Treating Inflammation in Polycystic Ovary Syndrome to Ameliorate Ovarian Dysfunction

NCT03229408 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 2017-0476R01DK107605
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Polycystic Ovary Syndrome

Keywords

Inflammation; Hyperandrogenism; Anovulation; Insulin Resistance

Outcome Measures

Primary Outcomes (2)

• Aim 1: HCG-stimulated Testosterone Area Under the Curve

  Data was generated from the post-treatment HCG stimulation test. Area under the curve calculated for serum measurements by chemiluminescence (Siemens Immulite 2000, Cary, NC) from blood samples drawn 0, 24, 48 and 72 hours after HCG administration.

  After 12 weeks of salsalate administration

• Aim 2: Lipid-stimulated NFкB Activation

  Data was generated from the post-treatment cream challenge test. Quantified in nuclear extracts by oligonucleotide-based ELISA (Active Motif, Carlsbad, CA) in mononuclear cells isolated from blood samples drawn while fasting (0 hour) and 2 hours after cream ingestion. Percent change was calculated using the 2 hour NFкB band intensity value determined by densitometry minus the 0 hour NFкB band intensity value divided by the 0 hour NFкB band intensity value, multiplied by 100.

  After 12 weeks of salsalate or placebo administration

Secondary Outcomes (6)

• Aim 1: Insulin Sensitivity (SI)

  After 12 weeks of salsalate or placebo adminitration

• Aim 1: Basal Testosterone Level

  After 12 weeks of salsalate or placebo administration

• Aim 1: Basal Androstenedione Level

  After 12 weeks of salsalate or placebo administration

• Aim 1: HCG-stimulated Androstenedione Area Under the Curve

  After 12 weeks of salsalate or placebo administration

• Aim 2: Lipid Stimulated ROS Generation

  After 12 weeks of salsalate or placebo administration

Study Arms (6)

Salsalate-Treated Lean PCOS without IR

EXPERIMENTAL

n=15

Drug: Salsalate

Placebo-Treated Lean PCOS without IR

PLACEBO COMPARATOR

n=15

Other: Placebo

Salsalate-Treated Lean PCOS with IR

EXPERIMENTAL

n=15

Drug: Salsalate

Placebo-Treated Lean PCOS with IR

PLACEBO COMPARATOR

n=15

Other: Placebo

Salsalate-Treated Obese PCOS

EXPERIMENTAL

n=15

Drug: Salsalate

Placebo-Treated Obese PCOS

PLACEBO COMPARATOR

n=15

Other: Placebo

Interventions

Salsalate DRUG

Lean PCOS Arms: Salsalate 1.5 gm PO bid; Obese PCOS Arm: Salsalate 2.0 gm PO bid

Also known as: Disalcid®, Salsitab®, Amigesic®

Salsalate-Treated Lean PCOS with IR; Salsalate-Treated Lean PCOS without IR; Salsalate-Treated Obese PCOS

Placebo OTHER

Appears identical to experimental drug

Placebo-Treated Lean PCOS with IR; Placebo-Treated Lean PCOS without IR; Placebo-Treated Obese PCOS

Eligibility Criteria

• Age: 18 Years - 40 Years
• Gender Eligibility Details: Polycystic ovary syndrome is a female endocrine disorder.
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• University of Illinois at Chicago: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

Frank González

Chicago, Illinois, 60612, United States

Location

Related Publications (1)

• Gonzalez F, Mather KJ, Considine RV, Abdelhadi OA, Acton AJ. Salicylate administration suppresses the inflammatory response to nutrients and improves ovarian function in polycystic ovary syndrome. Am J Physiol Endocrinol Metab. 2020 Oct 1;319(4):E744-E752. doi: 10.1152/ajpendo.00228.2020. Epub 2020 Aug 24.

  PMID: 32830548 BACKGROUND

Related Links

• Principal Investigator's research laboratory and research program description
• Principal Investigator's National Center for Biotechnology Information MyBibliography
• Principal Investigator's research profile
• Principal Investigator's career profile

MeSH Terms

Conditions

Polycystic Ovary Syndrome; Inflammation; Hyperandrogenism; Anovulation; Insulin Resistance

Interventions

salicylsalicylic acid; Sodium Salicylate

Condition Hierarchy (Ancestors)

Ovarian Cysts; Cysts; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Gonadal Disorders; Endocrine System Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; 46, XX Disorders of Sex Development; Disorders of Sex Development; Urogenital Abnormalities; Adrenogenital Syndrome; Male Urogenital Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Salicylic Acid; Salicylates; Hydroxybenzoates; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Hydroxy Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Phenols

Limitations and Caveats

The COVID-19 pandemic severely stunted participant accrual culminating in a limited sample size of completed subjects (salsalate; n=6; placebo; n=7). Therefore, combining weight class groups was a reasonable approach to compare outcome measures in salsalate versus placebo.

Results Point of Contact

• Title: Frank González
• Organization: University of Illinois at Chicago

frgz12@uic.edu

(312) 413-1984

Study Officials

• Frank González, M.D.

  University of Illinois at Chicago

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Laboratory for Reproductive Endocrine and Inflammation Research

Study Record Dates

• First Submitted: July 15, 2017
• First Posted: July 25, 2017
• Study Start: December 5, 2018
• Primary Completion: February 14, 2024
• Study Completion: February 28, 2024
• Last Updated: June 10, 2025
• Results First Posted: June 10, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)