br Discussion The present results

Discussion The present results demonstrate that high dose estrogen–progestogen OC treatment produced impaired glucose tolerance and glucose tolerance was preserved during low dose estrogen–progestogen, high or low dose progestogen-only OC use. The study also shows that impaired glucose tolerance induced by estrogen–progestogen OC treatment was associated with increased fasting plasma triglyceride and decreased HDL-cholesterol levels. Furthermore, the impaired glucose tolerance and unfavourable lipid profile associated with OC treatment in this animal model was not associated with increased fasting blood glucose and body weight gain. Most importantly, these results provide evidence that the use of estrogen–progestogen, but not progestogen-only OC might promote the development of impaired glucose tolerance and unfavourable lipid profile in a dose-dependent manner in the nonobese rats and/or in rats without impaired fasting blood glucose. These results are in Lamivudine to observations in earlier studies that suggested that OC-induced glucose intolerance was associated with obesity [25]. Our findings are consistent with recent observation [26], which demonstrated that OC-induced impaired glucose tolerance was worse in nonobese users of OC. Our finding may imply that estrogenic, but not progestogenic component of OC may pose additional cardiometabolic risks in nonobese users without hyperglycemic state. Clinical studies have shown that the degree of metabolic alteration varied by type and dose of the progestogen component [13] and that the higher androgenic formulations consistently had the strongest effects [14], [15]. Although, our finding that high dose progestogen-containing combined OC produced glucose intolerance and unfavourable lipid profile was not surprising based on the fact that the norgestrel used is structurally related to testosterone [27]. However, the fact that an equally potent androgenic progestogen, 19-nortestosterone derivative, levonorgestrel that was administered alone could not produce altered glucose tolerance and/or lipid profile in this study is surprising. These results imply that the observed alterations may be attributed to estrogenic component, ethinyl estradiol used, and at least in part might not be due to the progestogenic component used. The implication that estrogenic component rather than progestogenic component might be responsible for the metabolic alterations in this animal model is in consonance with data from human studies [28], [29] but not corroborated by other studies that showed that estrogen has a favourable metabolic effect [30], [31]. Although increases in both fasting blood glucose level and area under curve (AUC) following glucose load are associated with increased cardiovascular risk factors, increased AUC has been suggested to be a better predictor of cardiovascular disease risk than elevated fasting blood glucose [32], [33]. In our study, while fasting glucose was unaffected by estrogen–progestogen OC treatment, AUC for glucose was higher. In consonance with our findings, studies [2], [14], [15], [26], showed in premenopausal women that combined OC use did not affect fasting glucose but was associated with impaired glucose tolerance. Interestingly, this pattern was observed with hormone replacement therapy in postmenopausal women [34]. Glucose intolerance results from decreased sensitivity and insulin secretion or pancreatic β-cell function [35]. OC use might promote impaired glucose tolerance by affecting both pathways [36], although effects on insulin sensitivity seem to be the most important [37]. However, a proposed mechanism is reduced insulin receptor binding [14], [38]. This phenomenon has been demonstrated by comparing insulin receptor binding and affinity in monocytes isolated from OC users and non-users. In the normal menstrual cycle, insulin receptor binding and affinity are lower in the luteal than the follicular phase, implying that insulin resistance is worse in the luteal than follicular phase [39]. De Pirro et al. [38] demonstrated that women using OC have lower insulin binding and affinity similar to that observed in the luteal phase of the menstrual cycle in normal women.