Assessing C Reactive Protein/Albumin Ratio As a New Biomarker for Polycystic Ovary Syndrome: a Case–Control Study of Women from Bahraini Medical Clinics
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Open access Research BMJ Open: first published as 10.1136/bmjopen-2018-021860 on 27 October 2018. Downloaded from Assessing C reactive protein/albumin ratio as a new biomarker for polycystic ovary syndrome: a case–control study of women from Bahraini medical clinics Shirin Kalyan,1 Azita Goshtesabi,1 Sameh Sarray,2,3 Angela Joannou,1 Wassim Y Almawi3 To cite: Kalyan S, Goshtesabi A, ABSTRACT Strengths and limitations of this study Sarray S, et al. Assessing C Objective Polycystic ovary syndrome (PCOS) is an reactive protein/albumin ratio as endocrine disorder affecting approximately one in seven ► This analysis addressed previous limitations of a new biomarker for polycystic women who experience androgen excess, menstrual cycle ovary syndrome: a case–control studies, namely small sample sizes, heterogeneous irregularities, frequent anovulation and a tendency for study of women from Bahraini populations and confounding factors (such as body central obesity and insulin resistance. Chronic subclinical medical clinics. BMJ Open mass index), that have attempted to show polycystic inflammation is now recognised as being common in the 2018;8:e021860. doi:10.1136/ ovary syndrome (PCOS) is an inflammatory process. bmjopen-2018-021860 context of PCOS, which led to the postulation that PCOS ► The relationship between inflammation and PCOS may fundamentally be an inflammatory process. This was assessed using C reactive protein/albumin ra- ► Prepublication history for study aimed to: (1) evaluate serum C reactive protein this paper is available online. tio, which may be a better marker for inflammation (CRP)/albumin ratio as a potential predictive biomarker for To view these files, please visit in the context of metabolic dysfunction. PCOS; (2) compare the relationship between CRP/albumin the journal online (http:// dx. doi. ► Study used waist circumference as a substitute for and PCOS to variables classically associated with the org/ 10. 1136/ bmjopen- 2018- visceral adiposity; gold standard is CT or MRI. 021860). syndrome. Design Case–control study. Received 22 January 2018 Setting Adult obstetrics/gynaecology, endocrinology and Revised 13 August 2018 outpatient clinics; university hospital in Bahrain. 1 2 Accepted 27 September 2018 worldwide, and the prevalence of PCOS Participants 200 premenopausal women with a diagnosis appears to be increasing.1 This rise may partly of PCOS, and 119 ethnically matched eumenorrheic http://bmjopen.bmj.com/ be attributed to improved diagnosis as well as premenopausal women. Main outcome measures CRP/albumin ratio, to an increase in environmental factors that anthropometric measures, insulin resistance, androgen predispose to the development of this complex excess. metabolic condition. PCOS is characterised Results Independent of body mass index (BMI), receiver by androgen excess, menstrual irregularities, operating characteristic curve for CRP/albumin ratio as a ovulatory disturbances and is often associated selective biomarker for PCOS was 0.865 (95% CI 0.824 with central obesity and insulin resistance to 0.905), which was more sensitive than CRP alone. 3–5 (IR). As such, women with PCOS are at an on September 30, 2021 by guest. Protected copyright. Binary regression analysis showed that CRP/albumin ratio increased risk for a number of health issues, outperformed classical correlates, Free Androgen Index © Author(s) (or their including infertility, cardiovascular disease employer(s)) 2018. Re-use and insulin resistance, in predicting PCOS for every BMI 3 6 7 permitted under CC BY-NC. No category. (CVD) and diabetes. commercial re-use. See rights Conclusion CRP/albumin ratio, a marker for inflammation Possibly related to the constellation of and permissions. Published by related to metabolic dysfunction, was found to have a endocrine and metabolic dysfunction they BMJ. 1 stronger association with PCOS than either androgen experience, women with PCOS are also found CeMCOR, Division of excess or insulin resistance. Inflammation is known to be Endocrinology, Department of to have greater chronic subclinical inflamma- influenced by adiposity, but relative to controls, women 8–11 Medicine, University of British tion, which is often clinically assessed by with PCOS have higher levels of CRP/albumin irrespective Columbia, Vancouver, British measuring serum levels of C reactive protein of BMI. These findings support the view that inflammation Columbia, Canada (CRP). CRP is a liver-derived acute phase 2 plays a central role in the pathophysiology of PCOS. Department of Medical protein produced in response to IL-6 secreted Biochemistry, Arabian Gulf University, Manama, Bahrain from activated cells such as macrophages and 12 13 3Faculty of Sciences, El-Manar adipocytes. A meta-analysis of 31 studies University, Tunis, Tunisia INTRODUCTIOn concluded that systemic CRP levels are 96% Polycystic ovary syndrome (PCOS) is the higher in women with PCOS compared with Correspondence to 14 Dr Shirin Kalyan; most common reproductive disorder, control women. Collectively, these find- shirin. kalyan@ ubc. ca affecting 5%–15% of premenopausal women ings have given rise to the speculation that Kalyan S, et al. BMJ Open 2018;8:e021860. doi:10.1136/bmjopen-2018-021860 1 Open access BMJ Open: first published as 10.1136/bmjopen-2018-021860 on 27 October 2018. Downloaded from inflammation may play a pivotal role in the pathophysi- (Bahraini Ministry of Health; www. moh. gov. bh/ Content/ ology of PCOS.8–10 Files/ Publications/ statistics/ HS2015) and Z-value for Elevated serum CRP levels are linked to several health 95% CI. Women serving as controls were examined in risk factors experienced by women with PCOS, particularly the follicular phase of their menstrual cycle and had IR and heightened risk of type 2 diabetes.7 15 16 Chronic testosterone levels within range. A diagnosis of PCOS was inflammation also contributes to endothelial dysfunction, based on the 2003 Rotterdam Criteria, which requires exacerbating the development of atherosclerotic plaques, two of the three following criteria to be met: ultrasound triggering the onset of CVD.17 As such inflammation evidence of polycystic ovarian morphology, anovulation has been associated with both CVD and coronary artery and hyperandrogenism.24 Exclusion criteria included 10 disease in women with PCOS. hyperprolactinaemia, non-classical adrenal hyperplasia, In contrast to CRP, albumin is a negative acute phase androgen-producing tumours, 21-hydroxylase deficiency, response protein produced by the liver. Serum levels of Cushing’s syndrome and active thyroid disease (overt, albumin are reduced in individuals experiencing chronic central and subclinical hypothyroidism and hyperthy- 18 inflammation. In addition to its role as a binding mole- roidism). Additional exclusion criteria included extremes 19 cule for sex steroids, albumin also provides the majority of body mass index (BMI; <18 kg/m2 or >45 kg/m2), 18 of the total antioxidant capacity of normal plasma. The recent/present illness and treatment affecting carbohy- ratio of serum CRP levels over serum albumin (CRP/ drate metabolism or hormonal levels, for 3 months or albumin) was found to be strongly associated with more longer before inclusion the study. Women using antihy- severe metabolic dysfunction in premenopausal women pertensive, oral contraceptive, anti-inflammatory and with induced alterations to their ovarian hormone lipid-lowering drugs were also excluded. Demographic 20 status. CRP/albumin ratio was also found to be signifi- information, along with detailed personal and family cantly higher in premenopausal women with PCOS history of diabetes, hypertension, infertility, hypercho- relative to controls, and adversely predicted their bone 21 lesterolaemia and ischaemic heart disease were obtained quality. Given the ability of CRP/albumin to simulta- from all participants. This study was conducted in accor- neously capture chronic inflammation and metabolic dance with the Declaration of Helsinki, second guidelines. dysfunction in premenopausal women, we hypothesised that CRP/albumin ratio may serve as a strong predictor Biochemical analysis of PCOS in a cohort of similarly aged women. This case– Peripheral venous fasting blood samples were obtained control study investigated CRP/albumin ratio along with between 7:00 and 9:00 following an overnight (>12 hours) classical markers, androgen excess and IR, in their asso- fast during the early follicular phase of the menstrual ciation with PCOS in 319 premenopausal Bahraini Arab women. cycle (days 2±5) for control women, or women with PCOS who did not present with menstrual irregularities, http://bmjopen.bmj.com/ or any day for women with PCOS with menstrual irregu- larities. Serum samples were analysed for sex hormone METHODS binding globulin (SHBG) by sandwich ELISA (R&D Patient and public involvement Systems, Minneapolis, Minnesota, USA); assay sensitivity The development of the research question and the was 0.01 nmol/mL, and interassay and intra-assay preci- study’s setting was influenced by the wish many women sion (CV%) were 5.3% and 4.3%, respectively. Samples in Bahrain have to bear children. Infertility is a conse- quence of PCOS,22 and the combination of both can were tested in duplicates for adiponectin levels (Cat. impact women’s health-related quality of life.23 Patients No. DRP300) by sandwich ELISA (R&D Systems); assay on September 30, 2021 by guest. Protected copyright. were not involved in the design of the study or the recruit- sensitivity was 0.891 ng/mL,