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Physiology of gonadotropin-releasing hormone

Author
Corrine K Welt, MD
Section Editors
Robert L Barbieri, MD
William F Crowley, Jr, MD
Deputy Editor
Kathryn A Martin, MD

INTRODUCTION

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 [4]. 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 [5].

The critical role of migration has been confirmed in humans in a study of an aborted human fetus with Kallmann syndrome [6]. 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 [7]. 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)".)

     

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Literature review current through: Nov 2016. | This topic last updated: Wed Apr 08 00:00:00 GMT+00:00 2015.
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