Lh 9641

Keywords: lh 9641
Description: Normal reproductive function requires the precise temporal and quantitative regulation of hormone secretion at all levels of the hypothalamic–pituitary–gonadal axis. The hypothalamus

Normal reproductive function requires the precise temporal and quantitative regulation of hormone secretion at all levels of the hypothalamic–pituitary–gonadal axis. The hypothalamus contains gonadotropin-releasing hormone (GnRH) neurons which secrete pulsatile GnRH into the hypophyseal portal blood system through which it is transported to the anterior pituitary gland. GnRH binds to its receptor on gonadotrope cells, stimulating the biosynthesis and secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH and FSH travel through the peripheral circulation, acting at the gonads to stimulate gametogenesis (i.e., the development of mature eggs and sperm) and steroidogenesis (i.e. synthesis of the gonadal hormones ‒ estrogen, progesterone, and androgens). In the majority of physiologic conditions, the gonadal steroids feedback at the hypothalamus and pituitary to decrease GnRH and gonadotropin secretion. An exception is at the time of the periovulatory LH surge in females, believed to be due to positive feedback by rapidly rising estradiol levels.

Isolated in the early 1970s, GnRH was one of the earliest of the hypothalamic-releasing hormones to be sequenced and characterized. 1 It was initially believed that separate hypothalamic factors were responsible for LH and FSH secretion and, as a result, GnRH was originally termed luteinizing hormone-releasing factor (LHRH). This latter term is still occasionally used in the literature.

GnRH consists of 10 amino acids which have been highly conserved over millions of years of evolution (Figure 1). In common with other neuropeptides, GnRH is synthesized as part of a large prohormone that is cleaved enzymatically and further modified within the secretory granules. This 92 amino acid precursor protein is proteolytically cleaved to generate: (1) the GnRH decapeptide, (2) a 23 amino acid signaling sequence which directs intracellular packaging and secretion, (3) a three amino acid (Gly-Lys-Arg) proteolytic processing site, and (4) a 56 amino acid GnRH-associated protein (GAP) that is secreted with GnRH. The function of GAP is unknown but it has been proposed to inhibit prolactin secretion in some species. 2

Fig. 1 Comparison of the amino acid compositions of GnRH1 and GnRH2 with commonly used agonists and antagonists. Amino acid variations as compared with GnRH1 are color coded. Nal, napthyl-alanine; Aza-Gly, Aza-glycine (alpha carbon replaced with a nitrogen); CpA, cyanoproprionic amino acid; Pal, pyridyl-alanine

GnRH has a short half-life of approximately 2–4 min due to rapid cleavage by peptidases. As a result of this rapid degradation as well as massive dilution, the peripheral circulation does not contain biologically active concentrations of GnRH. Serum LH and FSH levels are used clinically as surrogate markers for the presence of pulsatile GnRH secretion. LH is a more accurate indicator of GnRH pulse characteristics (i.e.. frequency and amplitude) than is FSH which has a longer half-life.

The majority of our understanding of GnRH and GnRH-receptor (GnRHR) function is based on studies of a single isoform of each; however, recent studies have identified additional forms as described in subsequent sections. For this review, the terms "GnRH" and "GnRHR" will refer to the type 1 GnRH and GnRHR, respectively. Note also that human gonadotropin-releasing hormone should be abbreviated with all capitals (i.e. GNRH) according to the new nomenclature. As much of the available data have been obtained in non-human species, we have chosen to use the more common abbreviations.

While the majority of neural cells arise from neurons within the developing nervous system itself, GnRH neurons are unusual in that they are derived from progenitor cells in the epithelium of the olfactory placode. These nascent GnRH neurons migrate along the vomeronasal axons, across the cribiform plate and into the mediobasal hypothalamus where migration ceases and the neurons detach from their axonal guides. 3 Patients with delayed puberty due to abnormal GnRH neuronal migration frequently have associated anosmia, or the inability to smell, which reflects the fact that the GnRH neurons share common embryonic origins and migratory pathways with olfactory neurons. The identification of genes which direct normal GnRH migration and function is an active area of research. A long list of soluble factors have been identified which appear to be critical for the ultimate development of a network which contains the appropriate number and location of GnRH neurons. These include pathway markers (netrin‑1), cell cycle arrest (Gas6), signaling molecules (GABA), growth factors (fibroblast growth factors), and adhesion molecules (tenascin, phosphacan, and laminin). 4 Mutations in these genes result in clinical phenotypes including pubertal delay and infertility, and are discussed in the Section The GnRH receptor (GnRHR) below.

Estimates of the number of GnRH neurons vary, but are in the range of a few thousand, a remarkably small number in view of their critical function. 5 The cell bodies of these neurons are scattered across a number of hypothalamic nuclei, with the majority residing in the arcuate nucleus of the medial basal hypothalamus in the human. Most GnRH neurons send axonal projections to the median eminence which abuts the hypothalamic–pituitary portal system. This system consists of capillaries that arise from the superior hypophyseal arteries, traverse the pituitary stalk, and then form a capillary network within the pituitary gland. This anatomic relationship allows minute quantities of GnRH secreted by these axonal terminals to have direct access to the pituitary gonadotropes. The primary direction of this hypophyseal portal system is from the hypothalamus to the pituitary; however, retrograde flow also exists and provides a short feedback loop from the pituitary back to the hypothalamus.

A subset of GnRH neurons extend axons to other portions of the CNS, including the limbic system. While these projections are not directly involved in the modulation of gonadotropin secretion, they may help to link hormonal status to reproductive behavior. 6 Thus, GnRH neurons are positioned to both receive and generate neural and hormonal inputs, allowing for the complex integration of reproductive function and broader physiologic status.

In an elegant series of experiments, Ernst Knobil and colleagues demonstrated that pulsatile GnRH is required to achieve sustained gonadotropin secretion. 7 Using a primate model, continuous infusion of GnRH was found to rapidly suppress both LH and FSH secretion, an effect that was readily reversed with a return to pulsatile stimulation (Figure 2). Loss of the GnRH response with continuous treatment is now known to be due to rapid uncoupling of the GnRH receptor from its intracellular signaling molecules followed by downregulation of receptor number. This characteristic is exploited clinically by administration of long-acting GnRH agonists to treat steroid-dependent conditions such as endometriosis, leiomyomas, breast cancer, and prostate cancer. 8 Pulsatile activity is currently believed to be an intrinsic property of GnRH neurons with hormonal and neural inputs providing modulatory effects; however, it has never been definitively proven whether the pulse generator is within a single GnRH neuron or a property of the neuronal network. 9. 10

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