Send Orders for Reprints to
[email protected] Current Vascular Pharmacology, 2015, 13, 000-000
1
Excess Metabolic and Cardiovascular Risk is not Manifested in all Phenotypes of Polycystic Ovary Syndrome: Implications for Diagnosis and Treatment Georgios Daskalopoulos1,2, Artemis Karkanaki3,4, Athanasia Piouka5, Nikolaos Prapas3, Dimitrios Panidis5, Paraschos Gkeleris6 and Vasilios G. Athyros1,* 1
Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippocration Hospital, Thessaloniki, Greece; 2Lister Hospital, 32 Townsend Mews, Stevenage, SG1 3AT, Hertfordshire, UK; 3Third Department of Obstetrics and Gynaecology, Medical School, Aristotle University of Thessaloniki, Hippocration Hospital, Thessaloniki, Greece; 4Reproductive Medicine Clinic, St' Michael's Hospital, Southwell Street, BS2 8EG, Bristol, UK; 5Division of Endocrinology and Human Reproduction, Second Department of Obstetrics and Gynaecology, Medical School, Aristotle University of Thessaloniki, Hippocration Hospital, Thessaloniki, Greece; 6Third Cardiology Clinic, Medical School, Aristotle University of Thessaloniki, Hippocration Hospital, Thessaloniki, Greece Abstract: Aim: To assess the potential differences in the metabolic and cardiovascular disease (CVD) risk between the distinct phenotypes of the Polycystic Ovary Syndrome (PCOS) according to the Rotterdam definition regardless of body mass index (BMI). Patients-Methods: The study included 300 women; 240 women with PCOS, according to the Rotterdam criteria and 60 controls without PCOS. All women were further subdivided, according to their BMI, into normal-weight and overweight/obese and PCOS women were furthermore subdivided in 4 phenotypes of the syndrome. A complete hormonal and metabolic profile as well as the levels of high sensitivity C reactive protein (hsCRP) and lipoprotein-associated phospholipase A2 (Lp-PLA2) were measured. Outcomes: Levels of surrogate markers of subclinical atherosclerosis (hsCRP and Lp-PLA2), levels of evaluated CVD risk score using risk engines, and several correlations of CVD risk factors. Results: hsCRP levels were higher but not significantly so in PCOS women compared with controls. In lean PCOS patients, Lp-PLA2 levels were significantly higher, compared with lean controls, mainly in the 2 classic phenotypes. Overweight/obese patients in all 4 phenotypes had significantly higher Lp-PLA2 levels compared with overweight/obese controls. Evaluated CVD risk according to 4 risk engines was not different among phenotypes and between PCOS patients and controls. There were several correlations of risk factors with metabolic syndrome and non-alcoholic fatty liver disease requiring appropriate treatment. Conclusion: Only 2 of 4 Rotterdam phenotypes, identical with those of the classic PCOS definition, have excess cardiometabolic risk. These need to be treated to prevent CVD events.
Trial registration number: ClinicalTrials.gov Identifier: NCT01392781 Keywords: Polycystic ovary syndrome, cardiovascular risk, high sensitivity C reactive protein, lipoprotein-associated phospholipase A2, treatment, statins, insulin sensitizers, risk score engines. 1. INTRODUCTION Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder characterized by irregular menses, hyperandrogenism and/or polycystic ovaries [1,2]. PCOS may be related to both infertility and increased cardiovascular disease (CVD) risk [3]. The prevalence of PCOS is affected by *Address correspondence to this author at the Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippocration Hospital, 15 Marmara St, 55132, Thessaloniki, Greece; Tel: +30 2310 892606; Fax: +30 2310 835955; E-mail:
[email protected] 1570-1611/15 $58.00+.00
the definition used for its diagnosis. The National Institutes of Health/National Institute of Child Health and Human Disease (NIH/NICHD) definition, adopted in 1992, suggests a 4-8% prevalence in women of reproductive age [1], while the Rotterdam definition adopted in 2004 by the European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine (ESHRE/ASRM) suggests a 15-20% prevalence in women of reproductive age (i.e. about 3 times higher than the 1992 definition) [2]. The Rotterdam (ESHRE/ASRM) definition criteria allow the diagnosis of PCOS without the presence of hyperandrogenaemia or clinical hyperandrogenism [3]. On the other © 2015 Bentham Science Publishers
2 Current Vascular Pharmacology, 2015, Vol. 13, No. 00
hand, the 1992 (NIH/NICHD) definition criteria exclude the diagnosis of PCOS in women with regular menses and subclinical ovulatory dysfunction [4]. However, there is considerable variation in the presentation of PCOS phenotypes according to the 2 definitions involving insulin resistance (IR) and hyperinsulinaemia that leads to increased risk of dyslipidaemia, metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM) and CVD [5]. The use of an appropriate definition for the diagnosis of PCOS is essential not only to address patient concerns but also its management in the effort to prevent future metabolic, endocrine, psychiatric and CVD complications [4]. The evaluation of the actual CVD risk in women with PCOS is difficult requiring long-term follow-up studies with a large number of CVD events, which is impractical because PCOS involves, otherwise low CVD risk, young women. Besides, the phenotype varies throughout life and at time periods and during time periods when weight is controlled at low levels disease implications may become undetectable. Thus, there is a need to identify the metabolic and CVD risk load of each phenotype of the two definitions to avoid both underestimation of risk or unnecessary distress and treatment for probable risks [6-8]. The present study was undertaken to investigate the actual risk for metabolic and CVD complications that each phenotype, according to the 1992 and the Rotterdam definitions, carries. This will help physicians to protect women with PCOS from future health problems in a costeffective manner. 2. PATIENTS AND METHODS 2.1. Participants The study included 240 women with PCOS and 60 controls (women without the syndrome), all within reproductive age (age range: 20-36 years, mean age 28 years). Controls had normal ovulating cycles (28±2 days) and blood progesterone levels >10 ng/mL in the luteal phase of two consecutive cycles. Additionally, they presented no signs of hyperandrogenism or ovarian morphology. Patients with PCOS and controls were divided in groups by body mass index (BMI). Lean women had a BMI range of 20-25 Kg/m2, while overweight/obese women had a BMI range of 25-35 kg/m2. Diagnosis of PCOS was based on the revised criteria of Rotterdam [2], after exclusion of any other clinical entity that could possibly manifest as PCOS or affect their reproductive physiology. The first 2 phenotypes of PCOS according to the Rotterdam definition matched exactly the two phenotypes of the 1992 (NIH/NICHD) definition [1]. No participant reported the use of a CVD risk-modifying or any other medication that could interfere with the normal function of the hypothalamic-pituitary-gonadal axis. Diagnosis of MetS was based on the definition according to the Joint Interim Statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. [9]. Subjects with MetS should have at least 3 of the components: Elevated waist circumference (WC) 94 cm in men and 80 cm in women at a level between the iliac
Daskalopoulos et al.
crest and the lower ribs (specific for European populations), elevated triglycerides (TGs) 150 mg/dL or on drug treatment for elevated TGs, reduced high-density lipoprotein cholesterol (HDL-C)
