Endometriosis and Microvascular Dysfunction; Simvastatin and Duavee

NCT ID: NCT05059626

Last Updated: 2024-11-05

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 28 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-12-01
• Study Completion Date: 2026-12-31

Brief Summary

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

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.

Conditions

Endometriosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: SINGLE

Study Groups

Simvastatin

30 days of Simvastatin (10mg/day)

Group Type: OTHER

simvastatin 10mg

Intervention Type: DRUG

Simvastation acts as a systemic LOX inhibitor.

bazedoxifene + conjugated estrogen

30 days of bazedoxifene + conjugated estrogen (0.45mg/20mg/day)

Group Type: OTHER

Bazedoxifene 20/Estrogens,Con 0.45Mg Tb

Intervention Type: DRUG

Duavee is a selective estrogen receptor modulator.

Interventions

simvastatin 10mg

Simvastation acts as a systemic LOX inhibitor.

Intervention Type: DRUG

Bazedoxifene 20/Estrogens,Con 0.45Mg Tb

Duavee is a selective estrogen receptor modulator.

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

The John B. Pierce Laboratory

OTHER

Sponsor Role: collaborator

Penn State University

OTHER

Sponsor Role: lead

Responsible Party

Lacy Alexander

Professor of Kinesiology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

The John B. Pierce Laboratory

New Haven, Connecticut, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Lacy M Alexander, PhD

Role: CONTACT

lma191@psu.edu

814-867-1781

Susan K Slimak, RN

Role: CONTACT

sks31@psu.edu

814-863-8556

Facility Contacts

Nina Stachenfeld, Ph.D.

Role: primary

nina.stachenfeld@yale.edu

203-562-9901 ext. 219

Other Identifiers

18347

Identifier Type: -

Identifier Source: org_study_id