Clinical ScienceIncreased thrombin generation in women with polycystic ovary syndrome: A pilot study on the effect of metformin and oral contraceptives
Introduction
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age affecting 5%–10% of premenopausal women. The clinical identification of women with PCOS, as defined in the Rotterdam criteria, is based on anovulation, hyperandrogenism and polycystic ovaries and at least two of these three criteria must be accomplished to establish the PCOS diagnosis [1], [2]. PCOS is associated with insulin resistance and enhanced risk of type 2 diabetes. Patients with PCOS have increased levels of cardiovascular risk markers [3] increased risk of venous thromboembolism [4], [5] and significant subclinical atherosclerosis compared with healthy controls [6], [7], [8].
Life style intervention and treatment with metformin are applied to reduce insulin resistance and improve ovulation rates in women with PCOS [9]. Treatment with metformin may have beneficial effects on cardiovascular events [10], but no long term studies are available in patients with PCOS. The menstrual irregularities and hirsutism associated with PCOS are often treated with oral contraceptives (OC). Treatment with OC increases the risk of cardiovascular disease (CVD) in women without PCOS [11]. A comparable thrombogenic effect of OC treatment has been reported in women with PCOS [4], although recent studies have indicated that OC-treatment is without effect or may even reduce the cardiovascular risk in women with PCOS [5], [7], [12].
Measures of thrombin generation (TG) address the combined effect of multiple haemostatic risk markers for venous and arterial thrombotic disease [13], [14], [15], [16]. Elevated TG measures are associated with idiopathic and pregnancy related thrombosis [13], [16] and thrombin formation contributes to vascular calcification and atherosclerosis progression [17]. Age, body mass index (BMI), total cholesterol, trunk fat mass and low grade inflammation are shown to be potential confounders of measures of TG [18], [19] and several studies have indicated that also sex hormones may have significant impact on TG [20], [21], [22], [23]. It is of particular interest that OC treatment has been demonstrated to elevate measures of TG [24], whereas the function of thrombin is reduced in diabetic patients treated with metformin [25], [26]. TG has rarely been studied in women with PCOS [27] and no previous studies have addressed the long term effect of OC and/or metformin on TG measures in this group of women.
In the present study we evaluated the impact of PCOS on measures of TG by comparison with control subjects of similar age and BMI after adjustment for the effect of the confounders. Furthermore we evaluated whether 12 months’ treatment with metformin and/or OC affected TG measures in women with PCOS.
Section snippets
Patients
The study design has recently been published [28]. In brief, 90 white, non-diabetic women aged 18–39 years fulfilling the Rotterdam criteria for PCOS were included in the study. It should be noticed that TG as outcome measure was not defined in the original study [28], which was planned ultimo 2006. The power of the study was calculated using the area under the curve for insulin during two hours OGTT as the primary end point. No previous studies examined the effect of metformin and/or OC on TG
The Association Between PCOS and Measures of TG
Controls and patients with PCOS were comparable at baseline with respect to age (P = 0.29), BMI (P = 0.30), fibrinogen (P = 0.051), total cholesterol (P = 0.31) and trunk fat mass (P = 0.45). CRP, total testosterone and SHBG were log10-transformed to obtain normal distribution. CRP and total testosterone were significantly higher in women with PCOS than controls (P = 0.01 and P < 0.001, respectively), Table 1. The concentration of SHBG was significantly lower in women with PCOS than in controls (P = 0.008).
Discussion
The first part of this study, focusing on measures of TG in women with PCOS and controls, demonstrates that the TG potential, measured as ETP and peak thrombin concentration, is significantly higher, and that the lag time is significantly longer in women with PCOS than in healthy women with comparable age and BMI.
Previous studies have shown that age, BMI, total cholesterol, trunk fat mass and low grade inflammation are potential confounders of measures of TG [18], [19]. Additional studies have
Funding
Financial grants for the studies were provided by Jacob Madsen’s and Olga Madsen’s Foundation, Institute of Clinical Research, Odense University Hospital, Kolding Hospital, AP Møller’s Foundation, Bernhard and Marie Kleins Foundation, The Novo Nordisk Foundation, and The Danish Medical Association. Oral contraceptive pills and metformin tablets were sponsored by Sandoz. Sandoz was not involved in study planning or writing of article.
Conflict of Interest
None of the authors have any conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Supplementary data
The following are the Supplementary data to this article.
Acknowledgments
The authors thank Anette Riis Madsen, Lotte Hørlyck, Steffanie Anthony Christensen, Jane Nielsen, Donna Arbuckle-Lund, Elizabeth Hanmann, Jeannette Fogh Lindegaard, Mette Brøchner Hansen, Anne Mette Hangaard, Susanne Møller Pedersen, Geraldine Rasmussen, Thon Kowall Andersen, Anette Larsen and Kathrine Overgaard for excellent technical assistance.
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