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

The Pennsylvania State University (PENNSTATE)

Status and phase: Enrolling; Early Phase 1

Conditions: Endometriosis

Treatments: Drug: Salsalate Pill; Drug: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT05069740

18369

Details and patient eligibility

About

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.

Full 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.

Enrollment: 24 estimated patients

Sex: Female

Ages: 18 to 45 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Single Blind

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24 participants in 2 patient groups, including a placebo group

Salsalate

Experimental group

Description:

3000 mg/day salsalate (1500 mg twice daily) for 5 days

Treatment:

Drug: Salsalate Pill

Placebo

Placebo Comparator group

Description:

1 capsule contain microcrystalline cellulose filler (twice daily) for 5 days

Treatment:

Drug: Placebo