Endometriosis and Microvascular Dysfunction; Simvastatin and Duavee (Endo2/SA3)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Endometriosis
• Intervention / Treatment: Drug: simvastatin 10mg; Drug: Bazedoxifene 20/Estrogens,Con 0.45Mg Tb

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.

• Study Type: Interventional
• Enrollment (Estimated): 28
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Susan K Slimak, RN; Phone Number: 814-863-8556; Email: sks31@psu.edu
• Study Contact Backup: Name: Lacy M Alexander, PhD; Phone Number: 814-867-1781; Email: lma191@psu.edu

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Recruiting
      • The John B. Pierce Laboratory
      • Contact: Nina Stachenfeld, Ph.D.; Phone Number: 219 203-562-9901; Email: nina.stachenfeld@yale.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Penn State University
• Collaborators: The John B. Pierce Laboratory

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2023
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: September 10, 2021
• First Submitted That Met QC Criteria: September 20, 2021
• First Posted (Actual): September 28, 2021

Study Record Updates

• Last Update Posted (Estimated): November 5, 2024
• Last Update Submitted That Met QC Criteria: November 4, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Estrogen; Selective Estrogen Receptor Modulator; Skin blood flow; Intradermal Microdialysis
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genital Diseases, Female; Endometriosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Enzyme Inhibitors; Antimetabolites; Bone Density Conservation Agents; Hormone Antagonists; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Estrogens; Bazedoxifene; Simvastatin
• Other Study ID Numbers: 18347

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No