Endometriosis and Microvascular Dysfunction: Role of Inflammation

Endometriosis Clinical Trial

— Endo3/SA2  

Official title:

Mechanisms and Interventions Addressing Accelerated Cardiovascular Disease Risk in Endometriosis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05069740
• Other study ID #: 18369
• Status: Recruiting
• Phase: Early Phase 1
• Start date: February 1, 2022
• Est. completion date: December 31, 2026

Study information

• Verified date: February 2024
• Source: Penn State University
• Contact: Lacy M Alexander, Ph.D.
• Phone: 8148671781
• Email: lma191[@]psu.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to better understand the underlying mechanisms associated with elevated cardiovascular disease risk in women with endometriosis, and to measure the effectiveness of emerging endometriosis treatments on outcomes specific to cardiovascular dysfunction. Epidemiologic data demonstrate a clear association between endometriosis, reproductive risk factors, inflammation and cardiovascular (CV) risk. Circulating factors, low-density lipoprotein (LDL) and oxidized LDL (oxLDL), are two of many biomarkers of cardiovascular and inflammatory disease of endometriosis. An important signaling mechanism through which circulating LDL and oxLDL act is the lectin-like oxidized LDL receptor (LOX-1). LOX-1 signal transduction functionally results in pronounced endothelial dysfunction, a hallmark of CV. The investigators hypothesis that one factor mediating the elevated risk of cardiovascular disease in endometriosis is systemic inflammation and activation of LOX-1 receptor mechanisms.

Description:

Endometriosis is an estrogen-dependent gynecological disorder associated with considerable chronic pelvic pain, pain during intercourse, and is a major cause of infertility. This disorder affects 6% - 10% of reproductive age women and can be as high as 35-50% in women experiencing pain or infertility. Endometriosis derives from the presence of endometrium-like tissue in sites outside the uterine cavity. While endometriosis is a local inflammatory syndrome, the inflammatory process is systemic. Endometriosis is associated with higher risk of hypercholesterolemia and hypertension 8. Epidemiologic data demonstrate a clear association between endometriosis, reproductive risk factors, inflammation and cardiovascular (CV) risk. Endometriosis a disease of inflammation and increased systemic inflammatory cytokine production, although the precise mechanisms by which localized lesion results in systemic inflammation are incompletely understood. Published data confirm an elevation of several inflammatory cytokines in the circulation of women with endometriosis. Alterations in circulating miRNAs specific to endometriosis are one mechanism causing immune dysfunction and subsequent increased cytokine expression in areas remote from the endometriotic lesions. This aberrant increase in systemic cytokine production is a highly plausible putative link to accelerated vascular dysfunction and atherosclerosis in women with endometriosis. The circulating factors LDL and oxidized LDL are two of the many biomarkers of cardiovascular and inflammatory disease of endometriosis. An important signaling mechanism through which circulating LDL and oxLDL act is the lectin-like oxidized LDL receptor (LOX-1). LOX-1 is a ubiquitously expressed scavenger receptor, stimulated by oxLDL, Ang II, and other inflammatory cytokines, and inhibited by estrogen. LOX-1 is the upstream signaling initiator of mechanisms including increased oxidant production, reduced nitric oxide (NO) metabolism, and impaired intracellular trafficking. Thus, LOX-1 signal transduction functionally results in pronounced endothelial dysfunction.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 24
• Est. completion date: December 31, 2026
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 45 Years

Eligibility

Inclusion Criteria:

• Healthy women between the ages of 18 and 45 years (Controls), taking oral contraceptive or with regular menses every 26-34 days
• Women between the ages of 18 and 45 years with endometriosis (diagnosis by prior laparoscopy by subject's own physician <5 years prior, and reported by the subject to the researchers)
• Tylenol if the subject has acute pain is allowed
• Contraceptive use 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 (including salsalate or simvastatin)
• History of gastrointestinal bleeding

Related Conditions & MeSH terms

• Endometriosis

Intervention

Drug:
• Salsalate Pill
Salsalate acts as an NFkB inhibitor to reduce systemic inflammation
• Placebo
Placebo for the salsalate intervention

Locations

Country	Name	City	State
United States	The Pennsylvania State University	University Park	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Penn State University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	cutaneous vascular conductance	doppler flowmetry used to measure cutaneous vascular conductance (cvc = red cell flux/mean arterial pressure) to assess microvascular endothelial function	5 days after treatment
Primary	brachial artery diameter and blood flow velocity	continuous ultrasound imaging measurements of brachial artery diameter and blood flow velocity to assess endothelial function	5 days after treatment
Primary	Sera LOX-1 protein expression	Peripheral Blood Mononuclear Cell Isolation, LOX-1 expression quantified using real time pCR	5 days after treatment
Primary	Biopsy LOX-1 protein expression	Bio-Rad DC assay, western blot technique used for LOX-1 protein receptor expression	5 days after treatment
Secondary	sera reproductive hormone analysis	analysis of plasma estradiol, progesterone, and sex hormone binding globulin determined through hormone assay	5 days after treatment
Secondary	sera cytokine expression analysis	expression of cytokines CRP, TNF-a, IL-1B, IL-6, IL-8 determined through multiplex assay	5 days after treatment
Secondary	skin biopsy biochemical analysis	the expression of estrogen receptor alpha and beta, the protein pVASP/VASP, and the enzyme peNOS/eNOS is determined using Bio-Rad DC assay, western blot technique	5 days after treatment