It is well established that endotoxemia disrupts reproductive capability, and several proinflammatory cytokines, especially IL-1 beta, IL-6, and TNF-alpha in the brain, have been implicated in this endocrine aberration. However, no previous study has directly compared the effects of the three major proinflammatory cytokines (IL-1 beta, IL-6, and TNF-alpha) on the in vivo release of hypothalamic GnRH, a secretagogue of LH from the pituitary. Therefore, in this study, we addressed this issue with two complementary approaches involving push-pull perfusion in freely moving ovariectomized female rats. First, we examined the effects of systemic lipopolysaccharide (LPS) treatment on the release of plasma LH, and of GnRH, IL-1 beta, IL-6, and TNF-alpha in the hypothalamic medial preoptic area (MPOA), where the majority of GnRH neuronal perikarya are located. LPS inhibited the secretion of both LH and GnRH and concomitantly stimulated the release of all three cytokines. We next tested the effects of direct MPOA perfusion with the respective cytokines (at three different concentrations each) on the GnRH and LH secretion. IL-1 beta and TNF-alpha, at the concentrations that were observed in the MPOA after the LPS injection, were equipotent in inhibiting the GnRH-LH system, whereas IL-6 was ineffective (even at a supraphysiological concentration). These results strongly suggest that IL-1 beta and TNF-alpha may represent the major proinflammatory cytokines mediating the LPS-induced suppression of GnRH and LH release, whereas the role of IL-6 seems to be insignificant.
It is still not known whether leptin, an adipocyte‐derived hormone, acts directly within the hypothalamus to stimulate the gonadotropin‐releasing hormone (GnRH)‐luteinizing hormone (LH) system. In order to address this question, the present study examined the effects of direct intrahypothalamic perfusions with leptin on the in vivo release of GnRH in ovarian steroid‐primed ovariectomized rats utilizing the push‐pull perfusion technique. Both α‐melanocyte‐stimulating hormone (α‐MSH) and neuropeptide Y were also measured in the hypothalamic perfusates. In normally fed animals, the leptin infusion was without effect on the release of these three hypothalamic peptides and also without effect on plasma LH and prolactin (PRL), whether leptin was infused into the medial preoptic area (where the majority of GnRH neuronal cell bodies exist) or the median eminence‐arcuate nucleus complex (where axon terminals of GnRH neurons are located). In contrast, in 3‐day fasted rats leptin was effective in stimulating the secretion of GnRH, α‐MSH, and LH, regardless of the site of perfusion. These three hormones were increased in a temporal order of α‐MSH, GnRH and LH. Irrespective of the site of perfusion, leptin was without effect on the release of neuropeptide Y. Only when leptin was infused into the median eminence‐arcuate nucleus complex was PRL secretion also stimulated, although its onset was 1 h behind that of LH. The leptin‐induced elevations of GnRH, α‐MSH, LH and PRL were all dose‐dependently stimulated by subnormal (1.0 ng ml−1) and normal (3.0 ng ml−1) concentrations of leptin, but at higher concentrations (10 ng ml−1) it did not produce additional effects. Leptin infusion into the anterior hypothalamic area, a control site equidistant from both the medial preoptic area and the median eminence‐arcuate nucleus complex, did not produce a significant change in any of the hormones in either the fed or fasted rats. These results demonstrate for the first time that leptin can act at both the cell bodies and axon terminals of GnRH neurons to stimulate the release of the neurohormone in vivo, and they also suggest that α‐MSH may play a significant intermediary role in linking leptin and GnRH secretion.
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