Office Blood Pressure, Ambulatory Blood Pressure Monitoring, and Echocardiographic Abnormalities in Women With Polycystic Ovary Syndrome
Role of Obesity and Androgen Excess
Whether or not blood pressure (BP) and heart function of women with polycystic ovary syndrome (PCOS) are altered remains unclear, albeit subtle abnormalities in the regulation of BP observed in these women might suggest a mild masculinization of their cardiovascular system. To study the influence of obesity and androgen excess on BP and echocardiographic profiles of women with the syndrome, we conducted a cross-sectional case–control study comparing office and ambulatory BP monitoring, as well as echocardiographic assessments, in 63 premenopausal women with the classic phenotype, 33 nonhyperandrogenic women with regular menses, and 25 young men. Forty-nine subjects were lean and 72 had weight excess (body mass index ≥25 kg/m2). Participants had no previous history of hypertension and were nonsmokers. Men showed the highest BP readings, and the lowest readings were observed in control women, whereas women with PCOS had intermediate values. Undiagnosed hypertension was more common in subjects with weight excess irrespective of sex and hyperandrogenism. Women with PCOS and weight excess showed frequencies of previously undiagnosed hypertension that were similar to those of men with weight excess and higher than those observed in nonhyperandrogenic women. Lastly, male sex, weight excess and hypertension, the latter in men as well as in women with PCOS, increased left ventricular wall thickness. In summary, our results show that patients with classic PCOS and weight excess frequently have undiagnosed BP abnormalities, leading to target organ damage.
Albeit mainly a disorder of androgen excess, the polycystic ovary syndrome (PCOS) is frequently associated with insulin resistance and obesity.1 These and other cardiovascular risk factors cluster in PCOS patients from relatively early ages.2 Research into the pathogenic factors contributing to their cardiovascular risk may facilitate preventive strategies and targeted treatments.
It remains unclear whether blood pressure (BP) profiles of PCOS patients are altered.3 Many studies that suggested a higher prevalence of hypertension compared with nonhyperandrogenic women4,5 were uncontrolled for the influence of obesity.3 Therefore, the link between PCOS and hypertension might be actually derived from its association with adiposity.6 In our experience with PCOS patients, BP abnormalities are mostly dependent on the presence of obesity and often detected by ambulatory BP monitoring (ABPM).6 However, the positive association between testosterone (T) concentrations and BP in PCOS suggests that androgens may influence BP regulation in premenopausal women,7 as supported by the well-known sexual dimorphism in BP.8
Similarly, the association of PCOS with abnormalities in cardiac structure or function remains unanswered, because few echocardiographic studies that have explored echocardiographic parameters in PCOS patients yielded conflicting results.9,10
Sexual dimorphism in the prevalence of hypertension may suggest that subtle abnormalities in the BP profile of PCOS patients represent mild masculinization of their cardiovascular system, as has been demonstrated for body fat distribution and adipose tissue proteomes and adipokine gene expression profiles.11–13 However, the BP recordings of women with PCOS have, to date, not been compared with those of men.
To provide new insights on these crucial issues, we conducted a comprehensive cross-sectional study evaluating BP and echocardiographic profiles of a cohort of premenopausal women with PCOS and compared them with nonhyperandrogenic women and men.
The study population consisted of 121 young adults, including 63 women with PCOS, 33 nonhyperandrogenic women presenting with regular menses, and 25 young men. Subject characteristics (Text S1 in the online-only Data Supplement), methods and assays used to phenotype the study population (Text S2), and anthropometric and metabolic features of PCOS patients compared with control women and men (Table S1) are summarized in the online-only Data Supplement.
Office BP was determined as the mean of 2 manual sphygmomanometer readings in the sitting position by trained operators.14 For 24-hour ABPM, we used A&D TM2430EX oscillometric devices (A&D Company Limited, Tokyo, Japan) as described previously.6,15
We used the normative data derived from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure for office BP.14 ABPM abnormalities were defined from average BP recordings, as follows:14,16
24-hour average: normal if <130/80 mm Hg; abnormal if ≥130/80 but <135/85 mm Hg; and hypertension if ≥135/85 mm Hg.
Daytime average: normal if <135/85 mm Hg; abnormal if ≥135/85 but <140/90 mm Hg; and hypertension if ≥140/90 mm Hg.
Nighttime average: normal if <120/70 mm Hg; abnormal if ≥120/70 but <125/75 mm Hg; and hypertension if ≥125/75 mm Hg.
Systolic and diastolic BP loads were defined as the percentage of ambulatory pressures >140 and 90 mm Hg during daytime and >120 and 70 mm Hg during nighttime.
Echocardiography was conducted in a subset of subjects, including 36 PCOS patients, 22 control women, and 25 men. These subgroups of PCOS and control women were representative of those larger groups submitted to ABPM recordings in terms of anthropometric, metabolic, hormonal, and BP parameters (Tables S2 and S3).
For cardiac evaluation based on transthoracic echocardiography, we used a Nemio XG SSA-580A Ultrasound equipped with a PSM-30BT 3 to 5 MHz transducer (Toshiba Medical Systems, Alcobendas, Spain). Measurements were run by a cardiologist (D.M.) who was blinded to the clinical data of participants. Left ventricular mass (LVM) was calculated by Devereux formula.17 All structural parameters were indexed by height. Measurements were performed according to standards of the European Association of Cardiovascular Imaging (http://www.escardio.org/communities/EACVI/publications).
A priori sample size analysis was performed using the online calculator Ene 3.0 (http://www.e-biometria.com). Because we did not find a similar study design in the literature, we used as primary outcome the difference in hypertension frequencies, assessed by office readings, between obese and nonobese premenopausal nonhyperandrogenic women and PCOS patients.6 An experimental design comparing 31 control women and 31 PCOS patients would have power >0.80 to detect differences similar to those reported.6
Results are expressed as mean±SD or counts (percentage) unless otherwise stated. Nominal variables were analyzed by χ2 or Fisher exact tests as appropriate. Kolmogorov–Smirnov statistics served to test continuous variables for normality. Logarithmic transformations ensured a normal distribution as needed. We used univariate, 2-way general linear models to evaluate, within a single analysis, differences in continuous variables between men, control women, and PCOS patients, and weight subgroups. Significant differences among groups of subjects were analyzed applying Bonferroni correction. Because there were differences among study subgroups, age was introduced as a covariate in the analysis of other phenotypic variables. Stepwise multiple linear regression analyses were performed to identify the main determinants of systolic and diastolic BP among women with PCOS. Body mass index (BMI), free T, area under the curve of insulin (as a marker of hyperinsulinism), insulin sensitivity index, and 24-hour period heart rate (HR, as a marker of sympathetic overactivation)18 were introduced as independent variables. We used the Statistical Package for the Social Sciences 17.0 (SPSS Ibérica, Madrid, Spain) for analyses. P<0.05 was considered statistically significant.
Sex Steroid Profile of PCOS Patients, Control Women, and Men, and Impact of Weight Excess
These data are summarized in Table 1. Serum total and free T levels were increased in men compared with control women, with PCOS patients showing intermediate values. Free estradiol levels were reduced in both men and PCOS patients compared with control women. Weight excess interacted with the group of subjects on free T and estradiol concentrations. These concentrations increased in PCOS patients and control women presenting with weight excess, but tended to decrease or showed no changes in men with weight excess.
Office BP Recordings and ABPM
These data are summarized in Table 2. Most BP readings were higher in subjects with weight excess. Men presented with the highest values of systolic and diastolic BP in both office and ABPM recordings; nonhyperandrogenic women showed the lowest values; and PCOS patients showed intermediate values. Office diastolic BP, daytime systolic BP load, nighttime diastolic BP load, and 24-hour systolic BP of PCOS patients tended to be higher than those of control women and were similar to the highest values observed in men.
We found a few differences in the frequencies of abnormalities in BP. Weight excess was associated with office hypertension (Figure 1) and frequencies of abnormal diastolic BP during nighttime and 24-hour BP, irrespective of sex and PCOS (Table S4). The frequencies of daytime systolic hypertension and 24-hour systolic BP were higher in men compared with both groups of women. When analyzing the impact of weight excess on hypertension in men, PCOS patients, and control women separately, patients with PCOS and weight excess showed frequencies of office and ABPM hypertension that were similar to those of men with weight excess and higher than those observed in lean PCOS patients, lean men, and control women irrespective of their weight (Figure 1).
Subjects with weight excess as a whole had increased left atrial diameter, interventricular septum, posterior LV wall thickness, and LVM. Men showed increased LVM compared with both groups of women (Figure S1).
Regarding indexes of cardiac function, peak velocity of mitral inflow early wave and LV telesystolic diameter were slower in subjects with weight excess. None of the subjects studied had an abnormal mitral early-to-late wave ratio. Deceleration time was different among study subgroups, because PCOS patients, irrespective of their weight, showed a reduced early filling velocity. LV telesystolic and telediastolic diameters were larger in men irrespective of weight excess. No differences were observed in the ejection fraction.
We analyzed the impact of hypertension on echocardiographic profiles, although echocardiography was not conducted in 2 control women presenting with hypertension (Figure 2). Hypertensive PCOS patients and men presented with increased interventricular septum and posterior LV wall thickness, LVM, and ejection fraction compared with normotensive counterparts and nonhyperandrogenic women.
Main Determinants of Systolic BP, Diastolic BP, and LVM Among PCOS Patients
In regression models (Figure S2), after evaluating the relative contributions of independent variables to the variability of BP in PCOS patients, the main determinants of office systolic BP (BMI and free T), of office diastolic BP (BMI and 24-hour HR), of 24-hour systolic BP (BMI), and of 24-hour diastolic BP (24-hour HR) were assessed.
Likewise, after adding 24-hour systolic and diastolic BP as independent variables to the model, the main determinant of LVM in PCOS patients was BMI (Figure S3).
Our present results highlight the association of obesity with BP abnormalities in young adults.6 Additionally, our findings also suggest that PCOS patients may lose some of the protection against hypertension provided by sexual dimorphism: the negative effect of weight excess is more important in these patients than in control women, explaining why the frequency of hypertension in overweight and obese PCOS patients was similar to that found in men.
Weight excess and PCOS share several mechanisms that exert a deleterious influence on BP regulation. First, insulin resistance and hyperinsulinemia are common in PCOS patients and obese subjects.1 The relationship between insulin resistance and salt sensitivity has been demonstrated in hypertensive subjects.19 Hyperinsulinism also increases insulin-like growth factor-1 bioavailability,20 which is associated with vascular smooth muscle hypertrophy and higher peripheral resistances. Moreover, the role of insulin resistance and hyperinsulinism is in conceptual agreement with the beneficial effect of metformin on BP in these patients.15
Second, weight excess increases sodium reabsorption and impairs pressure natriuresis by the activation of the renin–angiotensin system and by altered intrarenal physical forces.21 Renin–angiotensin system overactivation leads to increased circulating aldosterone levels, and this elevation, even within the physiological range, predisposes to the development of hypertension.22 In PCOS patients, increased aldosterone levels have been found in association with weight excess and insulin resistance.23
Third, sympathetic nervous system activation is a common obesity feature. In accordance, subjects with weight excess in our study had higher average HR than their lean counterparts. Furthermore, PCOS patients may show sympathetic hyperactivity associated with insulin resistance, obesity, androgen excess, and obstructive sleep apnea.24 Sympathetic hyperactivity can increase tubular sodium reabsorption and cause peripheral vasoconstriction.21 Supporting this association, 24-hour HR was one of the main determinants for office and 24-hour diastolic BP in our PCOS patients.
Our results also agree with sexual dimorphism in BP in young adults. The balance between androgens and estrogens might underlie this dimorphism, because PCOS patients having androgen excess and decreased serum estradiol concentrations showed several BP measurements that were close to those of men, and free T was a significant contributor for office systolic BP in these women. Epidemiological data reveal that these sex differences in BP may have originated in adolescence. Although the effects on salt-sensitive hypertension of sex chromosomes and genes have been separated from those of sex hormones,8 a direct influence of sex steroids cannot be ignored. The impact of T is different in men and women because reduced levels in men of all ages have been associated with hypertension,25 whereas androgen excess has been related to arterial pressure and hypertension in women.7,26 This paradox may be explained by androgen excess leading to abdominal adiposity in women1 and androgen deficiency leading to sarcopenic obesity in men.1,27 In addition, several mechanisms might explain the relationship among hyperandrogenism and hypertension in PCOS patients. Hyperandrogenemia itself may activate renin–angiotensin system.28 Accordingly, prenatal exposure to androgen excess in sheep (an animal model of PCOS) has been associated with mild hypertension and sympathetic overactivity in adult life.29 Hence, the imbalance between androgens and estrogens, as found especially in our patients with PCOS and weight excess, may play a role on BP dysregulation.8
BP abnormalities found in hypertensive PCOS patients were accompanied by cardiac remodeling, suggesting early target organ damage. Adverse LV remodeling in PCOS has been previously reported. Wang et al10 found that young women with classic PCOS had increased LVM independently of their weight and office BP. Moreover, the finding of a shorter deceleration time in our PCOS patients is in line with previous studies showing subclinical diastolic dysfunction in PCOS patients.30 Our results, based on an accurate method for evaluating BP, indicate that undiagnosed hypertension and weight excess are the main contributors for this increase in wall thickness. All our hypertensive PCOS patients had weight excess as well, and subjects with weight excess presented with significantly larger LV dimensions compared with their lean counterparts. Therefore, we may assume that increased LVM and wall thickness found in our hypertensive PCOS patients resulted from the synergy between their weight excess and hypertension.
Our study is not free of limitations, including the relatively small sample of control women and men, and the presence of small but statistically significant differences in terms of age among study subgroups, although we thoroughly corrected for these in all subsequent comparisons. Because subjects with known hypertension were excluded, the study cannot address the overall incidence of elevated BP in PCOS. Furthermore, the absence of hypertension in our control women submitted to echocardiography precluded the full delineation of the contributions of weight excess and hypertension to echocardiographic profiles. Lastly, our results, having been derived from patients with classic PCOS phenotype, cannot be extrapolated to less severe PCOS phenotypes.
Patients with classic PCOS and weight excess show frequencies of undiagnosed office and ABPM hypertension that are similar to those of men with weight excess and higher than those observed in nonhyperandrogenic women. Likewise, previously undiagnosed hypertension in women with classic PCOS may have led to increased LVM, compared with nonhyperandrogenic women and normotensive patients with PCOS, and their LVM values were not different from those of men. These findings may have important clinical implications in a highly prevalent condition such as PCOS. Because of the frequent occurrence of abnormalities in BP, including undiagnosed hypertension and the evidence of subclinical cardiac remodeling, a comprehensive cardiovascular evaluation of these patients focusing on whether these disturbances are present in other metabolically less severe phenotypes of PCOS, such as as those without hyperandrogenism or ovulatory dysfuction, in comparison with a larger sample of nonhyperandrogenic women and men, is warranted.
Sources of Funding
This study was supported by grants Fondo de Investigación Sanitaria (PI080944 and PI1100357) from Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitiveness, and a grant (EC10-096) from Dirección General de Farmacia, Spanish Ministry of Health, Social Services, and Equality.
Novelty and Significance
What Is New?
We present, for the first time to our knowledge, a systematic assessment of blood pressure profiles and echocardiographic evaluation of cardiac function and structure in women with PCOS compared with premenopausal, nonhyperandrogenic control women and young adult men.
What Is Relevant?
Although PCOS has been known to affect ≈15% of premenopausal women worldwide, and cardiovascular risk factors cluster in women with this condition, the issue of whether or not these women have abnormalities in blood pressure is still a matter of controversy.
Patients with PCOS and weight excess show frequencies of undiagnosed hypertension that are similar to those of men with weight excess and higher than those observed in nonhyperandrogenic women. Previously undiagnosed hypertension in women with PCOS could lead to increased left ventricular mass reaching values similar to those of men.
Current address for D.M.: Department of Cardiology, Hospital Gómez Ulla, Madrid, Spain.
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.113.02468/-/DC1.
- Received September 23, 2013.
- Revision received October 8, 2013.
- Accepted November 5, 2013.
- © 2013 American Heart Association, Inc.
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