Abstract
Context
Polycystic ovary syndrome (PCOS) is associated with many traditional cardiovascular disease risk factors, but it is unclear whether PCOS is an independent risk factor for hypertension.
Objective
To investigate in a population-based setup whether PCOS associates with the risk of hypertension independently of body mass index (BMI) and with cardiovascular manifestations.
Design
Cross-sectional assessments in the Northern Finland Birth Cohort 1966 at ages 31 and 46 years.
Setting
General community.
Participants
Women who reported both oligo/amenorrhea and hirsutism at age 31 years and/or a diagnosis of PCOS by age 46 years [self-reported PCOS (srPCOS), n = 279] and women without PCOS symptoms or diagnosis (n = 1577).
Intervention
None.
Main Outcome Measures
Blood pressure (BP), BMI, and cardiovascular manifestations.
Results
Use of antihypertensive medication was significantly more common in women with srPCOS. At age 31 years, women with srPCOS had significantly higher systolic BP (SBP) and diastolic BP (DBP) than control women (SBP: normal weight: 119.9 ± 13.2 vs 116.9 ± 11.4 mm Hg, P = 0.017; overweight/obese: 126.1 ± 14.3 vs 123.0 ± 11.9 mm Hg, P = 0.031; and DBP: normal weight: 75.5 ± 10.0 vs 72.4 ± 9.6 mm Hg, P = 0.003; overweight/obese: 80.7 ± 11.8 vs 78.0 ± 10.6 mm Hg, P = 0.031). At age 46 years, srPCOS was significantly associated with hypertension (adjusted odds ratio = 1.56; 95% CI, 1.14 to 2.13) independently of BMI and with higher cardiovascular morbidity (6.8% vs 3.4%, P = 0.011). Hypertensive srPCOS displayed consistent, unfavorable changes in cardiac structure and function compared with controls.
Conclusion
Women with srPCOS displayed higher BP compared with controls already at early age and srPCOS was associated with hypertension independently of overweight/obesity. srPCOS was associated with increased cardiovascular morbidity in premenopausal women, suggesting that cardiovascular disease risk factors should be screened and efficiently managed early enough in women with PCOS.
In a prospective cohort study, polycystic ovary syndrome was associated with hypertension, independently of body mass index, and increased cardiovascular morbidity, in early premenopause.
Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting 6% to 18% of reproductive-aged women (1, 2). Even though women with PCOS usually seek medical help for irregular menstruation, hirsutism, or infertility, the syndrome is also characterized by several metabolic risk factors, such as insulin resistance, dyslipidemia, and metabolic syndrome (3). Most women with PCOS are overweight or obese (4), and they also more often present with increased abdominal fat accumulation than weight-matched controls (5). Insulin resistance and hyperandrogenism, together with excess weight, are key features of PCOS.
Although PCOS is strongly associated with many traditional cardiovascular disease (CVD) risk factors (3), it has remained unclear if PCOS is an independent risk factor for hypertension. An Australian study including 26 women with self-reported PCOS and hypertension (mean age, 28 to 33 years) reported that in a normal-weight group, self-reported hypertension was more prevalent in PCOS than in the control group, whereas in the overweight/obese group, the prevalence of hypertension was similar, and in the multivariate regression analysis, PCOS was not significantly associated with hypertension (6). Furthermore, a hospital-based study population of 35 women with PCOS who had underwent wedge resection reported that these women had significantly higher prevalence of hypertension based on hospital discharge register information, even though clinically measured blood pressure (BP) levels were similar between PCOS and control groups (7). In contrast, several studies found comparable 24-hour ambulatory BP levels between PCOS and control groups (8–10). Moreover, the respective roles of body mass index (BMI) and PCOS as risk factors for hypertension are still controversial, as obesity has been reported to be the main determinant of hypertension in women with PCOS in some studies (10), whereas others have claimed that hypertension was more prevalent in PCOS, independently of weight (6, 11). Of note, previous studies have been limited with a small number of study participants (n = 14 to 36) (6–10).
It is well known that increased BP may lead to altered cardiac structure and function and increase the risk of adverse cardiovascular outcome (12). Increased BP leads to a greater workload of the heart, inducing a compensatory cardiac muscle hypertrophy and increased left ventricle pressure, leading to enlargement of the left atrium (12). In a cross-sectional study on 18- to 30-year-old women, women with PCOS displayed higher left atrium size and left ventricular mass index as well as a lower left ventricular ejection fraction and early to late mitral flow velocity ratio, but the role of hypertension was not assessed (13). However, it has been also reported that women with PCOS have similar cardiac structure and function as control women (14, 15). Moreover, even though women with PCOS have an increased prevalence of CVD risk factors and subclinical atherosclerosis, it is still unclear whether women with PCOS have an increased morbidity and mortality due to CVDs (16).
The main goal of this study was to investigate the prevalence of hypertension and antihypertensive medication usage in a population-based setup at ages 31 and 46 years in women with self-reported PCOS (srPCOS) and to determine the respective roles of PCOS and obesity in affecting hypertension and associated echocardiographic examination findings at age 46 years. Second, we aimed to assess whether women with srPCOS have a higher prevalence of cardiovascular morbidity compared with controls by age 46 years.
Materials and Methods
Study population
The study population arises from the Northern Finland Birth Cohort 1966, which is a large prospective general population-based longitudinal birth cohort. All individuals with expected term during 1966 in the two northernmost provinces in Finland (Oulu and Lapland) were included into this birth cohort, and the study population comprised all individuals born alive during that year (12,231 births, 5889 females, 96.3% of all births during 1966 in that area). Enrollment in this database began at the 24th gestational week, and so far, this cohort population has been followed at birth and at ages 1, 14, 31, and 46 years. Postal questionnaires were sent at ages 14, 31, and 46 years, and the current study used these data collection points. At ages of 31 and 46 years, clinical examinations were also performed (http://www.oulu.fi/nfbc/node/40683, last accessed 9 June 2018).
In 1980, at age 14 years, a postal questionnaire including questions about weight and height was sent to 5764 females, and 95% of them (n = 5455) responded with help from their parents. No other clinical data were collected at that age. In 1997, at age 31 years, a postal questionnaire, including questions about health, behavior, work, and social background, was sent to 5608 women, and 4523 (81%) of them responded. In addition, those living in northern Finland or in the Helsinki metropolitan area (n = 4074 women) were invited to a clinical examination. In total, 3127 (77%) women participated in a clinical examination including anthropometric measurements and blood samples for hormonal and metabolic parameters.
In 2012, at age 46 years, comprehensive health research was carried out. A postal questionnaire and invitation to a clinical examination were sent to all individuals alive and with known addresses (n = 5123 women). Of them, 3706 (72%) women responded to the questionnaire and 3280 women (64%) participated in the clinical examination. Postal questionnaires covered all main health-related issues, such as medication use, and all previously made disease diagnoses, lifestyle habits, education, and work. Clinical examination included measurements of height, weight, waist and hip circumference, blood sampling, and cardiovascular health status. A flowchart of the study is presented in Fig. 1.
Figure 1.
The flowchart of the Northern Finland Birth Cohort 1966.
Definition of PCOS and control populations
At age 31 years, the postal questionnaire included questions on oligo/amenorrhea: “Is your menstrual cycle often (more than twice a year) longer than 35 days?” and excessive body hair: “Do you have bothersome, excessive body hair growth?” Of the women who responded to these questions, 4.1% (n = 125) reported both oligo/amenorrhea and hirsutism (OA+H), after excluding pregnant women, women using hormonal preparations (n = 1459), or not permitting the use of their data for data analysis (n = 41). The validity of this questionnaire to distinguish PCOS cases has already been shown in our previous studies from the same cohort as the women with OA+H present the typical hormonal, metabolic, and psychological characteristics for the syndrome (4, 17–19). At age 46 years, the postal questionnaire included the following question: “Have you ever been diagnosed as having polycystic ovaries and/or polycystic ovary syndrome (PCOS)?” to which 181 responded “yes.” Consequently, women who reported OA+H at age 31 years and/or a diagnosis of polycystic ovaries (PCOs)/PCOS by age 46 years were considered women with srPCOS (n = 279). Women without any PCOS symptoms at age 31 years and without diagnosis of PCO/PCOS by age 46 years were considered controls (n = 1577). More detailed information regarding this issue has been published previously (4).
Definitions of elevated BP and hypertension
The assessment and diagnosis of hypertension were based on the European guidelines (20).
Measured elevated BP
In the clinical examination, brachial systolic and diastolic BP was measured twice at age 31 years and three times at age 46 years with a 1-minute interval after 15 minutes of rest on the right arm of the seated participants using a manual mercury sphygmomanometer at age 31 years and an automated, oscillometric BP device with an appropriately sized cuff (Omron Digital Automatic Blood Pressure Monitor Model M10-IT; Omron, Kyoto, Japan) at age 46 years. Averages of systolic and diastolic BP were calculated, and elevated BP was defined as BP ≥130/85 mm Hg (“measured elevated BP” in the following text) at age 31 or 46 years. Women using antihypertensive medication were excluded from the analysis reporting mean values of systolic and diastolic BP.
Self-reported use of antihypertensive drugs
Information about antihypertensive medication was gathered from postal questionnaires at age 31 and 46 years, in which study participants reported all their medications, doses, and the reasons for use. The use of antihypertensive drugs was defined as “self-reported use of antihypertensive drugs” at age 31 or 46 years.
Hypertension at age 46 years
In the following text, “hypertension at age 46 years” (or “hypertensive at age 46 years”) is combined information from either self-reported use of antihypertensive medication at age 46 years and/or measured elevated BP at age 46 years.
Self-reported diagnosis of hypertension at age 46 years
Last, we considered separately a group of women with a self-reported diagnosis of hypertension in the questionnaire at age 46 years (“self-reported diagnosis of hypertension at age 46”).
Echocardiography
As a part of the clinical examinations at age 46 years, a subpopulation was enrolled to echocardiographic examinations in the Oulu research unit (Fig. 1). As a rule, every second individual attending the clinical examination was randomly enrolled to an echocardiographic examination without any preselection criteria and without the participant’s own wish influencing the enrollment. All participants accepted to take part to the echocardiography. In total, echocardiography was performed in 645 women, including 37 women with srPCOS and 283 control women. Transthoracic two-dimensional echocardiography was performed online by an experienced cardiologist (K.K.), using the General Electric Vivid E9 device with a M5S-D 1.5/4.6-MHz sector transducer for cardiovascular imaging (GE Health Medical, Horten, Norway). All measurements followed the American Society of Echocardiography guidelines (21). In addition, global longitudinal strain was assessed offline using the EchoPac 7 software (automated function imaging) (22). Global strain is a novel indicator of the overall systolic function of the left ventricle and may reveal heart disease at an early stage, when ejection fraction is still normal (23).
Definitions of CVD manifestation and cardiovascular mortality
The International Classification of Diseases, Revisions 8, 9, and 10 (ICD-8, ICD-9, and ICD-10, respectively) diagnostic codes for cardiovascular morbidity and events (I20, I21 to I25, I50, I60 to I63, I63 to I64, I65 to I68, I69, I70, G45, G46) were identified from hospital discharge, hospital outpatient clinic, and basic health care registers, with data covering years 1972 to 2015, 1998 to 2015, and 2011 to 2015, respectively. In Finland, all individuals have a unique personal identification number. The individuals with serious acute illness are treated in public special health care centers, which report the diagnosis to the hospital discharge and hospital outpatient clinic registers. The data from national registers can be linked to an individual. Cardiovascular mortality data were retrieved from the mortality register of Statistics Finland, which covers information about cause of death and time of death.
Statistical methods
BMI was calculated as the ratio of weight (kg) and height squared (m2). BMI values at ages 31 and 46 years were obtained mainly from the clinical examination and supplemented with self-reported BMI if clinically measured BMI was not available. There were no differences between the self-reported or clinically measured BMI values. Women with BMI <25.0 kg/m2 were classified as normal weight and with BMI ≥25.0 kg/m2 as overweight/obese (24), and this binary classification of BMI was used in the regression analysis. Differences in continuous parameters were analyzed by Student t test and by Mann-Whitney U test when appropriate. Continuous data were presented as means ± SD or as median (25% and 75% quartiles). Categorical data were analyzed using cross-tabulation and Pearson χ2 test or Fisher exact test. Binary logistic regression models were used to investigate the factors associated with hypertension, and the results were reported as adjusted odds ratios (AORs) with 95% CIs, with the adjustment for consumption of alcohol (not use, light, moderate, heavy use), smoking (never smoker, former smoker for >6 months, former smoker for <6 months, and current smoker), education (basic, secondary, tertiary), and use of hormonal contraceptives (no, yes). Effect sizes were reported as Cohen d values. Statistical analyses were performed using IBM SPSS Statistics 24.0 (IBM SPSS Statistics for Windows, v25.0, released 2017; IBM Corp., Armonk, NY). P < 0.05 was considered statistically significant.
Ethical approval
The study followed the principles of the Declaration of Helsinki. The Ethics Committee of the Northern Ostrobothnia Hospital District has approved the research. All participants took part on a voluntary basis and signed an informed consent.
Results
The clinical characteristics of srPCOS and control groups according to the BMI group are shown in Table 1. After BMI adjustment by general linear modeling, the women with srPCOS did not significantly differ from controls regarding waist circumference, serum levels of sex hormone binding globulin, total cholesterol and low-density lipoprotein, and free-androgen index, whereas women with srPCOS had significantly higher serum testosterone and lower high-density lipoprotein concentration than control women (data not shown). The glucose metabolism parameters have already been reported (25).
Table 1.
Clinical Characteristics of Control Women and Women With srPCOS According to Their BMIs at Ages 31 and 46 Years
| Characteristic | Normal-Weight Control Women (n = 577–765) | Normal-Weight Women With srPCOS (n = 62–100) | P Value a | Overweight/Obese Control Women (n = 336–698) | Overweight/Obese Women With srPCOS (n = 95–137) | P Value b |
|---|---|---|---|---|---|---|
| At age 31 y | ||||||
| BMI, kg/m2 | 21.61 ± 1.88 | 22.07 ± 1.72 | 0.006 | 28.85 ± 4.02 | 31.00 ± 5.71 | <0.001 |
| Waist circumference, cm | 73.32 ± 6.61 | 74.33 ± 6.76 | 0.163 | 89.94 ± 11.43 | 94.75 ± 15.78 | 0.006 |
| Systolic BP, mm Hg | 116.93 ± 11.36 | 119.87 ± 13.16 | 0.017 | 122.96 ± 11.94 | 126.10 ± 14.29 | 0.031 |
| Diastolic BP, mm Hg | 72.42 ± 9.60 | 75.53 ± 10.04 | 0.003 | 78.01 ± 10.57 | 80.73 ± 11.82 | 0.031 |
| At age 46 y | ||||||
| BMI, kg/m2 | 22.22 ± 1.79 | 22.60 ± 1.68 | 0.071 | 29.99 ± 4.65 | 31.37 ± 5.72 | 0.001 |
| Waist circumference, cm | 76.79 ± 5.83 | 78.96 ± 5.36 | 0.003 | 95.38 ± 11.31 | 97.99 ± 13.92 | 0.041 |
| Systolic BP, mm Hg | 115.58 ± 14.18 | 118.94 ± 16.56 | 0.083 | 124.46 ± 15.71 | 125.99 ± 16.73 | 0.386 |
| Diastolic BP, mm Hg | 78.21 ± 9.28 | 81.74 ± 11.61 | 0.024 | 85.78 ± 10.42 | 87.62 ± 10.66 | 0.114 |
Women were classified according to BMI as normal weight (BMI <25.00 kg/m2) or overweight/obese (BMI ≥25.00 kg/m2). The number of women in each group is shown in parentheses. Women using antihypertensive drugs were excluded from the analysis reporting mean values of systolic and diastolic BP. The values are reported as mean ± SD and differences between groups are analyzed using the Student t test. Significant P values appear in boldface type.
Comparison between normal-weight controls and women with srPCOS.
Comparison between overweight/obese control and women with srPCOS.
Prevalence of self-reported diagnosis of hypertension and use of antihypertensive drugs
The prevalence of self-reported diagnosis of hypertension at age 46 years was significantly greater among women with srPCOS compared with controls [Fig. 2(a), P < 0.001] at age 46 years. Furthermore, self-reported use of antihypertensive medication was significantly more common among women with srPCOS compared with control women both at age 31 years [Fig. 2(b), P = 0.022] and 46 years [Fig. 2(c), P < 0.001].
Figure 2.
Prevalence of (a) self-reported diagnosis of hypertension at age 46 years, (b) self-reported use of antihypertensive medication at age 31 years, and (c) self-reported use of antihypertensive medication at age 46 years. Data were analyzed using cross-tabulation and the χ2 test. *P < 0.05. ***P < 0.001.
Measured elevated BP at age 31 and 46 years
At age 31 years, normal-weight as well as overweight/obese women with srPCOS had significantly higher systolic and diastolic BP than normal-weight and overweight/obese control women, respectively. At age 46 years, in the normal-weight group, women with srPCOS displayed significantly higher diastolic but not systolic BP compared with controls, whereas there were no significant differences between overweight/obese srPCOS women and overweight/obese controls (Table 1).
At age 46 years, women with srPCOS had significantly more often BP levels ≥140/90 mm Hg than control women [32% (n = 67/207) vs 25% (n = 332/1328), P = 0.027]. Of these 67 women with srPCOS who had BP ≥140/90 mm Hg, 18 (27%) already used antihypertensive medication, whereas 46 (69%) did not. In three srPCOS cases, information about antihypertensive medication was lacking. If a cutoff of 130/80 mm Hg for hypertension was used, as much as 71% (n = 147/207) of women with srPCOS were hypertensive, compared with 59% (n = 777/1328) of control women (P = 0.001).
Echocardiography at age 46 years
The echocardiographic parameters did not significantly differ between srPCOS and control women. However, there was a small, nonsignificant trend toward higher measured values for interventricular septal thickness at diastole, left ventricular mass index, and left atrial systolic volume compared with control women. There were no differences between women with srPCOS and controls in diastolic filling pressure estimated with E/e′ measurement (Table 2). The Cohen d values varied from 0 to 0.33, representing very small or small effect sizes.
Table 2.
Echocardiography Parameters in Controls and in Women With srPCOS
| Characteristic | Controls (n = 192–285) | Women With srPCOS (n = 25–38) | P Value |
|---|---|---|---|
| LVEF biplane, % | 61.52 ± 5.9 | 60.80 ± 4.9 | 0.478 |
| Global strain | −21.71 ± 2.4 | −20.96 ± 2.1 | 0.137 |
| IVSd, cm | 0.87 ± 0.2 | 0.91 ± 0.1 | 0.154 |
| LVIDd, cm | 4.98 ± 0.5 | 5.02 ± 0.4 | 0.670 |
| LAESV, mL | 50.67 ± 15.1 | 53.09 ± 15.3 | 0.376 |
| LVMI | 150.43 ± 38.3 | 157.51 ± 32.0 | 0.283 |
| E/e′ (septal E′) | 7.50 ± 1.6 | 7.26 ± 1.5 | 0.386 |
| e′ septal mitral annulus | 0.12 ± 0.02 | 0.12 ± 0.02 | 0.477 |
| e′ lateral mitral annulus | 0.14 ± 0.03 | 0.14 ± 0.03 | 0.620 |
Data are presented as mean ± SD. Differences between groups were analyzed by the Student t test, as the data were normally distributed. Number of study participants is shown in parentheses.
Abbreviations: IVSd, interventricular septal end-diastole; LAESV, left atrium end-systolic volume; LVEF, left ventricular ejection fraction; LVIDd, left ventricular internal diameter end-diastole; LVMI, left ventricle mass index.
Hypertensive women with PCOS had significantly higher values for measured interventricular septal thickness at diastole, left ventricular mass index, and left atrial systolic volume compared with normotensive controls. Estimated left ventricular filling pressure (E/e′) was also increased in hypertensive women with PCOS compared with normotensive controls, suggesting modest alterations in diastolic function in this PCOS subgroup. Left ventricular systolic function was mildly decreased in hypertensive women with PCOS (assessed by global strain), even though the difference in left ventricular ejection fraction was not statistically significant compared with other groups. The Cohen d values varied from 0.33 to 0.82. Similarly, hypertensive control women exhibited significant unfavorable changes in the echocardiography parameters compared with their normotensive counterparts, and the Cohen d values varied from 0.46 to 0.62 (Table 3).
Table 3.
Echocardiography Parameters in Controls and in Women With srPCOS According to the Presence of Hypertension
| Characteristic | Normotensive Control (n = 89–121) | Normotensive srPCOS (n = 10–16) | P Value a | Hypertensive Control (n = 90–146) | Hypertensive srPCOS (n = 14–21) | P Value b | P Value c | P Value d |
|---|---|---|---|---|---|---|---|---|
| LVEF biplane, % | 61.77 ± 5.42 | 62.20 ± 4.95 | 0.760 | 61.33 ± 6.27 | 59.42 ± 4.59 | 0.204 | 0.077 | 0.559 |
| Global strain | −22.38 ± 2.26 | −21.25 ± 2.43 | 0.138 | −20.82 ± 2.16 | −20.51 ± 1.74 | 0.604 | 0.004 | <0.001 |
| IVSd, cm | 0.84 ± 0.15 | 0.89 ± 0.12 | 0.165 | 0.91 ± 0.16 | 0.92 ± 0.15 | 0.669 | 0.019 | <0.001 |
| LVIDd, cm | 4.95 ± 0.45 | 4.82 ± 0.30 | 0.283 | 5.03 ± 0.49 | 5.15 ± 0.42 | 0.311 | 0.066 | 0.160 |
| LAESV, mL | 49.98 ± 13.26 | 48.67 ± 14.10 | 0.713 | 51.83 ± 16.98 | 57.81 ± 15.48 | 0.160 | 0.024 | 0.345 |
| LVMI | 139.70 ± 31.88 | 141.79 ± 25.47 | 0.801 | 162.79 ± 39.87 | 170.24 ± 32.46 | 0.426 | <0.001 | <0.001 |
| E/e′ (septal E′) | 6.94 ± 1.29 | 6.69 ± 1.06 | 0.457 | 8.00 ± 1.77 | 7.66 ± 1.63 | 0.404 | 0.024 | <0.001 |
| e′ septal mitral annulus | 0.13 ± 0.02 | 0.13 ± 0.02 | 0.863 | 0.11 ± 0.02 | 0.12 ± 0.02 | 0.203 | 0.044 | <0.001 |
| e′ lateral mitral annulus | 0.15 ± 0.03 | 0.14 ± 0.03 | 0.275 | 0.13 ± 0.03 | 0.14 ± 0.03 | 0.098 | 0.008 | <0.001 |
Data are presented as mean ± SD. Differences between groups were analyzed by the Student t test, as the data were normally distributed. Number of study participants in each group is shown in parentheses. Normotensive: Normal BP (systolic BP <130 mm Hg and diastolic BP <85 mm Hg) at ages 31 and 46 years and no antihypertensive medication at age 31 or 46 years. Hypertensive: Elevated BP (systolic BP ≥130 mm Hg and/or diastolic BP ≥85 mm Hg) at age 31 or 46 years or antihypertensive medication at age 31 or 46 years. Significant P values appear in boldface type.
Abbreviations: IVSd, interventricular septal end-diastole; LAESV, left atrium end-systolic volume; LVEF, left ventricular ejection fraction; LVIDd, left ventricular internal diameter end-diastole; LVMI, left ventricle mass index.
Comparison between normotensive PCOS and normotensive control groups.
Comparison between hypertensive PCOS and hypertensive control groups.
Comparison between hypertensive PCOS and normotensive control groups.
Comparison between hypertensive and normotensive control groups.
Binary logistic regression analysis
In the crude univariate binary logistic regression analysis, srPCOS was significantly associated with hypertension (crude OR = 1.99; 95% CI, 1.40 to 2.52) at age 46 years, and this association remained significant (AOR = 1.78; 95% CI, 1.32 to 2.40) in the adjusted regression analysis (adjustment for consumption of alcohol, smoking, education, and use of combined contraceptive pills). In addition, in the regression analysis including also overweight/obesity at age 46 years as a covariate, srPCOS was associated with an increased risk of hypertension at age 46 years by 1.5-fold (AOR = 1.56; 95% CI, 1.14 to 2.13), independently of overweight/obesity (AOR for overweight/obesity at age 46 years = 3.62; 95% CI, 2.92 to 4.49).
Prevalence of CVD manifestations by age 46 years
The prevalence of any CVD was twice as high in women with srPCOS than in controls (6.8% vs 3.4%, P = 0.011), and the prevalence of myocardial infarction was already significantly higher in women with srPCOS (1.8% vs 0.5%, respectively, P = 0.034) at this early premenopausal age (Table 4). By age 46 years, two women with srPCOS, but no woman in the control group, had died as a result of ischemic heart disease.
Table 4.
Prevalence of Cardiovascular Morbidity (ICD Code) by Age 46 Years in Controls and in Women With srPCOS
| Characteristic | Controls, % | srPCOS, % | P Value |
|---|---|---|---|
| Angina pectoris (I20) | 0.4 (n = 6/1577) | 1.4 (n = 4/279) | 0.050 |
| Myocardial infarction (I21–I25) | 0.5 (n = 8/1577) | 1.8 (n = 5/279) | 0.034 |
| Heart failure (I50) | 0 (n = 0/1577) | 0.7 (n = 2/279) | 0.023 |
| Atherosclerosis (I70) | 0.1 (n = 2/1577) | 0.4 (n = 1/279) | 0.375 |
| Transitory cerebral ischemia (G45, G46) | 1.2 (n = 19/1577) | 2.2 (n = 6/279) | 0.207 |
| Intracranial hemorrhage (I60–I62) | 0.5 (n = 8/1577) | 0.7 (n = 2/279) | 0.659 |
| Stroke (I63–I64) | 1.0 (n = 16/1577) | 2.2 (n = 6/279) | 0.106 |
| “Others” (I65–I68) | 0.5 (n = 8/1577) | 0 (n = 0/279) | 0.233 |
| Sequelae of cerebrovascular disease (I69) | 0.7 (n = 11/1577) | 0.7 (n = 2/279) | 0.972 |
| Some CVD eventa | 3.4 (n = 53/1577) | 6.8 (n = 19/279) | 0.014 |
The data were collected from the hospital discharge, hospital outpatient clinic, and primary health care registers. The data were analyzed with cross-tabulation and χ2 test and Fisher exact test, when appropriate. Number of cases in each group is shown in parentheses. Significant P values appear in boldface type.
Combination of the ICD-8, ICD-9, and ICD-10 diagnostic codes for cardiovascular morbidity and events [angina pectoris, myocardial infarction, heart failure, atherosclerosis, transitory cerebral ischemia, intracranial hemorrhage, stroke, other disturbance in intracranial blood flow (I65–I68) and sequelae of cerebrovascular disease].
Discussion
To our knowledge, this is the largest general population-based prospective study with repeated cross-sectional assessments of Caucasian women with PCOS, providing well-documented information about hypertension based on the use of antihypertensive medication, diagnosis of hypertension set by a physician, and clinically measured BP level. Our main findings were that women with PCOS were significantly more often hypertensive and diagnosed with hypertension and more often used antihypertensive medication compared with controls. Moreover, elevated BP was associated with unfavorable changes in echocardiographic parameters in hypertensive women with srPCOS compared with normotensive women. Last, premenopausal women with srPCOS exhibited significantly increased cardiovascular morbidity, even though these results need to be interpreted with caution because of the small number of cases.
In the current study, women with srPCOS more often had hypertension at age 46 years and had significantly greater diastolic and systolic BP at age 31 years than control women, regardless of BMI. In addition, at age 46 years, normal-weight women with srPCOS had significantly higher diastolic but not systolic BP compared with normal-weight controls, whereas the difference between srPCOS and control women vanished in the overweight/obese groups. In line with the present findings, previous cross-sectional studies including adolescent (11) and young reproductive-aged women (6) have reported significantly higher BP levels in normal-weight women with PCOS compared with normal-weight controls, whereas overweight and obese PCOS and control groups had a similar prevalence of hypertension (6, 11). These findings, in keeping with ours, suggest that PCOS has an independent effect on BP levels, even in young, normal-weight women. Of note, however, in the regression analysis, overweight/obesity was associated with hypertension by a greater odds ratio that for srPCOS, outlining the important role of excess weight as a determinant of hypertension in women with PCOS. In addition, after including also the known potential effect modifiers/risk factors for elevated blood pressure (alcohol consumption, education, smoking, physical activity, diabetes, obstructive sleep apnea, and dyslipidemia) in the regression analysis, the results did not change (data not shown). In contrast, some studies found comparable 24-hour ambulatory BP levels between PCOS and control groups, but that finding might be due to small study populations (8–10). Of note, our study population included only women of Caucasian ethnicity and may therefore differ from other populations regarding the prevalence of hypertension and other cardiovascular risk factors, as race/ethnicity has also been reported to affect these risks in women with PCOS (26). Our results are therefore best generalized to Caucasian populations.
Women with srPCOS showed no statistically significant changes in echocardiographic features, although some unfavorable trends were observed (increase in left atrial size, intraventricular septum thickness, and left ventricular mass). These changes are recognized as an adaptation of the heart to elevated levels of BP and are thought to predispose later to heart failure with preserved ejection fraction (27). Hypertensive women with srPCOS had significantly higher values for left atrial size, intraventricular septum thickness, and left ventricular mass compared with normotensive controls, whereas normotensive srPCOS and control groups had comparable cardiac structure and function, suggesting that elevated BP is an important determinant of the cardiac structure and function in women with PCOS. The relatively small number and young age of the women studied most likely explain why there were only few statistically significant differences in the echocardiographic parameters. The results of previous studies investigating cardiac structure and function in PCOS have been inconsistent. Two previous studies, investigating PCOS women in their 20s and 30s, reported significantly greater left atrial diameter and left ventricular mass in women with PCOS, independently of BMI, suggesting the early beginning of heart failure with preserved ejection fraction or abnormalities in the filling phase of the left ventricle (13, 28). In contrast, other studies have not reported any significant difference in the echocardiographic parameters between women with PCOS and controls (14, 15). The controversial findings of these previous studies might be explained by the differences in the age and ethnicity of the study groups as well as the criteria used for the diagnosis of PCOS.
In the current study, women with srPCOS had a significantly higher prevalence of acute myocardial infarction by age 46 years than control women, and the prevalence of any CVD diagnosis was twice as high in the PCOS group, even though these were premenopausal women. However, these results need to be interpreted with caution, as the number of affected women with overt CVD was very small. Likewise, no firm conclusions can be drawn with regard to the risk of CVD mortality in the current study because the numbers were so small (two vs none). Previous studies have reported inconsistent findings with regard to the risk of cardiovascular morbidity in women with PCOS, possibly because of variable study designs and ages of the participants. Recently, a Danish study reported that the event rate for CVD was significantly higher in premenopausal PCOS population compared with controls (29). Also, a nationwide, register-based study of PCOS women aged 30 years reported that PCOS was associated with a twofold higher risk of stroke and thrombosis, whereas the risk of other CVD was not significantly increased (30). A 20-year, retrospective cohort study reported a significantly increased odds ratio for myocardial infarction and a significant correlation with age, history of hypertension, and smoking with cardiovascular outcome in patients with PCOS (31). On the contrary, a 21-year follow-up study of 35 postmenopausal women with PCOS who had a history of wedge resection showed a similar prevalence of myocardial infarction and stroke between PCOS and control groups (7), and a retrospective observational study did not find any increased risk for large-vessel disease in women with PCOS (mean age 30 years) (32). In addition, a recent study reported that women with high postmenopausal androgen levels and retrospectively diagnosed with PCOS did not display an elevated risk for CVD (33). It has been postulated that later age at menopause and, consequently, more prolonged estrogen exposure could alleviate the CVD burden in PCOS despite the high CVD risk profiles commonly present in these women. However, whether this is due to lack of reliable data for the diagnosis and/or the fact that the women in most studies have been too young for detecting CVD events remains to be resolved in future, longitudinal studies.
The modest difference in BP levels observed in women with srPCOS is significant, as an increase of BP of 1.5 to 2 mm Hg has been shown to have a marked impact on CVD risk at a population level (34). In that study, the reduction of even mildly and/or moderately elevated BP to normal levels was associated with a reduced risk of CVDs (34). Of note, at age 46 years, one-third of the women with srPCOS displayed measured BP levels over the generally accepted cutoff value for starting antihypertensive medication (BP ≥140/90 mm Hg). Furthermore, of the women with srPCOS who had BP ≥140/90 mm Hg, 27% were hypertensive despite the use of antihypertensive medication, and even worse, over two-thirds of them (69%) were probably not aware of their elevated BP levels. The follow-up evaluation of these women in the future will reveal whether the cardiovascular risk actually increases further in women with PCOS and clarify the respective roles of the risk factors linked to PCOS with regard to cardiovascular morbidity.
The strengths of this study are the general population-based cohort study design, high participation and response rates, and low dropout rates. We have also previously reported that there were no significant differences between dropout and follow-up groups of women with OA+H at age 31 years (4). Importantly, BP was clinically measured at both ages 31 and 46 years. We were not able to adjust the results for some potential confounding factors (high sodium or low potassium intake, family history, stress and use of nonsteroidal anti-inflammatory drugs), but adjustment for alcohol consumption, education, smoking, physical activity, diabetes, obstructive sleep apnea, and dyslipidemia did not change the results. The cardiovascular event diagnoses were based on hospital discharge and outpatient registers, which have been shown to have a very high coverage and accuracy (88% to 98%) for vascular diseases in Finland (35). The main limitation of this study is that the definition of PCOS is based on self-reported symptoms and diagnosis of PCOS, as that may be prone to misdiagnosis. However, we have previously shown that the presence of both self-reported oligoamenorrhea and hirsutism can accurately identify women with the typical endocrine, metabolic, and psychological profiles of PCOS (17–19), with oligoamenorrhea always being self-reported data. Moreover, the presence of both oligoamenorrhea and hirsutism fulfills both Rotterdam and National Institutes of Health criteria for PCOS. Despite this, our results suggest that even women with srPCOS, who probably have milder hormonal and metabolic alteration than women with PCOS attending clinics, have increased risk for hypertension and CVDs. Another limitation of the diagnosis is that the questionnaire at age 46 years did not distinguish between those women with PCOs and those with established PCOS. However, women with PCO were reported to show a similar metabolic status as control women (36), and thus we would expect that the differences between the PCOS and control groups would have been even greater if we would have been able to exclude women with PCOs only. Other limitations of this study include the relatively small number of women in the echocardiographic analysis and of those who had a diagnosis of CVD.
In conclusion, hypertension and use of antihypertensive medication were significantly more common among women with srPCOS compared with controls, and srPCOS was significantly associated with hypertension, independently of overweight/obesity. Moreover, normal-weight women with srPCOS displayed significantly higher BP levels than normal-weight controls already in their 30s. The hypertensive srPCOS women showed a consistent trend toward unfavorable changes in the cardiac structure and function, exposing them later to increased risk of heart failure with preserved ejection fraction. In addition, an increased prevalence of cardiovascular morbidity was already apparent in premenopausal women with srPCOS. Our results support strongly the recommendation of the Androgen Excess and PCOS (AE-PCOS) Society about the ideal BP for women with PCOS to be 120 mm Hg systolic and 80 mm Hg diastolic or lower (37). They are also in line with the results of the randomized, multicenter trial (Systolic Blood Pressure Intervention Trial) (38), recommending a goal of systolic BP level <120 mm Hg for people at high cardiovascular risk. Last, the present findings strengthen further the need for early systematic screening and efficient treatment of hypertension in women with PCOS, as recommended by the AE-PCOS Society (37) and the international evidence-based guideline for PCOS (39), as well as the importance of an active prevention and treatment of obesity in this particular group of women. Future prospective longitudinal studies are needed to establish the cause-effect relationship of PCOS and hypertension.
Acknowledgments
We thank the late Professor Paula Rantakallio for launching the Northern Finland Birth Cohort, the participants in the 31- and 46-year studies, and the Northern Finland Birth Cohort project center.
Financial Support: This work was supported by grants from the Finnish Medical Foundation, the North Ostrobothnia Regional Fund, Academy of Finland (project grants 315921, 104781, 120315, 129269, 1114194, 24300796, 295760), Center of Excellence in Complex Disease Genetics and SALVE, the Sigrid Juselius Foundation, University Hospital Oulu and University of Oulu (75617), Medical Research Center Oulu, National Institute for Health Research (UK), Genesis Research Trust (UK), NHLBI grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01), NIH/NIMH (5R01MH63706:02), ENGAGE project and grant agreement HEALTH-F4-2007-201413, EU FP7 EurHEALTHAgeing-277849 from the European Commission and the Medical Research Council (UK) (G0500539, G0600705, G1002319, G0802782, PrevMetSyn/SALVE), and the MRC, Centenary Early Career Award.
Disclosure Summary: The authors have nothing to disclose.
Glossary
Abbreviations:
- AOR
adjusted odds ratio
- BMI
body mass index
- BP
blood pressure
- CVD
cardiovascular disease
- ICD
International Classification of Diseases
- OA+H
oligo/amenorrhea and hirsutism
- PCOs
polycystic ovaries
- PCOS
polycystic ovary syndrome
- srPCOS
self-reported polycystic ovary syndrome
References
- 1. Franks S. Polycystic ovary syndrome. N Engl J Med. 1995;333(13):853–861. [DOI] [PubMed] [Google Scholar]
- 2. March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ, Davies MJ. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod. 2009;25(2):544–551. [DOI] [PubMed] [Google Scholar]
- 3. Fauser BC, Tarlatzis BC, Rebar RW, Legro RS, Balen AH, Lobo R, Carmina E, Chang J, Yildiz BO, Laven JS, Boivin J, Petraglia F, Wijeyeratne CN, Norman RJ, Dunaif A, Franks S, Wild RA, Dumesic D, Barnhart K. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril. 2012;97(1):28–38.e25. [DOI] [PubMed] [Google Scholar]
- 4. Ollila MM, Piltonen T, Puukka K, Ruokonen A, Järvelin MR, Tapanainen JS, Franks S, Morin-Papunen L. Weight gain and dyslipidemia in early adulthood associate with polycystic ovary syndrome: prospective cohort study. J Clin Endocrinol Metab. 2016;101(2):739–747. [DOI] [PubMed] [Google Scholar]
- 5. Carmina E, Bucchieri S, Esposito A, Del Puente A, Mansueto P, Orio F, Di Fede G, Rini G. Abdominal fat quantity and distribution in women with polycystic ovary syndrome and extent of its relation to insulin resistance. J Clin Endocrinol Metab. 2007;92(7):2500–2505. [DOI] [PubMed] [Google Scholar]
- 6. Joham AE, Boyle JA, Zoungas S, Teede HJ. Hypertension in reproductive-aged women with polycystic ovary syndrome and association with obesity. Am J Hypertens. 2014;28(7):847–851. [DOI] [PubMed] [Google Scholar]
- 7. Schmidt J, Landin-Wilhelmsen K, Brännström M, Dahlgren E. Cardiovascular disease and risk factors in PCOS women of postmenopausal age: a 21-year controlled follow-up study. J Clin Endocrinol Metab. 2011;96(12):3794–3803. [DOI] [PubMed] [Google Scholar]
- 8. Meyer C, McGrath BP, Teede HJ. Overweight women with polycystic ovary syndrome have evidence of subclinical cardiovascular disease. J Clin Endocrinol Metab. 2005;90(10):5711–5716. [DOI] [PubMed] [Google Scholar]
- 9. Zimmermann S, Phillips RA, Dunaif A, Finegood DT, Wilkenfeld C, Ardeljan M, Gorlin R, Krakoff LR. Polycystic ovary syndrome: lack of hypertension despite profound insulin resistance. J Clin Endocrinol Metab. 1992;75(2):508–513. [DOI] [PubMed] [Google Scholar]
- 10. Luque-Ramírez M, Alvarez-Blasco F, Mendieta-Azcona C, Botella-Carretero JI, Escobar-Morreale HF. Obesity is the major determinant of the abnormalities in blood pressure found in young women with the polycystic ovary syndrome. J Clin Endocrinol Metab. 2007;92(6):2141–2148. [DOI] [PubMed] [Google Scholar]
- 11. Zachurzok-Buczynska A, Szydlowski L, Gawlik A, Wilk K, Malecka-Tendera E. Blood pressure regulation and resting heart rate abnormalities in adolescent girls with polycystic ovary syndrome. Fertil Steril. 2011;96(6):1519–1525. [DOI] [PubMed] [Google Scholar]
- 12. Santos M, Shah AM. Alterations in cardiac structure and function in hypertension. Curr Hypertens Rep. 2014;16(5):428. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Orio F Jr, Palomba S, Spinelli L, Cascella T, Tauchmanovà L, Zullo F, Lombardi G, Colao A. The cardiovascular risk of young women with polycystic ovary syndrome: an observational, analytical, prospective case-control study. J Clin Endocrinol Metab. 2004;89(8):3696–3701. [DOI] [PubMed] [Google Scholar]
- 14. Selcoki Y, Yilmaz OC, Carlioglu A, Onaran Y, Kankilic MN, Karakurt F, Eryonucu B. Cardiac flow parameters with conventional and pulsed tissue Doppler echocardiography imaging in patients with polycystic ovary syndrome. Gynecol Endocrinol. 2010;26(11):815–818. [DOI] [PubMed] [Google Scholar]
- 15. Tekin A, Tekin G, Cölkesen Y, Kiliçdağ EB, Başhan I, Sezgin AT, Müderrisoğlu H. Left ventricular function in patients with polycystic ovary syndrome: a Doppler echocardiographic study. Exp Clin Endocrinol Diabetes. 2008;117(4):165–169. [DOI] [PubMed] [Google Scholar]
- 16. Dokras A. Cardiovascular disease risk in women with PCOS. Steroids. 2013;78(8):773–776. [DOI] [PubMed] [Google Scholar]
- 17. Karjula S, Morin-Papunen L, Auvinen J, Ruokonen A, Puukka K, Franks S, Järvelin MR, Tapanainen JS, Jokelainen J, Miettunen J, Piltonen TT. Psychological distress is more prevalent in fertile age and premenopausal women with PCOS symptoms: 15-year follow-up. J Clin Endocrinol Metab. 2017;102(6):1861–1869. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Taponen S, Martikainen H, Järvelin MR, Laitinen J, Pouta A, Hartikainen AL, Sovio U, McCarthy MI, Franks S, Ruokonen A. Hormonal profile of women with self-reported symptoms of oligomenorrhea and/or hirsutism: Northern Finland Birth Cohort 1966 study. J Clin Endocrinol Metab. 2003;88(1):141–147. [DOI] [PubMed] [Google Scholar]
- 19. Taponen S, Ahonkallio S, Martikainen H, Koivunen R, Ruokonen A, Sovio U, Hartikainen AL, Pouta A, Laitinen J, King V, Franks S, McCarthy MI, Järvelin MR. Prevalence of polycystic ovaries in women with self-reported symptoms of oligomenorrhoea and/or hirsutism: Northern Finland Birth Cohort 1966 Study. Hum Reprod. 2004;19(5):1083–1088. [DOI] [PubMed] [Google Scholar]
- 20. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, Christiaens T, Cifkova R, De Backer G, Dominiczak A, Galderisi M, Grobbee DE, Jaarsma T, Kirchhof P, Kjeldsen SE, Laurent S, Manolis AJ, Nilsson PM, Ruilope LM, Schmieder RE, Sirnes PA, Sleight P, Viigimaa M, Waeber B, Zannad F, Redon J, Dominiczak A, Narkiewicz K, Nilsson PM, Burnier M, Viigimaa M, Ambrosioni E, Caufield M, Coca A, Olsen MH, Schmieder RE, Tsioufis C, van de Borne P, Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Sirnes PA, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S, Clement DL, Coca A, Gillebert TC, Tendera M, Rosei EA, Ambrosioni E, Anker SD, Bauersachs J, Hitij JB, Caulfield M, De Buyzere M, De Geest S, Derumeaux GA, Erdine S, Farsang C, Funck-Brentano C, Gerc V, Germano G, Gielen S, Haller H, Hoes AW, Jordan J, Kahan T, Komajda M, Lovic D, Mahrholdt H, Olsen MH, Ostergren J, Parati G, Perk J, Polonia J, Popescu BA, Reiner Z, Rydén L, Sirenko Y, Stanton A, Struijker-Boudier H, Tsioufis C, van de Borne P, Vlachopoulos C, Volpe M, Wood DA. 2013 ESH/ESC guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013;34(28):2159–2219. [DOI] [PubMed] [Google Scholar]
- 21. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ; Task Force on Chamber Quantification; American College of Cardiology Echocardiography Committee; American Heart Association; European Association of Echocardiography, European Society of Cardiology. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18(12):1440–1463. [DOI] [PubMed] [Google Scholar]
- 22. Patrianakos AP, Zacharaki AA, Kalogerakis A, Solidakis G, Parthenakis FI, Vardas PE. Two-dimensional global and segmental longitudinal strain: are the results from software in different high-end ultrasound systems comparable? Echo Res Pract. 2015;2(1):29–39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Smiseth OA, Torp H, Opdahl A, Haugaa KH, Urheim S. Myocardial strain imaging: how useful is it in clinical decision making? Eur Heart J. 2015;37(15):1196–1207. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser. 2000;894:i–xii, 1–253. [PubMed] [Google Scholar]
- 25. Ollila MM, West S, Keinänen-Kiukaanniemi S, Jokelainen J, Auvinen J, Puukka K, Ruokonen A, Järvelin MR, Tapanainen JS, Franks S, Piltonen TT, Morin-Papunen LC. 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. Hum Reprod. 2016;32(2):423–431. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Chang AY, Oshiro J, Ayers C, Auchus RJ. Influence of race/ethnicity on cardiovascular risk factors in polycystic ovary syndrome: the Dallas Heart Study. Clin Endocrinol (Oxf). 2015;85(1):92–99. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P; ESC Scientific Document Group . 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37(27):2129–2200. [DOI] [PubMed] [Google Scholar]
- 28. Wang ET, Ku IA, Shah SJ, Daviglus ML, Schreiner PJ, Konety SH, Williams OD, Siscovick D, Bibbins-Domingo K. Polycystic ovary syndrome is associated with higher left ventricular mass index: the CARDIA women’s study. J Clin Endocrinol Metab. 2012;97(12):4656–4662. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Glintborg D, Rubin KH, Nybo M, Abrahamsen B, Andersen M. Cardiovascular disease in a nationwide population of Danish women with polycystic ovary syndrome. Cardiovasc Diabetol. 2018;17(1):37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Glintborg D, Hass Rubin K, Nybo M, Abrahamsen B, Andersen M. Morbidity and medicine prescriptions in a nationwide Danish population of patients diagnosed with polycystic ovary syndrome. Eur J Endocrinol. 2015;172(5):627–638. [DOI] [PubMed] [Google Scholar]
- 31. Mani H, Levy MJ, Davies MJ, Morris DH, Gray LJ, Bankart J, Blackledge H, Khunti K, Howlett TA. Diabetes and cardiovascular events in women with polycystic ovary syndrome: a 20-year retrospective cohort study. Clin Endocrinol (Oxf). 2013;78(6):926–934. [DOI] [PubMed] [Google Scholar]
- 32. Morgan CL, Jenkins-Jones S, Currie CJ, Rees DA. Evaluation of adverse outcome in young women with polycystic ovary syndrome versus matched, reference controls: a retrospective, observational study. J Clin Endocrinol Metab. 2012;97(9):3251–3260. [DOI] [PubMed] [Google Scholar]
- 33. Meun C, Franco OH, Dhana K, Jaspers L, Muka T, Louwers Y, Ikram MA, Fauser BCJM, Kavousi M, Laven JSE. High androgens in postmenopausal women and the risk for atherosclerosis and cardiovascular disease: the Rotterdam study. J Clin Endocrinol Metab. 2018;103(4):1622–1630. [DOI] [PubMed] [Google Scholar]
- 34. Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhäger WH, Bulpitt CJ, de Leeuw PW, Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C, O’Brien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A; The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators . Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet. 1997;350(9080):757–764. [DOI] [PubMed] [Google Scholar]
- 35. Sund R. Quality of the Finnish hospital discharge register: a systematic review. Scand J Public Health. 2012;40(6):505–515. [DOI] [PubMed] [Google Scholar]
- 36. Catteau-Jonard S, Bancquart J, Poncelet E, Lefebvre-Maunoury C, Robin G, Dewailly D. Polycystic ovaries at ultrasound: normal variant or silent polycystic ovary syndrome? Ultrasound Obstet Gynecol. 2012;40(2):223–229. [DOI] [PubMed] [Google Scholar]
- 37. Wild RA, Carmina E, Diamanti-Kandarakis E, Dokras A, Escobar-Morreale HF, Futterweit W, Lobo R, Norman RJ, Talbott E, Dumesic DA. Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. J Clin Endocrinol Metab. 2010;95(5):2038–2049. [DOI] [PubMed] [Google Scholar]
- 38. Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, Reboussin DM, Rahman M, Oparil S, Lewis CE, Kimmel PL, Johnson KC, Goff DC Jr, Fine LJ, Cutler JA, Cushman WC, Cheung AK, Ambrosius WT; SPRINT Research Group . A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103–2116. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39. Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, Piltonen T, Norman RJ; International PCOS Network . Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Clin Endocrinol (Oxf). 2018;89(3):251–268. [DOI] [PMC free article] [PubMed] [Google Scholar]