Phase 2 N=25 Randomized Quadruple-blind Basic Science

Treating Inflammation in Polycystic Ovary Syndrome to Ameliorate Ovarian Dysfunction

Polycystic Ovary Syndrome

Bottom Line

View on ClinicalTrials.gov: NCT03229408 ↗

Enrolled (actual)

Serious AEs

4.0%

Results posted

Jun 2025

Primary outcome: Primary: Aim 1: HCG-stimulated Testosterone Area Under the Curve — 4458; 7775 Nonograms*Hour per Deciliter (ng*hr/dL) — p=<0.004

Study Design & Population

Study type: Interventional
Phase: Phase 2
Interventions: Salsalate (Drug); Placebo (Other)
Age: Adult · 18+ yrs
Sex: Female
Sponsor: University of Illinois at Chicago
Primary completion: Feb 2024

Outcome Measures

Outcome	Result	p-value
PRIMARY Aim 1: HCG-stimulated Testosterone Area Under the Curve	4458; 7775	<0.004 sig
PRIMARY Aim 2: Lipid-stimulated NFкB Activation	37; 89	<0.03 sig
SECONDARY Aim 1: Insulin Sensitivity (SI)	2.63; 3.71	0.180
SECONDARY Aim 1: Basal Testosterone Level	38; 67	<0.002 sig
SECONDARY Aim 1: Basal Androstenedione Level	2.42; 3.69	<0.04 sig
SECONDARY Aim 1: HCG-stimulated Androstenedione Area Under the Curve	224; 405	<0.003 sig
SECONDARY Aim 2: Lipid Stimulated ROS Generation	31; 95	<0.0004 sig
SECONDARY Aim 2: Lipid-stimulated TNFα Secretion	7.9; 15.1	<0.007 sig

Summary

Polycystic Ovary Syndrome (PCOS) is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovaries. Insulin resistance (IR) is a common feature of PCOS, and the resultant hyperinsulinemia is theorized to promote hyperandrogenism in the disorder. However, 30-50% of women with PCOS who are lean do not have insulin resistance. Women with PCOS also exhibit chronic low-grade inflammation. In PCOS, glucose ingestion activates nuclear factor ĸB (NFĸB), the cardinal signal of inflammation culminating in upregulation of the inflammation pathway within mononuclear cells (MNC). This phenomenon is independent of excess adiposity and is highly correlated with circulating androgens. In addition, in vitro exposure to proinflammatory stimuli is capable of directly stimulating ovarian theca cell androgen production. Nonacetylated salicylates suppress NFĸB activation and are well tolerated in humans. The proposed research is a randomized double-blind placebo-controlled study of 90 women with PCOS. Forty-five subjects with PCOS (15 lean without IR), 15 lean with IR and 15 obese) receiving salsalate, a nonacetylated salicylate, at an oral dose of 3-4 gm daily for 12 weeks will be compared with 45 age- and body-composition-matched control women with PCOS receiving placebo. The overarching hypothesis is that inflammation contributes to ovarian dysfunction, independent of excess adiposity or IR. The specific aims are, I: To examine the effect of salsalate administration on the ovarian capacity to secrete androgen and on insulin sensitivity in PCOS. II: To examine the effect of salsalate administration on the inflammatory response of mononuclear cells induced by lipid ingestion and glucose infusion in PCOS. The approach involves evaluation of ovarian androgen secretion in response to human chorionic gonadotropin (HCG) administration and insulin sensitivity during the euglycemic phase of a two-step pancreatic clamp along with ovulation monitoring before and after salsalate administration. The inflammatory response of MNC to lipid ingestion and the hyperglycemic phase of the two-step clamp will also be evaluated during treatment by measuring reactive oxygen species, the mRNA and protein content of inflammation markers, NFĸB activation and cytokine release in culture. The investigators expect that women with PCOS receiving salsalate will exhibit decreased ovarian androgen secretion and reduced inflammation regardless of adiposity or IR status. These results will be significant if they show a causal contribution of inflammation to ovarian dysfunction in PCOS, thus improving our understanding of the pathogenesis of PCOS, opening previously unexplored therapeutic avenues that are not necessarily dependent on improving IR, and guiding the design of future studies aimed at determining what interventions will optimally attenuate inflammation in PCOS to reduce medical disease and enhance fertility.

Eligibility Criteria

Inclusion Criteria

Diagnosis of PCOS based on the presence of hyperandrogenism (skin manifestations of androgen excess such as hirsutism, acne or temporal balding - or -elevation of at least one serum androgen [i.e. total testosterone, free testosterone, androstenedione or dehydroepiandrosterone-sulphate] using predetermined local laboratory cutoffs), oligo/amenorrhea and evidence of withdrawal bleeding after progestin administration.
18-40 years of age.
Good health as evidenced by medical history, physical examination and gynecologic examination within 30 days prior to starting the study.
Willingness to provide informed consent according to the guidelines of the University of Illinois at Chicago (UIC) Institutional Review Board (IRB).
Willingness to use double-barrier contraception such as condoms and topical spermicide (foam, cream or gel), condom and diaphragm, diaphragm and topical spermicide or sponge with topical spermicide if sexually active. Use of a non-hormonal intrauterine device (IUD), or permanent sterilization of the subject or her partner (i.e. tubal ligation or vasectomy) is also acceptable in all instances.

Exclusion Criteria

Hyperprolactinemia.
Uncontrolled thyroid disease.
Evidence of Cushing's syndrome, nonclassic congenital adrenal hyperplasia or a hormone producing tumor based on physical findings and serum androgen levels on initial screening.
Known or suspected pregnancy.
Regular vigorous physical activity during previous 6 months.
Use of any medications known to affect carbohydrate or sex hormone metabolism such as oral contraceptives, progestins, glucocorticoids or insulin sensitizing agents within 30 days of beginning the study.
Acute or chronic inflammatory illnesses (e.g. upper respiratory infection, asthma, rheumatoid arthritis or systemic lupus erythematosus).
Type 1 or type 2 diabetes mellitus defined as having a fasting glucose >126 mg/dl and/or a 2-hour postprandial glucose >200 mg/dl.
Regular smoking defined as more than 2 cigarettes a month, or any smoking within 30 days of beginning the study.
History of any illness exacerbated by salicylate use (e.g. peptic ulcer hepatic or renal disease, anemia, thrombosis, coagulopathy, congestive heart failure, hypertension or gout).
Allergy to salicylate or dairy products.
Medication use interacting with salicylates such as anti-platelet drugs (e.g. cilostazol, clopidogrel), anticoagulants (e.g. enoxaparin, heparin, warfarin), corticosteroids (e.g., prednisone), certain diabetes drugs (e.g. sulfonylureas such as glyburide), certain anti-seizure drugs (e.g. phenytoin, valproic acid), cidofovir, cyclosporine, drugs for gout (e.g. probenecid, sulfinpyrazone), anti-hypertensives (e.g. angiotensin converting enzyme inhibitors such as captopril, angiotensin II receptor antagonists such as losartan, and beta blockers such as metoprolol), drugs that affect the acidity of urine (e.g. ammonium chloride, acetazolamide), lithium, methotrexate, oral bisphosphonates (e.g. alendronate), pemetrexed, selective serotonin reuptake inhibitor antidepressants (e.g. fluoxetine, sertraline), tenofovir, and diuretics (furosemide, hydrochlorothiazide, spironolactone).

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Data sourced from ClinicalTrials.gov (NCT03229408). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.