The cardiovascular risk profile of middle age women previously diagnosed with premature ovarian insufficiency: A case-control study

Abstract

Background: Cardiovascular disease (CVD) is the leading cause of death in women worldwide. The cardiovascular risk profile deteriorates after women enter menopause. By definition, women diagnosed with premature ovarian insufficiency (POI) experience menopause before 40 years of age, which may render these women even more susceptible to develop CVD later in life. However, prospective long-term follow up data of well phenotyped women with POI are scarce. In the current study we compare the CVD profile and risk of middle aged women previously diagnosed with POI, to a population based reference group matched for age and BMI.

Methods and findings: We compared 123 women (age 49.0 (± 4.3) years) and diagnosed with POI 8.1 (IQR: 6.8-9.6) years earlier, with 123 population controls (age 49.4 (± 3.9) years). All women underwent an extensive standardized cardiovascular screening. We assessed CVD risk factors including waist circumference, BMI, blood pressure, lipid profile, pulse wave velocity (PWV), and the prevalence of diabetes mellitus, metabolic syndrome (MetS) and carotid intima media thickness (cIMT), in both women with POI and controls. We calculated the 10-year CVD Framingham Risk Score (FRS) and the American Heart Association's suggested cardiovascular health score (CHS). Waist circumference (90.0 (IQR: 83.0-98.0) versus 80.7 (IQR: 75.1-86.8), p < 0.01), waist-to-hip ratio (0.90 (IQR: 0.85-0.93) versus 0.79 (IQR: 0.75-0.83), p < 0.01), systolic blood pressure (124 (IQR 112-135) versus 120 (IQR109-131), p < 0.04) and diastolic blood pressure (81 (IQR: 76-89) versus 78 (IQR: 71-86), p < 0.01), prevalence of hypertension (45 (37%) versus 21 (17%), p < 0.01) and MetS (19 (16%) versus 4 (3%), p < 0.01) were all significantly increased in women with POI compared to healthy controls. Other risk factors, however, such as lipids, glucose levels and prevalence of diabetes were similar comparing women with POI versus controls. The arterial stiffness assessed by PWV was also similar in both populations (8.1 (IQR: 7.1-9.4) versus 7.9 (IQR: 7.1-8.4), p = 0.21). In addition, cIMT was lower in women with POI compared to controls (550 μm (500-615) versus 684 μm (618-737), p < 0.01). The calculated 10-year CVD risk was 5.9% (IQR: 3.7-10.6) versus 6.0% (IQR: 3.9-9.0) (p = 0.31) and current CHS was 6.1 (1.9) versus 6.5 (1.6) (p = 0.07), respectively in POI versus controls.

Conclusions: Middle age women with POI presented with more unfavorable cardiovascular risk factors (increased waist circumference and a higher prevalence of hypertension and MetS) compared to age and BMI matched population controls. In contrast, the current study reveals a lower cIMT and similar 10-year cardiovascular disease risk and cardiovascular health score. In summary, neither signs of premature atherosclerosis nor a worse cardiovascular disease risk or health score were observed among middle age women with POI compared to population controls. Longer-term follow-up studies of women of more advanced age are warranted to establish whether women with POI are truly at increased risk of developing CVD events later in life.

Trial registration: ClinicalTrials.gov Identifier: NCT02616510.

Conflict of interest statement

During the most recent 4 year period B.C.J.M.F. has received fees or grant support from the following organizations (in alphabetic order); Abbott, Controversies in Obstetrics & Gynecology (COGI), Dutch Heart Foundation (Hartstichting), Dutch Medical Research Counsel (ZonMW), Ferring, London Womens Clinic (LWC), Menogenix, Myovant, OvaScience, Pantharei Bioscience, PregLem/Gedeon Richter, Reproductive Biomedicine Online (RBMO), Teva/Theramex, World Health Organisation (WHO). J.S.E.L. has received fees and grant support from the following organizations (in alphabetic order): Danone, Dutch Heart Foundation, Euroscreen, Ferring, Roche, Titus Healthcare and ZonMW. C.B.L. has over the most recent 5-year period received fees and grant support from the following organizations (in alphabetic order): Amsterdam UMC, Ferring, Merck and ZonMW. E.B., Y.A has over the most recent 4 year period received grant support from the Ducht Heart Foundation., M.K. is supported by the VENI grant (91616079) from ZonMw. J.R.v.L has over the most recent 5 year period received fees and grant support from the following organizations (in alphabetic order): Amgen, Amryt, Dutch Heart Foundation and Erasmus MC. M.G. received scientific congress fees from Merck and Gedeon Richter. The above mentioned competing interest does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Cardiovascular parameters and outcomes for cardiovascular disease in middle age women with POI and age and BMI-matched controls.

Abbreviations: cIMT = carotid intima media thickness, CVD = cardiovascular disease, IQR = inter-quartile range, MetS = metabolic syndrome, p = p-value, SD = standard deviation.

Fig 2. Risk groups of 10 year cardiovascular disease risk in women with POI and controls.

Low risk: 20%. Above the columns the numbers of patients which each column represent are listed. Abbreviations: p = p-value, POI: premature ovarian insufficiency.

Fig 3. Graph of the available components of the cardiovascular health metrics score in women with POI versus healthy controls.

Prevalence (%) of poor, intermediate and ideal cardiovascular heath metrics in women diagnosed with POI and controls. Abbreviations: BMI: body mass index, BP: blood pressure, (n) = number of patients included in each group per individual metric, p = p-value, POI: premature ovarian insufficiency.