The impact of hormonal modulation on systemic inflammation and central sensitization

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Abstract. Chronic pelvic pain remains a challenging condition to treat, in large part because underlying disease mechanisms are poorly understood. Endometriosis-associated pelvic pain (EAPP) is a common form of CPP wherein the severity of disease is only weakly associated with the degree of pain experienced. While pelvic inflammation is a well-established contributing factor to EAPP, we propose that low-grade systemic inflammation also contributes to the disease state by promoting central nervous system (CNS) sensitization. Emerging evidence from our group and others suggests that low-grade systemic inflammation can promote multiple aspects of CNS sensitization including clinical manifestations (comorbid pain conditions, widespread pain), hypersensitivity to experimental stimuli, and altered brain functional connectivity in pelvic pain. While hormonal suppression is effective for many women, and acts in part by dampening estradiol-dependent pelvic inflammation, little is known about the relative contributions of low-grade systemic inflammation and CNS sensitization to EAPP. We propose to use the FDA-approved, gonadotropin releasing hormone receptor antagonist, elagolix, available in two dosages, as a mechanistic probe to assess the effects of pelvic and systemic inflammation on EAPP. The presence of robust dose-dependent effects on EAPP and its comorbid symptoms suggests to us that the higher dose also reduces CNS sensitization, possibly due to reduced systemic inflammation. To investigate this hypothesis, we will conduct a double-blind, placebo controlled randomized clinical trial in which 200 women with EAPP will be randomly assigned to low-dose (150mg daily) or high-dose (400mg daily) elagolix or placebo with evaluation of pain mechanism outcomes prior to and after treatment. We will focus on two common patient phenotypes – those with EAPP only and those with EAPP and widespread pain (1:1 recruitment). In Aim 1, we will first define the relationship between pelvic inflammation, systemic inflammation, and CNS sensitization using well-vetted neurobiological measures of CNS sensitization. We anticipate that systemic inflammation will be associated with CNS sensitization, while pelvic inflammation will not be. In Aim 2, we will identify dose-dependent changes in CNS sensitization as well as systemic and pelvic inflammation during hormonal suppression for EAPP through the above-described clinical trial. We anticipate that both dosages will improve pelvic inflammation, but that systemic inflammation and CNS sensitization will be improved on high-dose elagolix. We furthermore anticipate that those with widespread pain will be more likely to respond to high-dose elagolix. In an exploratory Aim 3, we will determine if baseline levels of pelvic and/or systemic inflammatory activity, as well as CNS sensitization, predict the response to elagolix. These studies are critical to develop alternative mechanistic models of pain promotion and relief in this vulnerable group of patients and will have implications for understanding hormonal contributions to the female preponderance of chronic pain syndromes.