| Summary: | Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 6-7% of the population. It is characterised by chronic anovulation and hyperandrogenism with the clinical manifestation of oligomenorrhoea, hirsutism and acne. A ten to twenty fold increased risk for type 2 diabetes in PCOS patients compared to weight matched female control subjects makes the syndrome of high socioeconomic importance. The use of differing diagnostic criteria makes the comparison of studies on PCOS difficult until harmonisation through the Rotterdam consensus in 2004. Despite being removed from the diagnostic criteria by the the Rotterdam consensus, the LH/FSH ratio is still widely used as one of the diagnostic criteria for PCOS. Therefore to determine the usefulness of the LH/FSH ratio in the diagnosis of PCOS, I have conducted a study as described in chapter two and showed that an elevated LH to FSH ratio was as commonly found in normal women as those with PCO, and therefore of no diagnostic value. In January 2004, the European Society for Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) co-sponsored the Rotterdam polycystic ovary syndrome consensus workshop that published diagnostic guidelines, building on the consensus statement of the National Institutes of Health 1990. The Rotterdam criteria for the diagnosis of PCOS states 2 of the 3 features needs to be present to make the diagnosis, and with the exclusion of other aetiologies (congenital adrenal hyperplasia, androgen-secreting tumors, Gushing's syndrome). These features include (l)Oligo- or anovulation (2)Clinical and/or biochemical signs of hyperandrogenism and (3)Polycystic ovaries (either 12 or more follicles measuring 2-9 mm in diameter, or an ovarian volume of > 10 cm³ ). Following the introduction of this guideline, the diagnosis of PCOS in patients recruited for studies on PCOS have been standardised. However, the current biochemical test for hyperandrogenism in women is still not ideal, due to the variation in the assay at low values. All three of total testosterone, bioavailable testosterone and free androgen index (FAI) are currently used as markers of hyperandrogenism for the diagnosis of PCOS. In chapter three, I evaluated the variability of each of the three markers as well as their use in the diagnosis and monitoring patients with PCOS and found that FAI is a better diagnostic marker for hyperandrogenism in patients with PCOS, but once the diagnosis is made, all three methods are equally good in monitoring disease progression. It has now been recognised that the diagnosis of metabolic syndrome identifies patients at increased risk of developing cardiovascular disease, and attempts have been made to develop the most convenient and useful criteria for the diagnosis of this condition in clinical practice. With the pathogenesis of metabolic syndrome not well understood, central obesity and insulin resistance are acknowledged as important causative factors. Cardiovascular disease studies in PCOS had so far been inconclusive with some suggesting increased cardiac events among women with PCOS whilst other studies suggesting no increase compared with normal cycling women. This may be attributed to small sample size in studies and variation in characteristics of patients recruited as well as surrogate markers used. C-reactive protein (CRP) had been widely used as a marker of inflammation, endothelial dysfunction and risk of cardiovascular disease in general and in patients with PCOS. However, there had not been any studies on the biovailability of this marker as the potential utility of CRP as a marker of cardiovascular risk may be limited by the magnitude of this variability in both health and disease, since there can be substantial overlap between PCOS and control individuals. In chapter four, the biological variation of high sensitivity CRP in women with PCOS were compared to normal menstruating women. I found that while the mean concentration of CRP was higher in individuals with PCOS compared to healthy controls, the intraindividual variation of CRP was similarly large in both groups. Therefore, the potential utility of CRP as a marker of cardiovascular risk may be limited by the magnitude of this variability in both health and disease, since there can be substantial overlap between PCOS and control individuals. PCOS is associated with a high risk of progression to type 2 diabetes (T2DM) and impaired glucose tolerance. A history of T2DM in a first-degree relative appears to define a subset of PCOS subjects with a greater prevalence of insulin secretory defects. However, factors underlying the progression of PCOS to T2DM are unclear and may be due to either an increase in the underlying insulin resistance or the progression of beta cell failure. Chapter five described a comparison study between the insulin resistance and beta cell functions in patients with PCOS to that of diet controlled T2DM. I found that the progression from PCOS to the development of T2DM is unlikely to be due to a further increase in insulin resistance (or variability), but rather the progressive failure of pancreatic beta cells with a decrease in insulin production. Having established the effectiveness in the diagnosis of PCOS and its progression, I went on to establish the effectiveness of individual treatments of PCOS. The treatment of patients with PCOS requires that the specific goal(s) of the therapy be first established. Individual goals may include fertility, treatment for hirsutism and/or acne, achieving a regular menstrual cycle, weight reduction and the prevention of the long term consequences associated with PCOS (type 2 diabetes, dyslipidaemia and possibly cardiovascular disease) - or all of the above. Treatments aimed at modifying the long-term consequences on cardiometabolic aspect of PCOS include weight reduction strategies as well as the use of insulin sensitizers. There is currently insufficient data to suggest the superiority of one treatment over another or the use of these medications for treatment of cardiometabolic risks in patients with PCOS. Endothelial dysfunction had been recognised as an early marker for cardiovascular disease and chapter six compared the changes in endothelial function in women treated with either metformin or pioglitazone. I found that pioglitazone significantly improved endothelial function and hs-CRP whereas metformin did not produce significant improvements. Chapter seven evaluates the effects of orlistat, metformin and pioglitazone on metabolic profile and biological variability of IR in women with PCOS. The results showed that only orlistat reduced both IR and its variability significantly, though all three drugs were effective in reducing hyperandrogenism within the 12 week period of the study. These effects with orlistat were coupled with a significantly reduction in total cholesterol through a reduction in LDL. After conducting the above studies and searching through literatures, I found that studies in cardiometabolic risks in women with PCOS had so far shown conflicting results, and this may be due to the heterogeneity within the group. Chapter eight evaluates this heterogeneity particularly between anovulatory and ovulatory women with PCOS, where all subjects met the Rotterdam criteria. Women with anovulatory PCOS were found to have higher mean and biological variability of IR compared to those having an ovulatory cycle, and both were higher than women without PCOS. This suggests that the subset of patients who ovulate may be better protected against future cardiovascular consequences. In conclusion, this thesis demonstrated that LH/FSH ratio is of no use in the diagnosis of PCOS and that free androgen index appeared to be the best diagnostic marker when compared to total testosterone and bioavailable testosterone.
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