Endometriosis and Microvascular Dysfunction: Role of Inflammation (Endo3/SA2)

Mechanisms and Interventions Addressing Accelerated Cardiovascular Disease Risk in Endometriosis

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.

Study Overview

• Status: Recruiting
• Conditions: Endometriosis
• Intervention / Treatment: Drug: Salsalate Pill; Drug: Placebo

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. 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.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Lacy M Alexander, Ph.D.; Phone Number: 8148671781; Email: lma191@psu.edu
• Study Contact Backup: Name: Susan Slimak, RN; Phone Number: 814-863-8554; Email: sks31@psu.edu

Study Locations

• United States
  • Pennsylvania
    • University Park, Pennsylvania, United States, 16801
      • Recruiting
      • The Pennsylvania State University
      • Contact: Lacy M Alexander, PhD; Phone Number: 814-867-1781; Email: lma191@psu.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 41 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Salsalate; 3000 mg/day salsalate (1500 mg twice daily) for 5 days	Drug: Salsalate Pill; Salsalate acts as an NFkB inhibitor to reduce systemic inflammation
Placebo Comparator: Placebo; 1 capsule contain microcrystalline cellulose filler (twice daily) for 5 days	Drug: Placebo; Placebo for the salsalate intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
Sera LOX-1 protein expression	Peripheral Blood Mononuclear Cell Isolation, LOX-1 expression quantified using real time pCR	5 days after treatment
Biopsy LOX-1 protein expression	Bio-Rad DC assay, western blot technique used for LOX-1 protein receptor expression	5 days after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
sera reproductive hormone analysis	analysis of plasma estradiol, progesterone, and sex hormone binding globulin determined through hormone assay	5 days after treatment
sera cytokine expression analysis	expression of cytokines CRP, TNF-a, IL-1B, IL-6, IL-8 determined through multiplex assay	5 days after treatment
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

Collaborators and Investigators

• Sponsor: Penn State University

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2022
• 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 24, 2021
• First Posted (Actual): October 6, 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: inflammation; skin blood flow; Lectin-like oxidized LDL receptor (LOX-1); 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; Anti-Inflammatory Agents; Peripheral Nervous System Agents; Antirheumatic Agents; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Salicylsalicylic acid
• Other Study ID Numbers: 18369

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