . 1995;  52 139-144
  • 52 Grzegorzewski W J, Skipor J, Wasowska B, Krzymowski T. Countercurrent transfer of 125I-LHRH in the perihypophyseal cavernous sinus-carotid rete vascular complex, demonstrated on isolated pig heads perfused with autologous blood.  Domest Anim Endocrinol . 1997;  14 149-160
  • 53 Licht P, Cao H, Lei Z M, Rao C V, Merz W E. Novel self-regulation of human chorionic gonadotropin biosynthesis in term pregnancy human placenta.  Endocrinology . 1993;  133 3014-3025
  • 54 Huang Z H, Lei Z M, Rao C V. Novel independent and synergistic regulation of gonadotropin-alpha subunit gene by luteinizing hormone/human choriogonadotropin and gonadotropin releasing hormone in the alphaT3-1 gonadotrope cells.  Mol Cell Endocrinol . 1997;  130 23-31
  • 55 Mauri M. Sleep and the reproductive cycle: a review.  Health Care Women Int . 1990;  11 409-421
  • 56 Toth P, Lukacs H, Hiatt E S, Reid K H, Iyer V, Rao C V. Administration of human chorionic gonadotropin affects sleep-wake phases and other associated behaviors in cycling female rats.  Brain Res . 1994;  654 181-190
  • 57 Emanuele N V, Tentler J, Scanlon S, Reda D, Kirsteins L. Intracerebroventricular luteinizing-hormone (LH) depresses feeding in male-rats.  Neuroendocrinol Lett . 1991;  13 413-418
  • 58 Kawakami M, Sawyer C H. Induction of behavioral and electroencephalographic changes in the rabbit by hormone administration or brain stimulation.  Endocrinology . 1959;  65 631-643
  • 59 Telegdy G, Rozsahegyi G. Effect of gonadotropins on extinction of an avoidance conditioned reflex and exploratory behaviors in the rat.  Acta Physiol Acad Sci Hung . 1971;  40 209-214
  • 60 Lapthorn A J, Harris D C, Littlejohn A. Crystal structure of human chorionic gonadotropin.  Nature . 1994;  369 455-461
  • 61 Sato A, Perlas E, Ben-Menahem D. Cystine knot of the gonadotropin alpha subunit is critical for intracellular behavior but not for in vitro biological activity.  J Biol Chem . 1997;  272 18098-18103
  • 62 Patil A, Fillmore K, Valentine J, Hill D. The study of the effect of human chorionic gonadotrophic (HCG) hormone on the survival of adrenal medulla transplant in brain: preliminary study.  Acta Neurochir (Wien) . 1987;  87 76-78
  • 63 Patil A A, Nagaraj M P. The effect of human chorionic gonadotropin (HCG) on functional recovery of spinal cord sectioned rats.  Acta Neurochir (Wien) . 1983;  69 205-218
  • 64 Patil A A, Filmore K, Hill D. The effect of human chorionic gonadotropin (HCG) on restoration of physiological continuity of the spinal cord: a preliminary report.  Int Surg . 1990;  75 54-57
  • 65 Patil A A, Nagaraj M P. The effect of human chorionic gonadotropin hormone on functional recovery of the spinal cord in the rat after acute spinal cord sectioning [letter].  Neurosurgery . 1983;  12 593-594
  • 66 Simmet T, Peskar B A. Lipoxygenase products of polyunsaturated fatty acid metabolism in the central nervous system: biosynthesis and putative functions.  Pharmacol Res . 1990;  22 667-682
  • 67 Lammers C H, Schweitzer P, Facchinetti P. Arachidonate 5-lipoxygenase and its activating protein: prominent hippocampal expression and role in somatostatin signaling.  J Neurochem . 1996;  66 147-152
  • 68 Kaufmann W E, Andreasson K I, Isakson P C, Worley P F. Cyclooxygenases and the central nervous system.  Prostaglandins . 1997;  54 601-624
  • 69 Hayaishi O. Molecular mechanisms of sleep-wake regulation: roles of prostaglandins D2 and E2.  FASEB J . 1991;  5 2575-2581
  • 70 Sri Kantha S, Matsumura H, Kubo E. Effects of prostaglandin D2, lipoxins and leukotrienes on sleep and brain temperature of rats.  Prostaglandins Leukot Essent Fatty Acids . 1994;  51 87-93
  • 71 DuBois J H, Bolton C, Cuzner M L. The production of prostaglandin and the regulation of cell division in neonate rat primary mixed glial cultures.  J Neuroimmunol . 1986;  11 277-285
  • 72 McCann S M, Karanth S, Kimura M, Yu W H, Rettori V. The role of nitric oxide (NO) in control of hypothalamic-pituitary function.  Rev Bras Biol . 1996;  56 105-112
  • 73 Schweitzer P, Madamba S, Champagnat J, Siggins G R. Somatostatin inhibition of hippocampal CA1 pyramidal neurons: mediation by arachidonic acid and its metabolites.  J Neurosci . 1993;  13 2033-2049
  • 74 Schweitzer P, Madamba S, Siggins G R. Arachidonic acid metabolites as mediators of somatostatin-induced increase of neuronal M-current.  Nature . 1990;  346 464-467
  • 75 Palmer M R, Mathews W R, Hoffer B J, Murphy R C. Electrophysiological response of cerebellar Purkinje neurons to leukotriene D4 and B4 .  J Pharmacol Exp Ther . 1981;  219 91-96
  • 76 Kiesel L, Przylipiak A F, Habenicht A J, Przylipiak M S, Runnebaum B. Production of leukotrienes in gonadotropin-releasing hormone-stimulated pituitary cells: potential role in luteinizing hormone release.  Proc Natl Acad Sci U S A . 1991;  88 8801-8805
  • 77 Oliver C, Mical R S, Porter J C. Hypothalamic-pituitary vasculature: evidence for retrograde blood flow in the pituitary stalk.  Endocrinology . 1977;  101 598-604
  • 78 Knowles F. Ependyma of the third ventricle in relation to pituitary function.  Prog Brain Res . 1972;  38 255-270
  • 79 Ghinea N, Mai T V, Groyer-Picard M T, Milgrom E. How protein hormones reach their target cells: receptor-mediated transcytosis of hCG through endothelial cells.  J Cell Biol . 1994;  125 87-97
  • 80 Emanuele N, Oslapas R, Connick E, Kirsteins L, Lawrence A M. Hypothalamic LH may play a role in control of pituitary LH release.  Neuroendocrinology . 1981;  33 12-17
  • 81 Emanuele N, Lipov S, Anderson J. Subcellular localization of hypothalamic luteinizing hormone.  Neuroendocrinology . 1985;  40 339-344
  • 82 Rothman P A, Chao V A, Taylor M R, Kuhn R W, Jaffe R B, Taylor R N. Extraplacental human fetal tissues express mRNA transcripts encoding the human chorionic gonadotropin-beta subunit protein.  Mol Reprod Dev . 1992;  33 1-6
  • 83 Strauss B L, Pittman R, Pixley M R, Nilson J H, Boime I. Expression of the beta subunit of chorionic gonadotropin in transgenic mice.  J Biol Chem . 1994;  269 4968-4973
    >