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Department of Endocrinology, Hospital Universitario Ramón y Cajal and Universidad de Alcalá (M.L.-R., F.A.-B, J.I.B.-C, H.F.E.-M), and Department of Vascular Surgery, Hospital Universitario La Paz (C.M.-A), 28034 Madrid, Spain
Address all correspondence and requests for reprints to: Héctor F. Escobar-Morreale, M.D., Ph.D., Department of Endocrinology, Hospital Universitario Ramón y Cajal and Universidad de Alcalá, Carretera de Colmenar Viejo Km 9.1, 28034 Madrid, Spain. E-mail: hescobarm.hrc{at}salud.madrid.org.
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Abstract |
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Objective: Our objective was to evaluate the impact of obesity on the blood pressure profiles of PCOS patients.
Patients, Setting, and Design: Thirty-six PCOS patients and 20 healthy women participated in a case-control study at an academic hospital.
Main Outcome Measures: We conducted ambulatory blood pressure monitoring and office blood pressure determinations.
Results: Hypertension (defined as increased office blood pressure confirmed by ambulatory blood pressure monitoring or by masked hypertension) was present in 12 PCOS patients and eight controls (P = 0.618). No differences between patients and controls were found in office and ambulatory blood pressure monitoring values and heart rate, yet the nocturnal decrease in mean blood pressure was smaller in patients (P = 0.038). Obese women (13 patients and eight controls) had increased frequencies of office hypertension (29% compared with 3% in lean plus overweight women, P = 0.005), increased diastolic (P = 0.009) and mean (P = 0.015) office blood pressure values, and increased heart rate values during the daytime (P = 0.038), nighttime (P = 0.002), and 24-h (P = 0.009) periods, independently of having PCOS or not. The frequency of a nocturnal nondipper pattern was 62% in obese PCOS patients, compared with 26% in lean plus overweight PCOS patients (P = 0.036) and 25% in obese and in lean plus overweight controls.
Conclusions: Abnormalities in the regulation of blood pressure are common in young women with PCOS, yet, with the exception of the nondipper pattern, these abnormalities result from the frequent association of this syndrome with obesity.
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Introduction |
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Cardiovascular risk factors and subclinical atherosclerosis cluster in PCOS patients, although the demonstration of an increased rate of cardiovascular events in PCOS is still pending (5). Among others, increased prevalence of obesity (6), disorders of glucose tolerance (including type 2 diabetes) (7) and insulin resistance (8), and dyslipidemia (9) as well as nonclassic cardiovascular risk factors such as low-grade chronic inflammation (3), increased oxidative stress (10), and endothelial dysfunction (11) have been reported in PCOS patients.
However, hypertension is not characteristically associated with PCOS (12, 13, 14). Although the usually relatively young age of PCOS patients may explain the absence of hypertension despite the presence of insulin resistance (15), it is also possible that the office blood pressure measurements used in most studies are not sensitive enough to detect mild derangements in blood pressure regulation and that factors such as obesity may act as confounders obscuring the presence of actual abnormalities in the regulation of blood pressure in PCOS.
The association of obesity with hypertension is well known (16) and is explained by several etiopathogenic mechanisms including induction of insulin resistance, chronic inflammation, adrenergic hyperactivity, and secretion of several adipokines (17, 18).
In the present study, we have evaluated the impact of obesity on the 24-h blood pressure profiles of PCOS patients while considering also the influence of hyperandrogenism and insulin resistance on the abnormalities found.
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Patients and Methods |
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Thirty-six consecutive PCOS patients [age, 24.2 ± 6.2 yr (range, 14–42 yr); body mass index (BMI), 29.3 ± 6.2 (range, 18.8–47.5 kg/m2)] were recruited. The diagnosis of PCOS was based on the presence of clinical and/or biochemical hyperandrogenism, oligoovulation, and exclusion of secondary etiologies (19). Hirsutism was defined by a modified Ferriman-Gallwey score above 7, and oligomenorrhea (more than six cycles longer than 36 d in the previous year), amenorrhea (absence of menstruation for 3 consecutive months), and luteal phase progesterone measurements less than 4 ng/ml (12.7 nmol/liter) in women with regular menstrual cycles were considered indicative of oligoovulation. We also excluded hyperprolactinemia (serum prolactin levels < 24 ng/ml), thyroid dysfunction (serum TSH levels within the normal range), congenital adrenal hyperplasia (1–24 ACTH-stimulated serum 17-hydroxyprogesterone levels < 10 ng/ml), and virilizing tumors in all the patients (19).
The control group included eight healthy female volunteers and 12 consecutive patients who did not have any known metabolic comorbidity, reporting to the clinical practice of the authors solely for treatment of obesity [age, 26.7 ± 6.8 yr (range, 13–38 yr); BMI, 28.2 ± 6.9 kg/m2 (range, 19.8–40.4 kg/m2)] and selected to be similar in terms of age and BMI to the patients. None of the controls had signs or symptoms of hyperandrogenism, menstrual dysfunction, or history of infertility.
None of the patients and controls had either a personal history of hypertension, disorders of glucose tolerance, cardiovascular events, or sleep apnea or had received treatment with oral contraceptives, antiandrogens, insulin sensitizers, or drugs that might interfere with blood pressure regulation for the previous 6 months. Written informed consent was obtained from all the participants, and the study was approved by the local ethics committee.
Anthropometrics and analytical parameters
Clinical and anthropometrical variables, including a modified hirsutism score, BMI, and waist-to-hip ratio were determined by a single investigator in all the subjects. The waist-to-hip ratio was calculated by dividing the minimal waist circumference by the hip circumference at the level of greater trochanters, using a nonstretchable measuring tape. The percentage of body fat with respect to total body weight was estimated using a validated (20) hand-to-hand body fat monitor (Omron BF 300; Omron Corp., Kyoto, Japan).
Serum and plasma samples were obtained between d 5 and 10 of the menstrual cycle or during amenorrhea after excluding pregnancy. After a 3-d 300-g carbohydrate diet and 12-h overnight fasting, samples were obtained for the measurement of total testosterone, SHBG, 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone-sulfate, prolactin, and TSH. A complete serum biochemistry and lipid profiles were also obtained. Then, a 75-g oral glucose tolerance test was performed, and samples were obtained for measurement of serum insulin and plasma glucose at 0, 30, 60, 90, and 120 min. Samples were immediately centrifuged, and serum was separated and frozen at –20 C until assayed.
The technical characteristics of the assays employed for plasma glucose, lipid profile, and serum hormone measurements have been described elsewhere (21). The free testosterone concentration was calculated from total testosterone and SHBG concentrations as described by Vermeulen et al. (22). The composite insulin sensitivity index was calculated from the circulating glucose and insulin concentrations during the oral glucose tolerance test according to Matsuda and DeFronzo (23).
Blood pressure measurements
Office blood pressure was determined as the mean of two manual sphygmomanometer readings in the sitting position. Mean arterial blood pressure was calculated as [systolic + (2 x diastolic)]/3.
Twenty-four-hour ambulatory blood pressure monitoring was performed using an A&D TM2430EX oscillometric device (A&D Co., Ltd., Tokyo, Japan). The cuff (12 x 22 cm for lean patients, 14 x 30 cm for overweight or obese subjects) was placed on the nondominant arm in every woman. The period from 0700 to 2300 h was considered daytime, and from 2300 until 0700 h the next day was considered nighttime, reflecting the usual sleeping habits of Spaniards. Systolic, diastolic, and mean blood pressure as well as heart rate were measured every 20 min during daytime and every 30 min during nighttime.
The nocturnal decreases in systolic and diastolic blood pressure were calculated using the equation [(mean of diurnal blood pressure – mean of nocturnal blood pressure)/mean of diurnal blood pressure] x 100. Nondippers were defined as those subjects who did not show a reduction in mean systolic and diastolic blood pressures by at least 10% from day to night, and the remaining subjects were considered as dippers.
Office hypertension was defined by an office blood pressure of at least 140/90 mm Hg according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (24). For ambulatory blood pressure monitoring, we used the normative data for women in the 25- to 44-yr-old age range derived from the PAMELA study (25), which was conducted in a large sample of the general population of the city of Monza, Italy, that is similar to the population of Madrid, both cities being in the Mediterranean area. Women presenting with increased mean daytime, nighttime, or 24-h blood pressure values at or above the 95th percentile of the reference population were considered hypertensive.
Statistical analysis
Data are shown as means ± SD or as raw numbers and percentages, as appropriate. For continuous variables, normality was assessed using the Kolmogorov-Smirnov test, and logarithmic transformation was applied as needed to ensure a normal distribution.
Patients and controls were classified into nonobese (BMI < 30.0 kg/m2) or obese (BMI 
30.0 kg/m2) groups according to their BMI, because only a BMI of at least 30.0 kg/m2 is clearly associated with excess mortality (26). The differences in continuous variables depending on the grade of obesity and on having PCOS or being a control were evaluated by two-way ANOVA, and the interaction between obesity and PCOS was also analyzed.
For discontinuous variables, the Pearson’s 
2 test or the Fisher’s test was applied as appropriate. Binary logistic regression using a backward stepwise (probability for entry 
0.05, probability for removal 0.10) likelihood ratio method for introduction of independent variables was used to evaluate the main determinants of having hypertension and of having a nondipper pattern in the nocturnal change of blood pressure among age, BMI, heart rate, serum androgen concentrations, and insulin sensitivity. P < 0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Patients presenting with PCOS had increased hirsutism scores and serum total and free testosterone, androstenedione, and dehydroepiandrosterone-sulfate concentrations and reduced insulin sensitivity index, compared with nonhyperandrogenic controls (Table 1
). There was also a near-significant tendency toward reduced SHBG concentrations in PCOS patients compared with controls (Table 1). No statistically significant differences among PCOS patients and controls were observed in the prevalence of family history of hypertension (72 and 55%, 2 = 1.701; P = 0.192), in the frequency of smokers (47 and 45%, 2 = 0.026; P = 0.871), or in the frequency of impaired glucose tolerance (11 and 10%, 2 = 0.017; P = 0.999) or type 2 diabetes (2.8 and 0%, 2 = 0.556; P = 0.999) unmasked by the oral glucose tolerance test.
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). However, the nocturnal decrease in systolic, diastolic, and mean blood pressure tended to be less pronounced in PCOS patients compared with controls, and this tendency reached statistical significance for the decrease in mean blood pressure (Table 1).
According to office blood pressure measurements, four of the 36 PCOS patients and three of the 20 control women had grade 1 hypertension (11 and 15%, respectively, 2 = 0.178; P = 0.691). Ambulatory blood pressure monitoring was used to explore further the presence of abnormalities in blood pressure in patients and controls. Two of the four PCOS patients presenting with office hypertension actually had normal ambulatory blood pressure monitoring recordings, strongly suggesting the presence of white-coat hypertension in them. Yet ambulatory blood pressure monitoring confirmed hypertension in the other two patients presenting with office hypertension and revealed masked hypertension in another 10, raising the overall frequency of hypertension to 12 of 36 (33%) PCOS patients.
In controls, ambulatory blood pressure monitoring confirmed hypertension in the three women presenting with office hypertension and revealed masked hypertension in another five women, to give an overall frequency of hypertension in eight of 20 (40%) in the controls (2 = 0.249; P = 0.618 for the comparison with PCOS patients). Of note, an increase in blood pressure only during nighttime was responsible for masked hypertension in nine of the 10 PCOS patients and in three of the five controls presenting with this disorder.
Finally, 14 PCOS patients and five controls presented with a nondipper pattern in the nocturnal decrease of blood pressure (39 and 25%, respectively, 2 = 1.106; P = 0.293).
Influence of obesity on blood pressure abnormalities
Obesity, defined by a BMI at or above 30 kg/m2, was present in 13 PCOS patients and eight nonhyperandrogenic controls (36 and 40%, respectively, 2 = 0.083; P = 0.773). Considering this relatively large prevalence of obesity in our series, we aimed to study whether the abnormalities in the regulation of blood pressure observed in our young patients and controls actually depended on obesity.
There was no interaction between obesity and PCOS or control status on any of the dependent variables studied here, meaning that any observed effect of obesity was the same in PCOS patients and in nonhyperandrogenic controls.
In addition to the differences between PCOS patients and controls described earlier, obesity independently increased waist circumference, waist-to-hip ratio, fat mass expressed as percentage of body weight, and serum free testosterone and triglyceride levels and decreased serum SHBG and high-density lipoprotein cholesterol concentrations and the insulin sensitivity index (Table 2).
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and 2. Obesity significantly increased diastolic and mean office blood pressure values in both patients and controls (Fig. 1). In conceptual agreement, the frequency of office hypertension was 29% in obese women compared with only 3% in nonobese women (Table 3).
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), and there were no statistically significant differences among them in the frequencies of hypertension according to ambulatory blood pressure monitoring during the daytime, nighttime, and 24-h periods (Table 3). However, the average of the heart rate estimations obtained by ambulatory blood pressure monitoring was consistently increased in obese women compared with their nonobese counterparts during the daytime, nighttime, and 24-h periods (Fig. 1).
The frequency of abnormalities in blood pressure was not statistically different in PCOS patients and nonhyperandrogenic controls both in the nonobese and obese subgroups of women (Table 3). Finally, and although obesity did not influence the differences in the nocturnal decrease in blood pressure between PCOS patients and controls described above (Fig. 2), it has to be highlighted that the frequency of nondippers was especially high in obese PCOS patients, because this pattern was present in more than half of them (Fig. 2).
Determinants of blood pressure abnormalities
Considering that obesity in PCOS patients and controls not only was associated with blood pressure abnormalities but was also characterized by increasing heart rates and a more hyperandrogenic and insulin-resistant situation, we investigated, using two binary logistic regression models, which of these variables contributed with more intensity to the abnormalities in blood pressure. We did not include having or not PCOS as an independent variable in these models because the analyses described above did not indicate that PCOS was actually associated with most of the abnormalities in blood pressure regulation found in these women.
Including having or not hypertension (defined as office hypertension confirmed by ambulatory blood pressure monitoring or as masked hypertension) as the dependent variable and age, BMI, mean 24-h heart rate, free testosterone, and insulin sensitivity index as independent variables, the first model retained only the mean 24-h heart rate as a significant predictor of having hypertension (Nagelkerke’s R2 = 0.298; P = 0.002). Similarly, when the dipper or nondipper pattern of nocturnal decrease in blood pressure was introduced as the dependent variable and mean nighttime heart rate, age, BMI, free testosterone, and insulin sensitivity index were introduced as independent variables, the second model retained only the mean nighttime heart rate as a significant predictor of being nondipper (Nagelkerke’s R2 = 0.163; P = 0.015). Therefore, increased heart rate appeared to play a particularly important role in the blood pressure abnormalities observed in obese and PCOS women.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Office hypertension was present in two or four obese PCOS patients (depending on whether or not the two patients with white-coat hypertension are considered), a 5.6 or 11.1% frequency that is nevertheless considerably higher than the 1% prevalence found in the National Health and Nutrition Examination Survey III study for white women in the same age range (27).
But even more impressive is the finding of hypertension according to ambulatory blood pressure monitoring in 12 (33%) of the PCOS patients in our series, compared with less than 5% in the female European population of the same age range (28). Accordingly, ambulatory blood pressure monitoring was able to discover masked hypertension in 10 of the 36 PCOS patients. Of note, masked hypertension predicted cardiovascular morbidity and mortality in longitudinal studies (29), highlighting the importance of diagnosing hypertension in these patients.
However, it must be highlighted that the high frequency of hypertension in our series of young PCOS patients resulted very probably from the association of PCOS with obesity. On the one hand, hypertension presented with a similar frequency in the PCOS patients and in the nonhyperandrogenic controls (both groups having similar mean BMI and frequency of obesity), and no statistically significant differences were observed between the groups of PCOS patients and controls in the average values of systolic, diastolic, or mean blood pressure, either measured at the office or by ambulatory blood pressure monitoring during daytime, nighttime, or the 24-h period. On the other hand, obesity was associated with an increased frequency of office hypertension when considering PCOS patients and controls as a whole and resulted in increased average office diastolic and mean blood pressure values independently from the PCOS or control status. Obesity is a well-known risk factor for hypertension, obese subjects presenting with a 2-fold increase compared with lean individuals in the prevalence of office and ambulatory blood pressure monitoring hypertension in population-based studies (16).
Interestingly, ambulatory blood pressure monitoring revealed that obese women presented with increased heart rate during the daytime, nighttime, and 24-h period when compared with their nonobese counterparts, and the stepwise logistic regression model disclosed that heart rate was the major determinant of the presence or absence of hypertension in our series of young women.
Sympathetic activation plays a central role among the mechanisms proposed to mediate the facilitation of hypertension in obese subjects (30), in conceptual agreement with the presence of increased heart rate in our obese women. The excess in fat mass leads to insulin resistance, increased free fatty acids levels, obstructive sleep apnea, and increased secretion of inflammatory cytokines and leptin, factors that may induce sympathetic activation (30). The latter, aside from aggravating insulin resistance, induces vasoconstriction and sodium retention (by activating the renin angiotensin system) leading finally to hypertension (30).
The only abnormality that appears to be influenced by PCOS in addition to obesity was the nocturnal decrease of blood pressure. A nondipper pattern was observed in as many as 62% of obese PCOS patients, as compared with 25% of nonobese and obese controls and 26% of nonobese PCOS patients, confirming previous reports of the presence of a nondipper pattern in nocturnal blood pressure in most adolescent obese girls with PCOS (31). Once again, the major determinant of the presence or absence of such a pattern was the nocturnal heart rate in the stepwise logistic regression model. Accordingly, the average nocturnal decrease in systolic, diastolic, and mean blood pressure tended to be the smaller in obese PCOS patients compared with the other groups of women, but these differences did not reach statistical significance except for the nocturnal decrease in mean blood pressure. Because the nondipper pattern in nocturnal blood pressure is associated with organ damage progression and increased incidence of cardiovascular disease (32), even in normotensive subjects (33), our present results suggest that the subgroup of obese women suffering PCOS might be especially at risk for adverse cardiovascular events from early ages.
The fact that the detection of the abnormalities in blood pressure described above required 24-h blood pressure monitoring in most of the women studied here may contribute to explain the controversial issue of hypertension in PCOS (34). Of note, the use of ambulatory blood pressure monitoring in PCOS patients has been restricted to studies that used different criteria to define PCOS and were either small (12, 13, 14) or did not consider specifically the role of obesity on the possible blood pressure abnormalities of these patients (12, 13, 35, 36). In agreement with our present results, most of these studies (12, 13, 14, 36) compared the 24-h blood pressure profiles of PCOS patients with those of selected controls finding no differences but did not address whether hypertension, either masked or clinically apparent, was frequent in these women. Only an article by Orbetzova et al. (35) of Bulgaria describes, in its English abstract, the presence of hypertension according to ambulatory blood pressure monitoring and a nondipper pattern in the nocturnal decrease in blood pressure in 26 and 51% of a series of 35 moderately obese young PCOS patients, in noticeable agreement with our present findings. Unfortunately, this abstract (35) does not mention the use of a control group of nonhyperandrogenic women, precluding a direct comparison with our study.
However, our present study is not free of limitations, including the relatively small number of patients and controls analyzed and the fact that obesity was very frequent in our series, making difficult the extrapolation of our present results to populations in which the prevalence of obesity is different. Therefore, larger population-based studies are needed before making clinically relevant recommendations derived from these data, especially when considering that the long-term consequences of the abnormalities of blood pressure regulation described here may be quite distinct from those of traditional office-based hypertension diagnosis.
In conclusion, abnormalities in the regulation of blood pressure, including clinical and masked hypertension and a nondipper pattern in the nocturnal decrease in blood pressure, are common in young women with PCOS. Obesity, possibly through sympathetic activation, plays a major role in the development of these abnormalities, further highlighting the impact of weight excess on the clinical manifestations and on the cardiovascular risk profile of PCOS. However, with the exception of the nondipper pattern in the nocturnal decrease in blood pressure, the abnormalities in the regulation of blood pressure reported here are not specific to PCOS (given their presence in similar frequencies in nonhyperandrogenic women) and result from the frequent association of this syndrome with obesity.
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Acknowledgments |
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Footnotes |
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Present address for M.L.-R.: Department of Endocrinology, Hospital Universitario de La Princesa, Madrid, Spain.
Disclosure Statement: The authors have nothing to declare.
First Published Online March 27, 2007
Abbreviations: BMI, Body mass index; PCOS, polycystic ovary syndrome.
Received January 25, 2007.
Accepted March 16, 2007.
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, P < 0.05 when comparing PCOS patients with controls, irrespective of obesity.