Treating Inflammation in Polycystic Ovary Syndrome to Ameliorate Ovarian Dysfunction

PCOS is characterized by hyperandrogenism, ovarian dysfunction and polycystic ovarian morphology. Obesity and IR are common features of PCOS. Under the current model of pathophysiology of PCOS, the compensatory hyperinsulinemia of IR is the primary driver of hyperandrogenism. This concept was born from the cross-sectional observation that insulin is positively correlated with androgens in obese women with PCOS, and is supported by reports of increased androgen production from theca cells obtained from obese women with PCOS following insulin exposure in vitro and increases in circulating androgens in women with PCOS following insulin infusion in vivo. However, these in vitro - in vivo responses were elicited with supraphysiological insulin concentrations. Physiological insulin infusion on the other hand does not augment androgen levels in PCOS. The current model also does not explain the cause of hyperandrogenism and ovarian dysfunction in the 30-50% of women with PCOS who are lean and lack IR. Thus, some other factor contributes to these abnormalities in PCOS.

The investigators have shown that ingestion of glucose and saturated fat elicits an inflammatory response from circulating MNC in lean women with PCOS who lack excess abdominal adiposity. The hallmark of this response is increased activation of NFĸB, the cardinal signal of inflammation. These findings illustrate the separate and discrete role of MNC in manifesting inflammation in PCOS and that MNC are an excellent model to assess systemic inflammation in PCOS.

The investigators have also shown that in PCOS, there is a link between molecular markers of inflammation from MNC and circulating androgens. Chronic suppression of ovarian androgen production does not ameliorate inflammation in lean women with PCOS. However, in vitro exposure of ovarian theca cells to proinflammatory stimuli upregulates CYP17, the androgen producing enzyme and increases testosterone.

Salsalate is an inexpensive, safe, well-tolerated, well-understood anti-inflammatory agent that inhibits NFĸB activation when used at higher doses. The salsalate dose required to achieve a salicylate level in the upper therapeutic range is dependent on body mass. This is achieved in lean individuals using 3.0 gm/day as the maximum dose recommended in the salsalate package insert. Individuals across the obese range (30-40 kg/m2) require >3.0 gm/day to achieve the same objective. Salsalate and other salicylates have also been shown to decrease IR. However, the ability of salsalate to decrease IR would not be necessary if the beneficial anti-inflammatory effect of salsalate to reduce hyperandrogenism is on the ovaries. In fact, we have shown that in lean insulin-sensitive women with PCOS, salsalate reduces HCG-stimulated ovarian androgen secretion by 44% and normalizes basal testosterone levels. Studies performed by the investigators in MNC also confirm the ability of salsalate to suppress NFĸB activation. Together these observations validate the use of these measurements as endpoints to assess the effects of salsalate to probe the pathophysiology of PCOS.

Salsalate raises circulating insulin due to its ability to decreased insulin clearance from the liver which confounds the assessment of insulin sensitivity from post-treatment hyperinsulinemic-euglycemic clamp studies. Performance of a novel minimal model-based analysis from an insulin-modified frequently-sampled intravenous glucose tolerance test (FS-IVGTT) is able to address this confounding factor. With this approach, hepatic and extrahepatic insulin clearance can be estimated before and after salsalate treatment to obtain measures of insulin sensitivity that take into account the salsalate-induced alteration in insulin clearance.