ABSTRACT
I. INTRODUCTION The presence of infectious and inflammatory diseases, critical illness, and a variety of trauma often leads to low sex steroid levels and decreased reproductive activity [1-7]. Numerous mechanisms have been invoked to explain this phenomenon, and an overview of presently available information suggests that two types of neurosecretagogues play a critical role: corticotropin-releasing factor (CRF), a peptide released in the brain during stress that inhibits luteinizing hormone (LH)–releasing hormone (LHRH) and LH synthesis and/or release [8], and pro-inflammatory cytokines, which can inhibit both the synthesis/ secretion of hypothalamic LHRH [9,10] and testicular steroidogenesis [11]. Pro-inflammatory cytokines such as tumor necrosis factor- (TNF-), interleukin-1 (IL-1) and IL-6 are proteins that were originally thought to be released only by activated immune cells during infection or inflammation. We now know that these proteins may also be present under basal, nonpathological conditions in the brain [12] and can be synthesized in (and released from?) nonimmune cells such as glial and neural cells [13-17]. In addition, there is convincing evidence that TNF-, IL-1, and IL-6 secretion is stimulated by nonimmune (neurogenic) stressors such as footshocks, restraint and, in humans, mental stress and strenuous exercise [18-23]. Not surprisingly, the array of circumstances during which proinflammatory cytokines are now thought to modulate reproductive functions has increased accordingly [2]. This chapter is not meant as an inclusive overview of all of the effects of CRF and cytokines on the hypothalamic-pituitary-gonadal (HPG) axis, nor does it
describe all of the secretagogues that are released by these peptide/proteins and therefore potentially participate in their influence. The role of CRF on LHRH/LH release has already been addressed in detail [9], and the conclusions discussed in this review remain valid. Rather, we will first focus on what we consider the most salient facts regarding the sites at which pro-inflammatory cytokines modify the release of LHRH, LH, and testosterone (T) in males and some of the mechanisms involved in this influence. Second, we will discuss recent findings, mostly obtained in our laboratory, that point to a neural pathway through which the brain exerts a very rapid inhibitory influence on Leydig cell activity that is independent of the pituitary, but is activated by CRF and specific cytokines. The literature that we cite should be regarded as illustrative rather than comprehensive.
