Physiology of gonadotropin-releasing hormone
- Corrine K Welt, MD
Corrine K Welt, MD
- Professor of Medicine
- University of Utah School of Medicine
- Section Editors
- Robert L Barbieri, MD
Robert L Barbieri, MD
- Editor-in-Chief — Obstetrics, Gynecology and Women's Health
- Section Editor — General Gynecology and Female Reproductive Endocrinology
- Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology
- Harvard Medical School
- William F Crowley, Jr, MD
William F Crowley, Jr, MD
- Section Editor — Female Reproductive Endocrinology
- Daniel K Podolsky Professor of Medicine
- Harvard Medical School
Control of the reproductive axis originates in the hypothalamus with the periodic pulsatile release of gonadotropin-releasing hormone (GnRH). In response to GnRH (also called luteinizing hormone releasing hormone or LHRH), the pituitary releases pulses of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), into the blood stream. These hormones then induce gonadal production of a variety of hormones, such as estradiol, progesterone, inhibins, and testosterone, that play an important role in the regulation of reproduction.
RELEASE OF GNRH
Several elements are necessary for the normal release of and response to gonadotropin-releasing hormone (GnRH): migration of the secretory neurons via the proper route to the proper location must take place in the developing embryo and secretion must occur in a pulsatile fashion in response to neuroendocrine inputs and sex steroids.
Embryonic migration — GnRH is released from a small number of hypothalamic neurons that appear to arise in the developing embryo from an epithelial cluster of cells in the olfactory placode outside the central nervous system, although evidence in zebrafish suggest the neurons arise from the anterior pituitary placode and cranial neural crest, then transiently associate with the olfactory placode [1-3]. Regardless of their site of origin, fetal cells in the olfactory area can respond to odorant stimuli and secrete GnRH . These neurons then migrate into the olfactory bulb and olfactory tract before continuing to move into the medio-basal hypothalamus in the preoptic area and the arcuate nucleus.
Migration is an essential feature of developing GnRH neurons as demonstrated by studies in which the GnRH neurons in fetal hypothalamic tissue were transplanted to the floor of the third ventricle in GnRH-deficient (hpg) mice. The GnRH neurons migrated to the correct hypothalamic location and sent projections to the median eminence .
The critical role of migration has been confirmed in humans in a study of an aborted human fetus with Kallmann syndrome . The fetus had the same X chromosome deletion as its living GnRH-deficient brother. Neuropathologic examination showed arrest of the GnRH neurons at the cribriform plate of the ethmoid sinus at a time when the GnRH neurons in a normal fetus would have already migrated to the hypothalamus. These observations facilitated the discovery that anosmin-1, the protein encoded by the KAL1 gene responsible for X-linked Kallmann syndrome, plays a role in GnRH neuronal migration . The fibroblast growth factor receptor 1 (FGFR1) also plays a role in GnRH neuronal migration, and mutations in FGFR1 and its ligand FGF8 are associated with Kallmann syndrome [8-10]. The association of GnRH neurons with the olfactory bulb and tract is thought to explain the high frequency of anosmia (lack of smell) in patients with GnRH deficiency [11,12]. Other gene mutations resulting in GnRH deficiency are reviewed in detail separately. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)".)
- Schwanzel-Fukuda M, Jorgenson KL, Bergen HT, et al. Biology of normal luteinizing hormone-releasing hormone neurons during and after their migration from olfactory placode. Endocr Rev 1992; 13:623.
- Schwanzel-Fukuda M, Pfaff DW. Origin of luteinizing hormone-releasing hormone neurons. Nature 1989; 338:161.
- Whitlock KE. Origin and development of GnRH neurons. Trends Endocrinol Metab 2005; 16:145.
- Barni T, Maggi M, Fantoni G, et al. Sex steroids and odorants modulate gonadotropin-releasing hormone secretion in primary cultures of human olfactory cells. J Clin Endocrinol Metab 1999; 84:4266.
- Gibson MJ, Krieger DT, Charlton HM, et al. Mating and pregnancy can occur in genetically hypogonadal mice with preoptic area brain grafts. Science 1984; 225:949.
- Schwanzel-Fukuda M, Bick D, Pfaff DW. Luteinizing hormone-releasing hormone (LHRH)-expressing cells do not migrate normally in an inherited hypogonadal (Kallmann) syndrome. Brain Res Mol Brain Res 1989; 6:311.
- Soussi-Yanicostas N, Faivre-Sarrailh C, Hardelin JP, et al. Anosmin-1 underlying the X chromosome-linked Kallmann syndrome is an adhesion molecule that can modulate neurite growth in a cell-type specific manner. J Cell Sci 1998; 111 ( Pt 19):2953.
- Tsai PS, Moenter SM, Postigo HR, et al. Targeted expression of a dominant-negative fibroblast growth factor (FGF) receptor in gonadotropin-releasing hormone (GnRH) neurons reduces FGF responsiveness and the size of GnRH neuronal population. Mol Endocrinol 2005; 19:225.
- Dodé C, Levilliers J, Dupont JM, et al. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet 2003; 33:463.
- Falardeau J, Chung WC, Beenken A, et al. Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. J Clin Invest 2008; 118:2822.
- Kallman, FJ, Schoenfeld, WA, Barrera, SE. The genetic aspects of primary eunoichidism. Am J Ment Defic 1944; 48:203.
- Spratt DI, Carr DB, Merriam GR, et al. The spectrum of abnormal patterns of gonadotropin-releasing hormone secretion in men with idiopathic hypogonadotropic hypogonadism: clinical and laboratory correlations. J Clin Endocrinol Metab 1987; 64:283.
- Chen WP, Witkin JW, Silverman AJ. beta-Endorphin and gonadotropin-releasing hormone synaptic input to gonadotropin-releasing hormone neurosecretory cells in the male rat. J Comp Neurol 1989; 286:85.
- Wetsel WC, Valença MM, Merchenthaler I, et al. Intrinsic pulsatile secretory activity of immortalized luteinizing hormone-releasing hormone-secreting neurons. Proc Natl Acad Sci U S A 1992; 89:4149.
- Skynner MJ, Sim JA, Herbison AE. Detection of estrogen receptor alpha and beta messenger ribonucleic acids in adult gonadotropin-releasing hormone neurons. Endocrinology 1999; 140:5195.
- Roy D, Angelini NL, Belsham DD. Estrogen directly respresses gonadotropin-releasing hormone (GnRH) gene expression in estrogen receptor-alpha (ERalpha)- and ERbeta-expressing GT1-7 GnRH neurons. Endocrinology 1999; 140:5045.
- Ojeda SR, Ma YJ. Glial-neuronal interactions in the neuroendocrine control of mammalian puberty: facilitatory effects of gonadal steroids. J Neurobiol 1999; 40:528.
- Topaloglu AK, Reimann F, Guclu M, et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet 2009; 41:354.
- Pimstone B, Epstein S, Hamilton SM, et al. Metabolic clearance and plasma half disappearance time of exogenous gonadotropin releasing hormone in normal subjects and in patients with liver disease and chronic renal failure. J Clin Endocrinol Metab 1977; 44:356.
- Clarke IJ. Variable patterns of gonadotropin-releasing hormone secretion during the estrogen-induced luteinizing hormone surge in ovariectomized ewes. Endocrinology 1993; 133:1624.
- Crowley WF Jr, Filicori M, Spratt DI, Santoro NF. The physiology of gonadotropin-releasing hormone (GnRH) secretion in men and women. Recent Prog Horm Res 1985; 41:473.
- Weiss J, Duca KA, Crowley WF Jr. Gonadotropin-releasing hormone-induced stimulation and desensitization of free alpha-subunit secretion mirrors luteinizing hormone and follicle-stimulating hormone in perifused rat pituitary cells. Endocrinology 1990; 127:2364.
- Belchetz PE, Plant TM, Nakai Y, et al. Hypophysial responses to continuous and intermittent delivery of hypopthalamic gonadotropin-releasing hormone. Science 1978; 202:631.
- Conn PM, Crowley WF Jr. Gonadotropin-releasing hormone and its analogues. N Engl J Med 1991; 324:93.
- Crowley WF Jr, Comite F, Vale W, et al. Therapeutic use of pituitary desensitization with a long-acting lhrh agonist: a potential new treatment for idiopathic precocious puberty. J Clin Endocrinol Metab 1981; 52:370.
- Labrie F, Dupont A, Bélanger A, et al. Treatment of prostate cancer with gonadotropin-releasing hormone agonists. Endocr Rev 1986; 7:67.
- Klijn JG, de Jong FH, Lamberts SW, Blankenstein MA. LHRH-agonist treatment in clinical and experimental human breast cancer. J Steroid Biochem 1985; 23:867.
- Filicori M, Hall DA, Loughlin JS, et al. A conservative approach to the management of uterine leiomyoma: pituitary desensitization by a luteinizing hormone-releasing hormone analogue. Am J Obstet Gynecol 1983; 147:726.
- Barbieri RL. New therapy for endometriosis. N Engl J Med 1988; 318:512.