Treating Inflammation in Polycystic Ovary Syndrome to Ameliorate Ovarian Dysfunction
Status:
Recruiting
Trial end date:
2022-07-31
Target enrollment:
Participant gender:
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.
Phase:
Phase 2
Details
Lead Sponsor:
University of Illinois at Chicago
Collaborator:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)