Neuroimmune and Endocrine Interactions Driving Female-biased Mechanisms in Reproductive Physiology and Pain

Sex and gender disparities in healthcare have a profound negative impact on women’s health. Until recently, most preclinical neuroscience research has relied almost entirely on male animals to the exclusion of females due to perceived confounds by hormonal cycling. The usage of female animals in preclinical settings in recent years has opened a realm of possibility in neuroscience research as many groups have demonstrated sex biases in neuroimmune and endocrine crosstalk. Several disorders exhibit female-biased prevalence, including many chronic pain disorders and reproductive system disorders. Additionally, treatments for these disorders are often less effective in women and come with ill-tolerated side effects. Thus, there is a strong need to study female- biased mechanisms in these disorders to improve therapeutics and patient outcomes. This work focuses the role of metabolic stress, both cellular and whole-body, in the regulation of female fertility. First, we induced whole-body metabolic stress via consumption of a high-fat diet by young female mice and measured changes in estrous cycling and serum progesterone. We found that a high-fat diet induces transient shifts in estrous cycling and progesterone levels prior to overt weight gain. Next, we utilized a transgenic mouse model with conditional removal of LKB1 in peripheral sensory neurons to model neuronal metabolic stress. Females with LKB1 deletion have greatly enhanced fertility compared to wild-type mice, with no effect of LKB1 removal in male mice. Further, LKB1 in sensory neurons promotes ovarian innervation. We then utilized a preclinical model of chronic muscle pain to validate a battery of pain and functional assessments. Those measurements were directly compared to pain and functional assessments performed in a clinical trial with women with FM. Finally, we assessed changes in adaptive immune cell phenotypes before and after treatment with IL-5, a cytokine previously demonstrated to play a unique role in chronic muscle pain and women with FM. Overall, this work highlights female biased mechanisms that modulate neuroendocrine communication and fertility and neuroimmune crosstalk during chronic muscle pain.