SAT-418 Estradiol Enhances the Inhibitory Effect of the Cytokine Interleukin 1B on Pulsatile LH Secretion in Female Mice

Abstract

Inflammatory and infectious processes can disrupt reproduction function and fertility in a wide range of species including humans, domesticated species and laboratory animals. Immune cells produce cytokines in response to systemic stressors such as lipopolysaccharide and these cytokines have the potential to disrupt the central mechanisms controlling gonadotropin secretion and ovulatory cyclicity in females. When administered peripherally, interleukin (IL)1B, a member of the interleukin-1 family of cytokines, has been shown to inhibit the proestrus luteinizing hormone (LH) surge in intact female rats. However, in male gonadectomized rats, IL1B delivered via intraperitoneal (i.p.) injection does not alter LH secretion, so the effect of IL1B may depend on the presence of gonadal steroids. Here, we began by investigating whether peripheral IL1B can inhibit mean LH secretion in female mice and if estradiol is necessary for this inhibition. Female C57bl6 mice (10 wk) were ovariectomized and implanted with a silastic capsule containing oil or 100ng estradiol, which approximates a diestrus level. LH was measured prior to and 60, 120 and 180 min following i.p. administration of 2ng/g IL1B or saline (control) from tail-tip blood samples. In oil treated females, mean LH did not significantly change following saline, compared to pretreatment levels. Treatment with IL1B elicited a 39% reduction in LH at 120 min; LH was not significantly different 60 or 180 min following IL1B. In animals treated with estradiol, IL1B elicited a more rapid and robust reduction in LH at all three time points. LH was reduced by 50%, 71% and 68%, at 60, 120 and 180 min, respectively. These data indicate that estradiol enhances the LH response to peripheral IL1B. Based on these findings, we have conducted two experiments. First, we performed a study (N=13) to measure pulsatile LH prior to and following i.p. administration of 2ng/g IL1B or saline (control) in ovariectomized C57bl6 mice pretreated with estradiol. Second, we are investigating the neural pathways whereby IL1B may access the kisspeptin and GnRH circuit to influence LH pulsatility using c-Fos as a marker. These data suggest that estradiol affects neural pathways by which stress hormones influence reproduction and may indicate why women are differentially responsive to inflammatory signals depending on their ovarian cycle stage.