Inflammation in Polycystic Ovary Syndrome: underpinning of insulin resistance and ovarian dysfunction

Abstract

Chronic low-grade inflammation has emerged as a key contributor to the pathogenesis of Polycystic Ovary Syndrome (PCOS). A dietary trigger such as glucose is capable of inciting oxidative stress and an inflammatory response from mononuclear cells (MNC) of women with PCOS, and this phenomenon is independent of obesity. This is important because MNC-derived macrophages are the primary source of cytokine production in excess adipose tissue, and also promote adipocyte cytokine production in a paracrine fashion. The proinflammatory cytokine tumor necrosis factor-α (TNFα) is a known mediator of insulin resistance. Glucose-stimulated TNFα release from MNC along with molecular markers of inflammation are associated with insulin resistance in PCOS. Hyperandrogenism is capable of activating MNC in the fasting state, thereby increasing MNC sensitivity to glucose; and this may be a potential mechanism for promoting diet-induced inflammation in PCOS. Increased abdominal adiposity is prevalent across all weight classes in PCOS, and this inflamed adipose tissue contributes to the inflammatory load in the disorder. Nevertheless, glucose ingestion incites oxidative stress in normal weight women with PCOS even in the absence of increased abdominal adiposity. In PCOS, markers of oxidative stress and inflammation are highly correlated with circulating androgens. Chronic suppression of ovarian androgen production does not ameliorate inflammation in normal weight women with the disorder. Furthermore, in vitro studies have demonstrated the ability of pro-inflammatory stimuli to upregulate the ovarian theca cell steroidogenic enzyme responsible for androgen production. These findings support the contention that inflammation directly stimulates the polycystic ovary to produce androgens.

Figure 1

(A) The change from baseline (%) in ROS generation from mononuclear cells (MNC) when fasting samples (pre) were compared to the samples collected 2 hours after glucose ingestion (post). * the percent (%) change in ROS generation in normal weight women with PCOS was greater than that of normal weight ovulatory controls, P < 0.009. † the % change in ROS generation in obese women with PCOS was greater than that of normal weight ovulatory controls, P < 0.003. (B) Representative EMSA bands from the 4 study groups showing the change in quantity of NFκB in nuclear extracts from MNC when fasting samples (pre) were compared to the samples collected 2 hours after glucose ingestion (post). Densitometric quantitative analysis of intranuclear NFκB protein content in MNC. Compared to normal weight ovulatory controls, the % change in NFκB activation was significantly greater in obese ovulatory controls (*, P<0.03), in normal weight women with PCOS (†, P<0.006), and in obese women with PCOS (‡, P<0.002). Adapted from González et al. [5,9], with permission. Copyright The Endocrine Society, 2006.

Figure 2

(A) Representative EMSA bands from the two study groups showing the quantity of NFκB in nuclear extracts from mononuclear cells (MNC) in samples collected in the fasting state (0) and 2 hours post-glucose ingestion (2), before and after treatment with DHEA or placebo. Densitometric quantitative analysis comparing the change from baseline (%) in MNC-derived activated NFκB between the two study groups for fasting samples before and after (before versus after, 0) DHEA or placebo administration (left panel); and for fasting and 2 hour post-glucose ingestion samples for each OGTT (before, 0 versus 2; after, 0 versus 2) as a measure of the response to glucose challenge before and after DHEA or placebo administration (right panel). After DHEA administration, the % change in activated NFκB was significantly greater compared to placebo in the fasting state (*, P<0.04), and in response to glucose ingestion (†, P<0.005). (B) Comparison between groups of the change from baseline (%) in TNFα mRNA content in MNC for fasting samples before and after (before versus after, 0) DHEA or placebo administration (left panel); and for fasting and 2 hour post-glucose ingestion samples for each OGTT (before, 0 versus 2; after, 0 versus 2) as a measure of the response to glucose challenge before and after DHEA or placebo administration (right panel). Values are normalized to 28S rRNA expression. After DHEA administration, the percent (%) change in TNFα mRNA transcripts significantly increased compared to placebo in the fasting state (*, P<0.05), and in response to glucose ingestion (†, P<0.05). Adapted from González et al. [43], with permission. Copyright The American Physiological Society, 2011.

Figure 3

The incremental change (Δ) from baseline in (A) serum C-reactive protein (CRP) levels and (B) body weight after 3 and 6 months of gonadotropin-releasing hormone (GnRH) agonist administration. The incremental Δ in CRP was significantly (*, P<0.009) higher in obese women with PCOS compared to normal weight ovulatory controls after 3 and 6 months of GnRH agonist treatment; and compared to obese ovulatory controls (†, P<0.005) and normal weight ovulatory controls (‡, P<0.007) after 6 months of treatment. The incremental Δ in body weight was significantly higher in obese women with PCOS compared to obese ovulatory controls (*, P<0.02) and normal weight ovulatory controls (†, P<0.04) after 3 and 6 months of GnRH agonist treatment. González et al. [44].