Salicylate administration suppresses the inflammatory response to nutrients and improves ovarian function in polycystic ovary syndrome

Abstract

Oxidative stress (OS) and inflammation are often present in polycystic ovary syndrome (PCOS). We examined the effects of salsalate treatment on nutrient-induced OS and inflammation, ovarian androgen secretion, ovulation, and insulin sensitivity in PCOS. Eight lean insulin-sensitive women with PCOS and eight age- and body composition-matched ovulatory controls for baseline comparison participated in the study. The women with PCOS underwent a 12-wk treatment of salsalate, a nonsteroidal anti-inflammatory drug, at a dose of 3 g daily. Markers of OS and inflammation were quantified in mononuclear cells (MNC) and plasma from blood drawn fasting and 2 h after saturated fat ingestion before and after treatment. Ovarian androgen secretion was assessed from blood drawn fasting and 24, 48, and 72 h after human chorionic gonadotropin (HCG) administration before and after treatment. Ovulation was documented based on biphasic basal body temperatures and luteal range progesterone elevations. A two-step pancreatic clamp was performed pre- and posttreatment to measure basal endogenous glucose production (EGP) and the steady-state glucose disposal rate (GDR) during the euglycemic phase and markers of OS and inflammation in MNC and plasma during the hyperglycemic phase. Salsalate administration suppressed lipid- and glucose-stimulated reactive oxygen species generation, activated nuclear factor-κB and circulating tumor necrosis factor-α, normalized basal androgen levels, and lowered HCG-stimulated androgen secretion without altering EGP or GDR. Four salsalate-treated subjects responded with two consecutive ovulations. We conclude that in PCOS, salsalate-induced suppression of OS and inflammation ameliorates ovarian androgen hypersecretion and may induce ovulation while maintaining insulin action.

Keywords: inflammation; nutrients; ovarian hyperandrogenism; oxidative stress; polycystic ovary syndrome; salicylates.

Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the authors.

Figures

Fig. 1.

Plasma salicylate levels in women with polycystic ovary syndrome (PCOS) were undetectable (

Fig. 2.

Comparison of the change from baseline (%) in mononuclear cell (MNC)-derived markers of oxidative stress and inflammation in women with PCOS before and after salsalate treatment in response to saturated fat ingestion (n = 8) [p47phox protein content (A), activated NF-κB (B), and IκBα protein content (C)] and in response to the hyperglycemic phase of the pancreatic clamp (n = 5) [p47phox protein content (D), activated NF-κB (E), and IκBα (F) protein content]. Representative Western blots in A, C, D, and F show the change in quantity of p47phox and IκBα in MNC homogenates, and the representative electrophoretic mobility shift assay bands in B and E show the change in quantity of NF-κB in nuclear extracts from MNC in samples collected at 0 and 2 h after the respective pro-oxidant or proinflammatory triggers. The samples used to quantify p47phox and IκBα protein content and activated NF-κB by densitometry were run on the same gel. Data are presented as means ± SE. *Pretreatment significantly different compared with posttreatment (paired Student’s t test); P < 0.0001 (A), P < 0.0007 (B), P < 0.0003 (C), P < 0.002 (D), and P < 0.04 (E) and (F).

Fig. 3.

Basal levels of testosterone (A) and androstenedione (B) in women with polycystic ovary syndrome (PCOS) before and after salsalate treatment (n = 8) and in control subjects (n = 8) at baseline. Area under the curve (AUC) for human chorionic gonadotropin (HCG)-stimulated testosterone (C) and androstenedione (D) secretion in women with PCOS before and after salsalate treatment. *Significantly decreased after treatment (paired Student’s t test); P < 0.002 (A) and (C), P < 0.03 (B), and P < 0.02 (D).