Overweight and obese but not normal weight women with PCOS are at increased risk of Type 2 diabetes mellitus-a prospective, population-based cohort study

Abstract

Study question: What are the respective roles of polycystic ovary syndrome (PCOS), long-term weight gain and obesity for the development of prediabetes or Type 2 diabetes mellitus (T2DM) by age 46 years?

Summary answer: The risk of T2DM in women with PCOS is mainly due to overweight and obesity, although these two factors have a synergistic effect on the development of T2DM.

What is known already: PCOS is associated with an increased risk of prediabetes and T2DM. However, the respective roles of PCOS per se and BMI for the development of T2DM have remained unclear.

Study design, size, duration: In a prospective, general population-based follow-up birth cohort 1966 (n = 5889), postal questionnaires were sent at ages 14 (95% answered), 31 (80% answered) and 46 years (72% answered). Questions about oligoamenorrhoea and hirsutism were asked at age 31 years, and a question about PCOS diagnosis at 46 years. Clinical examination and blood sampling were performed at 31 years in 3127 women, and at 46 years in 3280 women. A 2-h oral glucose tolerance test (OGTT) was performed at 46 years of age in 2780 women.

Participants/materials, setting, methods: Women reporting both oligoamenorrhoea and hirsutism at age 31 years and/or diagnosis of PCOS by 46 years were considered as women with PCOS (n = 279). Women without any symptoms at 31 years and without PCOS diagnosis by 46 years were considered as controls (n = 1577). The level of glucose metabolism was classified according to the results of the OGTT and previous information of glucose metabolism status from the national drug and hospital discharge registers.

Main results and the role of chance: PCOS per se significantly increased the risk of T2DM in overweight/obese (BMI ≥ 25.0 kg/m²) women with PCOS when compared to overweight/obese controls (odds ratio: 2.45, 95% CI: 1.28-4.67). Normal weight women with PCOS did not present with an increased risk of prediabetes or T2DM. The increase in weight between ages 14, 31 and 46 years was significantly greater in women with PCOS developing T2DM than in women with PCOS and normal glucose tolerance, with the most significant increase occurring in early adulthood (between 14 and 31 years: median with [25%; 75% quartiles]: 27.25 kg [20.43; 34.78] versus 13.80 kg [8.55; 20.20], P < 0.001).

Limitations, reasons for caution: The diagnosis of PCOS was based on self-reporting, and the questionnaire at 46 years did not distinguish between polycystic ovaries only in ultrasonography and the syndrome. Ovarian ultrasonography was not available to aid the diagnosis of PCOS.

Wider implications of the findings: These results emphasize weight management already during adolescence and early adulthood to prevent the development of T2DM in women with PCOS, as the period between 14 and 31 years seems to be a crucial time-window during which the women with PCOS who are destined to develop T2DM by 46 years of age experience a dramatic weight gain. Furthermore, our results support the view that, particularly in times of limited sources of healthcare systems, OGTT screening should be targeted to overweight/obese women with PCOS rather than to all women with PCOS.

Study funding/competing interests: Finnish Medical Foundation; North Ostrobothnia Regional Fund; Academy of Finland (project grants 104781, 120315, 129269, 1114194, 24300796, Center of Excellence in Complex Disease Genetics and SALVE); Sigrid Juselius Foundation; Biocenter Oulu; University Hospital Oulu and University of Oulu (75617); Medical Research Center Oulu; National Institute for Health Research (UK); National Heart, Lung, and Blood Institute (grant 5R01HL087679-02) through the STAMPEED program (1RL1MH083268-01); National Institute of Health/National Institute of Mental Health (5R01MH63706:02); ENGAGE project and grant agreement HEALTH-F4-2007-201413; EU FP7 EurHEALTHAgeing-277849 European Commission and Medical Research Council, UK (G0500539, G0600705, G1002319, PrevMetSyn/SALVE) and Medical Research Center, Centenary Early Career Award. The authors have no conflicts of interests.

Trial registration number: N/A.

Keywords: BMI; Polycystic ovary syndrome; Type 2 diabetes mellitus; prediabetes; weight gain.

Figure 1

Flow chart of the prospective, population-based cohort study of the risk of Type 2 diabetes mellitus (T2DM) in women with polycystic ovary syndrome (PCOS). NGT: Normal glucose tolerance, Pre-DM: Prediabetes. *Some of the women with previously diagnosed T2DM had participated in the oral glucose tolerance test (OGTT), as they were not currently using medication and did not have fasting capillary blood glucose level over 8.0 mmol/l. ¹Excluded from NGT group: women using hormonal contraception or pregnant at age 31 years (n = 734), with isolated oligoamenorrhoea at age 31 years (n = 127), with isolated hirsutism at age 31 years (n = 139) and women who did not respond to the question about PCOS symptoms at age 31 years or about diagnosis of PCOS at 46 years (n = 212). ²Excluded from Pre-DM group: women using hormonal contraception or pregnant at age 31 years (n = 95), with isolated oligoamenorrhoea at age 31 years (n = 22), with isolated hirsutism at age 31 years (n = 16) and women who did not respond to the question about PCOS symptoms at age 31 years or about diagnosis of PCOS at 46 years (n = 45). ³Excluded from T2DM group: women using hormonal contraception or pregnant at age 31 years (n = 44), with isolated oligoamenorrhoea at age 31 years (n = 12), with isolated hirsutism at age 31 years (n = 13) and women who did not respond to the question about PCOS symptoms at age 31 years or about diagnosis of PCOS at 46 years (n = 27).

Figure 2

The prevalence of pre-DM, T2DM, nAGM and AGM in whole study population (A), in overweight/obese population (B) and in lean population (C). AGM: Abnormal glucose tolerance (including pre-DM, newly detected T2DM [nT2DM] and previously diagnosed T2DM [pT2DM]). Newly detected AGM (nAGM): Pre-DM or nT2DM in the OGTT at age 46 years. The BMI-status is based on 46-years data. *P < 0.05, **P < 0.01 and ***P < 0.001 when comparing women with PCOS to control women. The prevalences and differences between the PCOS and control women were analysed by cross-tabulation and Chi-squared test. Below each bar, the numerator describes the number of affected women and the denominator describes the total number of women in each group.

Figure 3

Odds ratios (ORs) for Type 2 diabetes. The analysis has been made by binary logistic regression analysis and the ORs are adjusted for education level, alcohol consumption, smoking, and current use of combined contraceptives and of cholesterol-lowering drugs. Age is given in years.

Figure 4

ORs for prediabetes. The analysis has been made by binary logistic regression analysis and the ORs are adjusted for education level, alcohol consumption, smoking, and current use of combined contraceptives and of cholesterol-lowering drugs. Age is given in years.

Figure 5

Development of BMI during life in the women with PCOS according to the glucose metabolism status assessed at age 46 years. BMI values are reported as mean ± SE at each time point (14, 31 and 46 years) and the differences between groups were analysed using Mann–Whitney U-test and compared with the women with NGT in the same time point. *P < 0.05, **P < 0.01 and ***P < 0.001 AGM: Pre-DM or T2DM [i.e. previously diagnosed or OGTT screened T2DM], nAGM: Pre-DM or screened T2DM in the OGTT. T2DM: including both previously diagnosed or OGTT detected. At age 14 years BMI information was available from 115 women in the PCOS + NGT group, 18 women in the PCOS + T2DM group, 21 women in the PCOS + pre-DM group, 39 women in the PCOS + AGM group and 29 women in the PCOS + nAGM group. At 31 years, BMI information was available from 134 women in the PCOS + NGT group, 22 women in the PCOS + T2DM group, 23 women in the PCOS + pre-DM group, 45 women in the PCOS + AGM group and 33 women in the PCOS + nAGM group. At 46 years, BMI information was available from 138 women in the PCOS + NGT group, 21 women in the PCOS + T2DM group, 24 women in the PCOS + pre-DM group, 45 women in the PCOS + AGM group and 34 women in the PCOS + nAGM group.