Endometriosis and Microvascular Dysfunction; Simvastatin and Duavee

Study Overview
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Brief Summary
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Purpose: To determine the effects of SERM and simvastatin interventions on endothelial dysfunction in women with endometriosis. Hypothesis: Treatment with the SERM (bazedoxifene + conjugated estrogen) or with simvastatin will decrease systemic inflammation and improve specific measures of cardiovascular function including endothelium-dependent vasodilation.

Detailed Description
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Endometriosis is an estrogen dependent gynecological disorder associated with considerable chronic pelvic pain, pain during intercourse and is a major cause of infertility. While endometriosis is a local inflammatory syndrome, the inflammatory process is systemic and underlies many of the co-morbidities associated with this devastating disease. Endometriosis and atherosclerotic cardiovascular disease (CVD) are both inflammation-induced diseases. Robust epidemiologic data demonstrate a clear association between endometriosis, reproductive risk factors, inflammation and CVD risk, the leading cause of death in women worldwide. 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. Moreover, there is a significant gap in prior research into the role of inflammatory signaling, CVD risk and effective interventions to mitigate cardiovascular comorbidities. Endometriosis and Endothelial Dysfunction: Circulating LDL and oxidized (ox)LDL are two of many biomarkers of cardiovascular and inflammatory disease elevated in women with endometriosis. These circulating factors and inflammatory cytokines stimulate the ubiquitously expressed scavenger lectin-like oxidized LDL receptor (LOX-1) on the vasculature resulting in increased oxidant production and reduced nitric oxide (NO) metabolism, resulting in pronounced endothelial dysfunction, one of the earliest detectable indicators of increased CVD risk. Interestingly, estrogen directly inhibits LOX-1-dependent endothelial dysfunction. Our working model is that endometriosis-associated systemic inflammatory mediators increase LOX-1 receptor activity and result in endothelial dysfunction. Therapies approved in 2018 for the treatment of endometriosis reduce endogenous estrogen production (elagolix) or selectively modulate estrogen receptors (SERM, bazedoxifene). Additionally, in preclinical models, therapies that modulate vascular function (statins) are also efficacious for reducing endometriosis proliferation. However, to date no studies have evaluated outcomes specific to systemic inflammation and cardiovascular function with these emerging endometriosis therapies. This is a single arm pre/post study design. Only women with endometriosis will complete this study. Women will be between the ages of 18 and 45 years and previously diagnosed (within the past 5 years) with endometriosis. Once consented and screened, each subject is block randomized to either 30 days of a treatment (Simvastatin or 30 days of SERM (bazedoxifene + conjugated estrogen; BZE+CE)) and , or statin. This will be done in a counterbalanced fashion. Subjects will only complete one of the treatments and the placebo with a 60 day washout to minimize potential carryover effects. On day 30 of pretreatment , each subject participates in a cutaneous microdialysis (MD) and flow mediated dilation (FMD) experiment. After a 60-day washout, the participant will start either the treatment or placebo and returns to repeat the study with the other pre-treatments (SERM/Statin/Placebo)undergo the MD and FMD experiments. These treatments/placebo are blinded to the investigators collecting and analyzing the data.

Official Title
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Mechanisms and Interventions Addressing Accelerated Cardiovascular Disease Risk in Women With Endometriosis

Conditions
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Endometriosis

Intervention / Treatment
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* Drug: simvastatin 10mg
* Drug: Bazedoxifene 20/Estrogens,Con 0.45Mg Tb


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women between the ages of 18 and 45 years with endometriosis (diagnosis by prior laparoscopy by subject's own physician <10 years prior, and reported by the subject to the researchers) Tylenol if the subject has acute pain is allowed IUD contraceptive use (copper or levonogestrel) is allowed Exclusion Criteria: Use of nicotine-containing products (e.g. smoking, chewing tobacco, etc.) Diabetes (HbA1C .6.5%) BP>140/90 Taking pharmacotherapy that could alter peripheral vascular control (e.g. insulin sensitizing, cardiovascular medications) Pregnancy Breastfeeding Taking illicit and/or recreational drugs Abnormal liver function Rash, skin disease, disorders of pigmentation, known skin allergies Diagnosed or suspected metabolic or cardiovascular disease Persistent unexplained elevations of serum transaminases Known allergy to latex or investigative substances

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a single arm randomized study. Only women with endometriosis will complete this study. Once consented and screened, each subject is block randomized to either 30 days of a treatment (Simvastatin or 30 days of SERM (bazedoxifene + conjugated estrogen; BZE+CE)). This will be done in a counterbalanced fashion. Subjects will have the option of completing the other arm of the study but will undergo a 60 day washout to mimimize carry over effect. We will use Research Randomizer software. These treatments are blinded to the investigators collecting the data and performing the data analysis.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Simvastatin<br>30 days of Simvastatin (10mg/day) | Drug: simvastatin 10mg<br>* Simvastation acts as a systemic LOX inhibitor.<br>|
| Other: bazedoxifene + conjugated estrogen<br>30 days of bazedoxifene + conjugated estrogen (0.45mg/20mg/day) | Drug: Bazedoxifene 20/Estrogens,Con 0.45Mg Tb<br>* Duavee is a selective estrogen receptor modulator.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in skin blood flow | cutaneous vascular conductance (units = red cell flux/mean arterial pressure) | before intervention and 30 days post-intervention | 
| Change in peripheral blood flow | brachial artery flow mediated dilation | before intervention and 30 days post-intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in LOX-1 activity | LOX-1 receptor expression | before intervention and 30 days post-intervention | 
| Change in reproductive hormones | blood hormone concentrations | before intervention and 30 days post-intervention | 
| Change in inflammation | inflammatory cytokine concentration | before intervention and 30 days post-intervention | 
| Change in microRNA activity | microRNA expression | before intervention and 30 days post-intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Skin blood flow, Estrogen, Selective Estrogen Receptor Modulator, Intradermal Microdialysis