GnRH- 1 is a decapeptide encoded by the GNRH1 gene on human chromosome 8 (8p11.2- p21). GNRH1 produces a 92- amino acid precursor peptide (prepro- GnRH) with the following segments: a 23- amino acid signal sequence, GnRH, a 3- amino acid proteolytic processing site, and a 56- amino acid GnRH- associated peptide. Essentially all mammalian species demonstrate the same amino acid structure of GnRH- 1: (pyro) Glu- His- Trp- Ser- Tyr- Gly- Leu- Arg- Pro- Gly- NH2.
Although loosely affiliated from an anatomical perspective, GnRH neurons are highly integrated from a functional perspective. GnRH neurons exhibit extensive connections to other GnRH neurons and to other neuronal populations. GnRH neuronal activity is characterized by episodic and coordinated bursts of action potential firing, which presumably correlate to changes in GnRH release at the median eminence. Episodic firing rate activity— with periods of high and low firing rates— appears to be an intrinsic property of GnRH neurons, but firing patterns and rates are substantially influenced by complex afferent neuronal networks (vide infra).
GnRH is released into the hypophyseal portal system in epi sodic bursts (Figure 1). Intermittent GnRH presentation to gonadotropes is an absolute requirement for maintenance of gonadotropin synthesis and secretion: there are no known parallel or backup systems. In particular, intermittent GnRH stimulation increases or maintains GnRH receptors on gonadotropes— the ‘self- priming’ or ‘autopriming’ effect, which is partly mediated via GnRH receptor density on gonadotrope cells. Absent or in appropriate GnRH secretion in humans leads to pubertal failure, hypogonadotropic hypogonadism, and infertility, all of which can be reversed with pulsatile exogenous GnRH administration.
Fig1. Temporal relationship between pulses of GnRH in the pituitary portal system and pulses of LH in the peripheral circulation ( jugular vein). These data were obtained from a sheep model. Adapted with permission from Moenter SM, Brand RM, Midgley AR, Karsch FJ. Dynamics of gonadotropin- releasing hormone release during a pulse. Endocrinology 1992; 130:503– 10. (Ref 8) Copyright © 1992, Oxford University Press.
Gonadotropin responses to GnRH can decrease with higher GnRH pulse frequencies [10]. Continuous GnRH receptor stimulation markedly reduces gonadotropin synthesis and secretion (de sensitization) (Figure 2), which is partly a reflection of reduced GnRH receptor expression on gonadotropes (i.e. receptor downregulation). Desensitization can be achieved for therapeutic purposes with long- acting GnRH receptor agonists, which transiently increase gonadotropin release, but subsequently cause desensitization of gonadotropin secretion. Competitive GnRH receptor antagonists are also available: these peptides reversibly bind to, but do not stimulate, the GnRH receptor, reducing gonadotropins within 24 to 72 hours.
Fig2. Impact of pulsatile vs. continuous GnRH administration in GnRH- deficient monkeys. These monkeys were gonadectomized (but sex steroid- replaced) and rendered GnRH deficient via radiofrequency ablation of the arcuate nucleus. Normal gonadotropin secretion is maintained with intermittent exogenous GnRH administration. However, continuous GnRH infusion markedly downregulates luteinizing hormone and follicle- stimulating hormone production. Adapted with permission from Belchetz PE, Plant TM, Nakai Y, Keogh EJ, Knobil E. Hypophysial responses to continuous and intermittent delivery of hypothalamic gonadotropin- releasing hormone. Science 1978; 202:631– 33. Copyright 1978 © The American Association for the Advancement of Science
