Circulating osteoprotegerin and soluble receptor activator of nuclear factor κB ligand in polycystic ovary syndrome: relationships to insulin resistance and endothelial dysfunction

Abstract

Objective: There is plenty of evidence that osteoprotegerin (OPG) is linked to subclinical vascular damage and predicts cardiovascular disease in high-risk populations. Our aim is to investigate the relationships of OPG/free soluble receptor activator of nuclear factor kB ligand (sRANKL) to insulin resistance, brachial artery flow-mediated vasodilation (FMD), and the carotid artery intima-media thickness (CIMT) in polycystic ovary syndrome (PCOS), a disorder characterized by hyperandrogenism, impaired glucose control, and endothelial injury. Design: A cross-sectional, observational study. Methods: Hormonal and metabolic profiles, FMD, CIMT, serum OPG, and ampli-sRANKL were assessed in 64 young PCOS patients and 20 controls of similar age. Body composition was measured by dual energy X-ray absorptiometry. Results: OPG was significantly lower in PCOS and related negatively to free testosterone and positively to estradiol (E 2 ) levels. In multivariate analysis, OPG but not ampli-sRANKL correlated positively to fasting insulin, insulin sensitivity indices, and FMD. Neither OPG nor ampli-sRANKL was associated with CIMT. Significantly lower adjusted FMD values were demonstrated in women in the upper OPG quartile group (O2.65 pmol/l) compared with all other quartile groups together (PZ0.012). In PCOS, multiple regression analysis retained E 2 /sex hormone-binding globulin ratio, fat mass, and homeostasis model assessment of insulin resistance as independent predictors of OPG. Conclusions: In PCOS, circulating OPG is related to both endothelial dysfunction and insulin resistance, independent of obesity and androgen excess, suggesting OPG as a useful biomarker of these effects. Further studies are needed to evaluate OPG in relation to cardiovascular events and cardiovascular mortality in PCOS.

A comparison of osteoprotegerin with adiponectin and high-sensitivity C-reactive protein (hsCRP) as a marker for insulin resistance

“…The absence of a significant relationship between OPG and HOMA-IR is in contrast to a number of other studies [10,[13][14][15] which consisted of patients with relatively high levels of IR -including patients with type 2 diabetes [13,14] or a previous history of gestational diabetes [10]. In a group of 106 obese patients (18 with type 2 diabetes), Gannage-Yared et al found a positive association between OPG and HOMA-IR (r =0.295, P < .01) [13].…”

“…In the group as a whole, there was a weak but statistically significant relationship between OPG and HOMA-IR (r = 0.146, P = .04). Pepene et al found a positive correlation between OPG and HOMA-IR (r =0.311, P = .021) in a group of women of whom three quarters had polycystic ovarian syndrome -a condition strongly associated with IR [15].…”

Bone mineral density and vitamin D in PCOS and hirsutism

“…Preserved BMD and the hyperinflammatory state in PCOS could be associated with increased OPG levels. Recent studies, however, reported decreased [53,54] or unchanged [55] OPG levels in PCOS patients versus controls. OPG levels were positively associated with vitamin D, BMD and testosterone, but also with I-CTP, a marker of bone resorption [55].…”

“…OPG levels were positively associated with vitamin D, BMD and testosterone, but also with I-CTP, a marker of bone resorption [55]. In contrast, Pepene and Escobar-Morreale reported inverse associations between OPG, Ferriman-Gallwey score and free testosterone levels in PCOS, but did not measure BMD [54,53]. Intervention studies in hypogonad men [45] and in transsexual women [56] documented significantly increased BMD [45] and increased OPG/RANKL levels [56] after testosterone treatment, thus supporting the positive association between testosterone levels, OPG and BMD.…”

“…Increased alkaline phosphatase [22] and I-CTP [55] and decreased OPG [53,54] could suggest increased bone turnover in PCOS patients. These findings could support that increased BMD in hirsutism and PCOS could be due to increased peak bone mass.…”