Neuroendocrine signals in the regulation of gonadotropin-releasing hormone secretion.

Gonadotropin-releasing hormone (GnRH) is a key hypothalamic peptide that controls the secretion of pituitary gonadotropins, particularly luteinizing hormone (LH), and hence gonadal function. Hypothalamic GnRH is released in a pulsatile manner. In the female, the pattern of GnRH pulses, i.e., pulse frequency and amplitude, varies during different reproductive stages and among different species. Several central and peripheral signals modulate GnRH neuronal activities. Some of these signals are stimulatory to GnRH release, e.g., norepinephrine (NE) and neuropeptide Y (NPY); some are inhibitory, e.g., beta-endorphin and interleukin-1; others are both stimulatory and inhibitory, e.g., estradiol-17 beta (E2). The neuronal structures and chemical interactions that result in pulsatile GnRH release remain unresolved. However, the core of the so-called 'GnRH pulse-generator' likely involves NE and NE transporter (NET, the protein for pre-synaptic re-uptake of NE). Both secretion and re-uptake of NE may determine hypothalamic NE availability. Many of the GnRH-stimulating and GnRH-inhibiting signals may influence the 'pulse-generator' by acting on GnRH neurons as second level signals. Hypothalamic GnRH is also released in a "surge" manner that is triggered either by increasing levels of circulating steroids (E2 and progesterone) during the preovulatory period in spontaneous-ovulating species, or by coitus in induced-ovulating animals. The sequential steps and mechanisms by which the GnRH surge occurs after E2 or coitus are not clear. However, it is unlikely that the E2 or coital stimuli act directly on GnRH neurons; E2 receptors have not been found in GnRH cells whereas coital signals must stop in the brainstem before they reach the hypothalamus. The brainstem may be an extra-hypothalamic site where both E2 and coital stimuli are transformed into GnRH-stimulating signals. One such signal may be NE whose brainstem cell bodies send terminals into the hypothalamus. Evidence from our laboratory suggests that a hypothalamic NE surge occurs at the time of the preovulatory GnRH surge in both the monkey and rabbit. Moreover, gene expression of both tyrosine hydroxylase (the rate-limiting enzyme for NE synthesis) and NET (the rate-limiting factor for synaptic NE transmission) in the brainstem increases after E2 in the monkey and after coitus in the rabbit. Other hypothalamic and/or brainstem signals, i.e., NPY, galanin, beta-endorphin, nitrous oxide and gamma aminobutyric acid, are likely involved in generating, maintaining and/or modulating the GnRH surge process. A better understanding of the up-stream GnRH-regulating signals will help improve treatments for many reproductive disorders associated with stress, obesity, infection and aging.