The Effects of the Mediators of Systemic Inflammatory Response on Reproductive Function

Mediators and products of the systemic inflammatory response affect the hypothala-mic-pituitary-gonadal axis at multiple levels. In the testis, Leydig cells and interstitial testicular macrophages are functionally related; the interactions between these two cell types can be both beneficial and deleterious (19). During development, the presence of interstitial macrophages is necessary for Leydig cell maturation (19). However, inflammatory mediators produced by the activated macrophage-derived cells inhibit the production of steroid hormones by Leydig cells. Activated macrophages produce proinflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), that act as transcriptional repressors of several steroidogenic enzymes in the Leydig cell (19,20). In addition, macrophages produce reactive oxygen species (ROS) that inhibit steroidogenic acute response (StAR) protein expression. The net result is decreased testosterone production by the Leydig cells.

The mediators of inflammatory and stress responses can activate the hypothala-mic-pituitary-adrenal axis, which inhibits hypothalamic GnRH secretion (21-24). Inputs from the cerebral cortex, subcortical systems, the sensory organs, and sensory nerves, generated in response to stress, induce corticotropin-releasing hormone (CRH) production that inhibits GnRH secretion and the LH response to gonadotropin-releasing hormone (GnRH) and increases Cortisol secretion. Glucocorticoids inhibit GnRH secretion, the pituitary LH response to GnRH, and testicular steroidogenesis. In addition, several products and mediators of the systemic inflammatory response exert direct inhibitory effects on hypothalamic GnRH secretion and Leydig cell steroidogenesis. Endotoxin administration in animal models suppresses GnRH secretion, reduces pulsatile LH secretion, and attenuates the LH response to GnRH (22,23). Endotoxin administration also disrupts the estradiol-induced LH surge in the female rat by interfering with the early activating effects of the estradiol signal (24). Inhibitory effects of endotoxin on GnRH secretion are mediated partly through increased cortisol secretion; however, direct inhibitory effects of endotoxin on GnRH secretion that are independent of the activation of the hypothalamic-pituitary-adrenal axis have also been demonstrated (22).

Several proinflammatory cytokines—IL-1a, IL-ip, and TNF-a—inhibit LH secretion; of these, IL-ip is the most potent inhibitor (25). IL-ip, generated within the central nervous system (CNS) during the course of the inflammatory response, upregulates opioid and tachykinin peptides in the hypothalamus (25). These two groups of neu-ropeptides—the opioids and the tachykinins—convey the cytokine signal to neuroendocrine neurons and cause hypothalamic GnRH suppression.

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