Mechanisms and interventions addressing accelerated cardiovascular disease risk in women with endometriosis

Endometriosis and is a debilitating estrogen-dependent gynecological disorder deriving from the presence of
endometrium like tissue in sites outside the uterine cavity. Approximately 6-10% of women have endometriosis
and suffer from symptoms including chronic pelvic pain, pain during intercourse, infertility, and other co-
morbidities associated with systemic inflammation. The widespread nature of this disease extends to impact
overall health, including contributing to elevated risk of cardiovascular disease (CVD) --the leading cause of
death in women. Endometriosis and atherosclerotic CVD are both inflammation-induced diseases. Estrogen
exposure is beneficial for women from a CVD standpoint, but the standard of treatment for endometriosis
includes estrogen suppression. This creates a conundrum for the long-term management of CVD risk in women
with endometriosis. This proposal fills a significant gap in prior research into the role of inflammatory signaling,
CVD risk and effective interventions to mitigate cardiovascular comorbidities. Circulating oxidized lipids and
inflammatory cytokines that are elevated in women with endometriosis stimulate the ubiquitously expressed
scavenger lectin-like oxidized LDL receptor (LOX-1) on the vasculature resulting in pronounced endothelial
dysfunction, one of the earliest detectable indicators of increased CVD risk. Estrogen directly inhibits LOX-1-
dependent endothelial dysfunction and thus the standards of care for endometriosis treatment may be
exacerbating CVD risk. Our working model is that endometriosis-associated systemic inflammatory mediators
increase LOX-1 receptor activity and result in endothelial dysfunction. Our global hypothesis is that in women
with endometriosis increased CVD risk is the result chronic systemic inflammation inducing endothelial
dysfunction, mediated through LOX-1 receptor, and this CVD risk is exacerbated by standard estrogen
suppression treatments. In this application, we use a multipronged approach including in vivo and ex vivo human
physiological experiments to determine the role of inflammation and estrogen suppression on cardiovascular
specific outcomes in the setting of endometriosis. This series of studies in women with endometriosis will
delineate the roles of estradiol (Specific Aim 1) and systemic inflammation (Specific Aim 2) in endometriosis-
associated accelerated CVD risk. These studies will evaluate novel signaling mechanisms including the linkage
common to both CVD and endometriosis through the downstream activation of the ubiquitous scavenger receptor
LOX-1. We will also test the effects of two distinct interventions (Specific Aim 3) including the selective estrogen
receptor modulator bazedoxifene, and the statin simvastatin in mitigating CVD risk in women with endometriosis.
Our studies have the potential to identify clinically relevant therapeutic targets and interventions thus decreasing
CVD burden in women with endometriosis.

Grant Number: 5R01HL161000-04
NIH Institute/Center: NIH
Principal Investigator: Lacy Alexander