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AHA 2017 definition of high blood pressure: implications for women with polycystic ovary syndrome
ACC/AHA 2017 definition of high blood pressure: implications for women with polycystic ovary syndrome Lucas Bandeira Marchesan, B.Sc.a and Poli Mara Spritzer, M.D., Ph.D.a,b a Gynecologic Endocrinology Unit, Division of Endocrinology, Hospital de Clínicas de Porto Alegre (HCPA) and b Laboratory of Molecular Endocrinology, Department of Physiology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
Objective: To assess the association of insulin resistance markers, body mass index (BMI), age, and androgen levels with systemic arterial hypertension (SAH) defined according to 2017 American College of Cardiology/American Heart Association (ACC/AHA) criteria in polycystic ovary syndrome (PCOS); and to determine the risk of metabolic abnormalities in the presence of SAH defined by both the 2017 ACC/AHA and Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) criteria in women with PCOS. Design: Cross-sectional study. Setting: Research center. Patient(s): Biobanked samples obtained from 233 women with PCOS and 70 controls without hirsute, ovulatory dysfunction. Intervention(s): Metabolic, hormonal, and biochemical assessment. Main Outcome Measure(s): Blood pressure status according to 2017 ACC/AHA and JNC7 criteria and prevalence of metabolic abnormalities. Result(s): The prevalence of SAH among women with PCOS was 65% (n ¼ 152) using 2017 ACC/AHA criteria and 26.6% (n ¼ 62) considering JNC7 criteria. The 90 women whose SAH status was changed by 2017 ACC/AHA criteria were categorized as stage 1 SAH (systolic blood pressure 130–139 mmHg and/or diastolic blood pressure 80–89 mmHg), requiring nonpharmacologic therapy only (lifestyle changes). The prevalence of SAH in the control group was 41.4% (n ¼ 29) according to 2017 ACC/AHA criteria and 12.8% (n ¼ 9) according to JNC7 criteria. In all groups, SAH was associated with higher homeostasis model assessment and insulin levels compared with normal blood pressure (P< .01). In women with PCOS, the risk ratio for glucose R100 mg/dL (prevalence ratio 3.88, 95% confidence interval [CI] 1.30–11.55), high-density lipoprotein (HDL) <50 mg/dL (prevalence ratio 2.13, 95% CI 1.45– 3.12), and triglycerides R150 mg/dL (prevalence ratio 3.39, 95% CI 1.56–7.35) was higher with SAH versus normal blood pressure when 2017 ACC/AHA criteria were applied, and did not increase or increased slightly when JNC7 criteria were applied (glucose R100 mg/dL, prevalence ratio 1.38, 95% CI 0.99–1.91), HDL <50 mg/dL (prevalence ratio 1.1, 95% CI 0.99–1.37), and triglycerides R150 mg/dL (prevalence ratio 1.48, 95% CI 1.13–1.94). Conclusion(s): The risk of cardiometabolic co-morbidities was increased in women with SAH defined by 2017 ACC/AHA criteria. Lower cutoffs for abnormal blood pressure seem appropriate for women with PCOS, providing a simple screening tool for cardiometabolic co-morbidities and an opportunity for early primary prevention. (Fertil SterilÒ 2019;111:579–87. Ó2018 by American Society for Reproductive Medicine.) El resumen está disponible en Español al final del artículo. Key Words: Hypertension, polycystic ovary syndrome, androgen, insulin resistance, cardiovascular diseases Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertilityand-sterility/posts/40659-26689
Received July 20, 2018; revised and accepted November 21, 2018. L.B.M. has nothing to disclose. P.M.S. has nothing to disclose. gico (grant INCT/CNPq/FAPERGS: 465482/2014-7). Supported by the Conselho Nacional de Desenvolvimento Científico e Tecnolo Reprint requests: Poli Mara Spritzer, M.D., Ph.D., Division of Endocrinology, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350 Porto Alegre, RS, Brazil (E-mail: [email protected]). Fertility and Sterility® Vol. 111, No. 3, March 2019 0015-0282/$36.00 Copyright ©2018 American Society for Reproductive Medicine, Published by Elsevier Inc. https://doi.org/10.1016/j.fertnstert.2018.11.034 VOL. 111 NO. 3 / MARCH 2019
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W
omen with polycystic ovary syndrome (PCOS) face increased cardiovascular risk when compared with healthy women of the same age. Polycystic ovary syndrome, otherwise characterized by an association between hyperandrogenism and ovulatory dysfunction, is also often associated with obesity (1, 2), lipid abnormalities (3, 4), insulin resistance (IR) (5), and high blood pressure/systemic arterial hypertension (SAH) (6–8). The mechanism underlying the increased prevalence of SAH in PCOS has been linked to a series of factors such as obesity in and of itself (9), heart autonomic dysfunction (10–12), hyperandrogenism (13, 14), and IR (15). The American College of Cardiology/American Heart Association (ACC/AHA) has recently issued a new guideline for the diagnosis and management of high blood pressure/ SAH (16), proposing more stringent cutoffs for high blood pressure compared with the previous cutoffs recommended by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC7 report (17). The 2017 ACC/AHA guideline, which was mainly based on observational data and was influenced, at least in part, by the Randomized Trial of Intensive versus Standard Blood-Pressure Control (SPRINT) trial (18), led to a substantial increase in the prevalence of SAH in the American general population (19). The SPRINT trial (18) compared intensive versus standard blood pressure control in patients aged 50 years or older with increased blood pressure and at least one additional cardiovascular risk factor. The study's intensive control arm targeted a systolic blood pressure (SBP) of <120 mmHg, whereas the standard control arm targeted a SBP of <140 mm Hg. The intervention was interrupted early after a median follow-up of 3.26 years owing to a significantly lower rate of the primary composite outcome (myocardial infarction, acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes) in the intensive control group compared with the standard control group. The impact of the 2017 ACC/AHA cutoffs for young adult populations at higher cardiovascular risk has not yet been established. Therefore, the aims of the present study were [1] to assess the association of IR markers, body mass index (BMI), age, and androgen levels with blood pressure levels and SAH status according to 2017 ACC/AHA criteria in PCOS; and [2] to determine the prevalence of metabolic abnormalities, such as dysglycemia, dyslipidemia, obesity, and central adiposity, in the presence of SAH as defined by both 2017 ACC/AHA and JNC7 criteria in women with PCOS.
None of the PCOS or control women had received any drugs known to interfere with hormone and metabolic variables (i.e., oral contraceptive [OC] pills, antiandrogens, metformin, fibrates, statins) for at least 3 months before the samples were collected. Diabetic and pregnant women, as well as those presenting other causes of hyperandrogenism were excluded. In accordance with the Rotterdam criteria, 180 women were classified as having classic PCOS (c-PCOS [A þ B phenotypes]), defined by biochemical and/or clinical hyperandrogenism and oligomenorrhetc and amenorrheic cycles, <9 cycles/year, with or without polycystic ovary (PCO) appearance at ultrasound. The other 53 women were classified as having ovulatory PCOS (ov-PCOS [C phenotype]), characterized by hyperandrogenism, with or without PCO appearance at ultrasound, and regular ovulatory menstrual cycles confirmed by luteal phase P>3.8 ng/mL (22).
Measurements In addition to the samples for biochemical tests, information was available on weight, height, waist circumference (waist measured at the midpoint between the lower rib margin and the iliac crest) (23), and blood pressure (measured after a 10-minute rest, in the sitting position, with feet on the floor and the arm supported at heart level). Body mass index was calculated as weight in kilograms divided by squared height in meters.
Hormonal and Metabolic Assessment Samples were obtained between days 2 and 10 of the menstrual cycle, or on any day if the patient was amenorrheic. All samples were obtained between 8 and 10 AM. Blood samples were drawn after an overnight 12-hour fast for determination of plasma cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. Low-density lipoprotein (LDL) cholesterol was estimated indirectly with the formula LDL ¼ total cholesterol - HDL - triglycerides/5 (24). Glucose and insulin were measured before and 2 hours after the ingestion of a 75-g oral glucose load. Blood samples were also drawn for measurement of sex hormone-binding globulin (SHBG) and total T. Free androgen index was estimated by dividing total T (nmol/L) by SHBG (nmol/L) 100 (25). Homeostasis model assessment index of IR (HOMA-IR index) was calculated by multiplying insulin (mIU/mL) by glucose (mmol/L) and dividing this product by 22.5 (26). The cutoff point to define IR was arbitrarily defined as a HOMA-IR index R2.5 (27).
MATERIALS AND METHODS Study Design and Participants
Assays
This is a cross-sectional study of biobanked samples (stored in aliquots at -80 C) obtained from 233 women with PCOS and 70 women without hirsute, ovulatory dysfunction (regular cycles and luteal phase P>3.8 ng/mL), who were prospectively recruited and participated in studies conducted at our research center from 2008 to 2012 (10, 20, 21). The study protocol was approved by the local Research Ethics Committee, and written informed consent was obtained from all subjects at the time of recruitment.
Total cholesterol, HDL cholesterol, triglycerides, and glucose were determined using a colorimetric-enzymatic method (Siemens Advia System). Insulin, LH, SHBG, and DHEAS serum concentrations were measured with electrochemiluminescent immunoassays (Roche diagnostic) with sensitivity of 0.20 mIU/mL, 0.10 mIU/mL, 0.35 nmol/L, and 0.10 mg/dL, respectively, intra-assay coefficient of variation (CV) of <3% and interassay CV of <5%. Serum total T (sensitivity <0.10 ng/mL) levels were measured in a subgroup of patients
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Statistics for Windows, version 20 (IBM Corp.). Data were considered to be significant at P< .05.
Definitions of SAH
RESULTS
The SAH was defined as SBP R130 mmHg or diastolic blood pressure (DBP) R80 mmHg (16). In addition, for comparative analyses, the previous JNC7 criteria (17) for SAH were also considered (SBP R140 mmHg or DBP R90 mmHg).
Statistical Analysis The Shapiro-Wilk normality test and descriptive statistics were used to evaluate the distribution of data. Results are presented as means SD, or median and interquartile range. Correlations between variables were performed by twotailed Spearman rank correlation test considering the nonGaussian distribution of variables. For the other analyses, non-Gaussian variables were log-transformed for statistical analysis and reported after being back-transformed into their original units of measure. Metabolic variables were adjusted for BMI and age by analysis of covariance (ANCOVA) and Bonferroni test. For comparisons between categorical variables c2 tests were used. Two-way ANCOVA, with age and BMI as covariates, was used for testing the interaction between SAH and PCOS phenotypes with IR and T. Prevalence ratios were determined for metabolic disturbances in hypertensive and normotensive women with PCOS, according to 2017 ACC/AHA or JNC7 blood pressure cutoffs. All analyses were performed using the IBM SPSS
Clinical, hormonal, and metabolic characteristics of women with c-PCOS, ov-PCOS, and controls are summarized in Table 1. Women with the c-PCOS phenotype were younger than controls (P< .01). The BMI, SBP, and DBP levels were higher in women with c-PCOS (P< .01) and T levels differed significantly among the three groups (P< .01). Metabolic variables were higher in women with c-PCOS, even after adjustment for age and BMI, except for fasting glucose and HDL, which were similar in all groups. The prevalence of obesity, defined as BMI R30 kg/m2, was similar in the control (43.9%) and PCOS (52.8%) groups, with no statistical difference. The prevalence of SAH among women with PCOS was 65% (n ¼ 152) and 26.6% (n ¼ 62), considering 2017 ACC/ AHA and JNC7 criteria. The group of 90 women with PCOS whose SAH status changed with application of the 2017 ACC/AHA criteria were categorized as stage 1 SAH (SBP 130–139 mmHg and/or DBP 80–89 mmHg), requiring only nonpharmacologic therapy (lifestyle changes). Also, when applying 2017 ACC/AHA criteria, the frequency of SAH in women with c-PCOS was significantly higher than those with ov-PCOS and in the control group (Table 1). Overall age- and sex-adjusted SAH prevalence in women has been previously estimated as 43% with 2017 ACC/AHA criteria (16).
TABLE 1 Clinical, hormonal, and metabolic profile of patients with classic polycystic ovary syndrome, ovulatory polycystic ovary syndrome, and controls at the time of sample collection. Clinical, hormonal, and metabolic profile Age (y) BMI (kg/m2) FGS SBP (mmHg) DBP (mmHg) DHEAS (mg/dL) T (ng/mL)d SHBG (nmol/L) FAId Glucose (mg/dL) Glucose 120 (mg/dL) Insulin (mU/L) HOMA-IR index Total cholesterol (mg/dL) HDL (mg/dL) LDL (mg/dL) Triglycerides (mg/dL) SAH 2017 ACC/AHA % (n) SAH JNC7 % (n)
Classic PCOS (n [ 180) a
25 (21–29) 32.52 7.41a 11 (8–16)a 120 (115–130)a 80 (75–90)a 198.4 (130.8–281.1)a 1.0 (0.69–1.23)a 24.35 (17.36–36.3)a 14.8 (8.34–22.55)a 90 (83–96) 110.5 (96–133.25)a 19.57 (11.9–33.6)a 4.28 (2.52–7.63)a 190.26 43.2a 45 (40–55) 117.4 37.5a 109 (70–157)a 70 (126)a 29.4 (53)a
Ovulatory PCOS (n [ 53) a,b
26.5 (21–31) 25.69 6.14b 13 (10–17.75)a 115 (110–130)b 78 (68.5–80)b 246 (132.9–366.2)a 0.48 (0.4–0.73)b 36.5 (23.35–48.85)b 4.67 (3.53–8.32)b 85 (79.5–91) 97 (82–116.5)b 11.95 (6.6–17.5)b 2.5 (1.45–3.92)b 170.3 29b 53 (46–59) 99.75 26b 74 (55–109)b 49.1 (26)b 17 (9)a
Controls (n [ 70) b
29 (26–34) 28.71 5.71b 3 (0–5)b 110 (108–120)b 72.5 (69.5–80)b 154.2 (100.15–204)b 0.26 (0.19–0.39)c 39.1 (29.93–58.15)b 2.15 (1.27–3.77)c 88 (83.25–93.75) 93.5 (85.25–107.7)b 9.05 (6.07–12.61)b 2.01 (1.34–2.79)b 169 30.8b 50 (45–57) 100.4 26.7b 66.5 (50–100.5)b 41.4 (29)b 12.8 (9)b
P value < .01 < .01 < .01 < .01 < .01 < .01 < .01 < .01 < .01 .07e < .01e < .01e < .01e < .01e .08e < .001e < .001e < .001 .01
Note: Values are expressed as mean SD, median (25–75 interquartile range), or % and number. a,b,c Statistical difference by analysis of variance (ANOVA) and Bonferroni tests (continuous variables) and c2 test (categorical variables). dT and FAI were reanalyzed in a subgroup of samples (125 classic PCOS, 31 ovulatory PCOS, and 33 controls) in which T was measured by radioimmunoassay. eP value adjusted for age and BMI. ACC/AHA ¼ American College of Cardiology/American Heart Association; BMI ¼ body mass index; DBP ¼ diastolic blood pressure; FAI ¼ free androgen index; FGS ¼ Ferriman Gallwey score; Glucose 120 ¼ plasma glucose value 120 minutes after a standard dose of 75 g of oral glucose; HDL ¼ high-density lipoprotein cholesterol; JNC7 ¼ Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; LDL ¼ low-density lipoprotein cholesterol; PCOS ¼ polycystic ovary syndrome; SAH ¼ systemic arterial hypertension; SBP ¼ systolic blood pressure; SHBG ¼ sex hormone binding globulin. Marchesan. High blood pressure criteria and PCOS. Fertil Steril 2018.
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ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY Figure 1 shows the association of HOMA-IR, insulin, and T levels with 2017 ACC/AHA blood pressure status (normal blood pressure or SAH) in the three groups (c-PCOS, ovPCOS, and controls), using age and BMI as covariates. The HOMA-IR, insulin, and T levels were more elevated in patients with c-PCOS and patients with ov-PCOS presented intermediate values between those found for c-PCOS and controls. In all groups, SAH was associated with higher HOMA-IR and insulin levels compared with normal blood pressure, with no interaction between blood pressure status and groups (P< .01). The T levels did not differ between normal blood pressure and SAH groups, and there was no interaction with groups (P¼ .18). The HOMA-IR, T, and free androgen index correlation with SBP and DBP levels in all groups combined (Fig. 2). The HOMA-IR was positively correlated with SBP and DBP levels. Androgen levels presented a weak correlation with SBP and a moderate one with DBP. Figure 3A presents the frequency of waist circumference >88 cm, dysglycemia, BMI R25 and R30 kg/m2, and lipid abnormalities in women with PCOS and with SAH or normal blood pressure according to 2017 ACC/AHA and JNC7 criteria. The prevalence of metabolic abnormalities was high in women with PCOS and with SAH regardless of the defining criteria. However, these metabolic disturbances were more frequent in participants with normal blood pressure defined by JNC7 criteria than in those with normal blood pressure according to the 2017 ACC/AHA guidelines. Also, the risk ratio for these abnormalities in the presence of SAH versus normal blood pressure ranged from around 2 for BMI R25 kg/m2 to 3.8 times for glucose R100 mmol/L when 2017 ACC/AHA criteria were applied (Fig. 3B), and around 1.4 times when JNC7 criteria were applied. No significant increase in risk was detected for glucose R100 mmol/L and
HDL<50 mmHg (Fig. 3B) in a patient with normal blood pressure by the JNC7 criteria. The absolute number of control women with SAH was low according to both criteria, as well as the frequency of metabolic abnormalities (Supplemental Fig. 1 and Supplemental Table 1, available online). Except for BMI R25 kg/m2 (prevalance ratio 1.64, 95% confidence interval 1.12–2.4) in women with SAH defined according to the 2017 ACC/AHA criteria, no other clinically relevant risk factors were found for SAH in the control group, regardless of blood pressure criteria (Supplemental Table 1).
DISCUSSION In the present study, we found that the risk of cardiometabolic co-morbidities was higher in women with SAH as defined by the 2017 ACC/AHA criteria. In this group, the prevalence of dysglycemia and hypertriglyceridemia was more than three times higher than in the PCOS group with normal blood pressure. In contrast, when using the JCN7 cutoffs for SAH, the risk for metabolic abnormalities became less important in this population. This is possibly explained by the classification of a part of the group at risk for metabolic co-morbidities into the normal blood pressure category by the JCN7 cutoffs. The status of these women was changed to SAH when the 2017 ACC/AHA cutoffs were applied. These data suggest that lower cutoffs for abnormal blood pressure, as recently proposed by the ACC/ AHA, could be especially relevant and appropriate for women with PCOS, a subgroup of patients with a higher number of cardiovascular risk factors compared with the general population (1, 4–8, 28, 29), and provide a simple screening tool for cardiometabolic co-morbidities and the opportunity to introduce early primary prevention strategies. To our knowledge, this is the first study to assess the impact of the new SAH definition in a population with PCOS.
FIGURE 1
Association of homeostasis model assessment insulin resistance (HOMA-IR), insulin, and T levels with phenotypes and systemic arterial hypertension (SAH) according to 2017 American College of Cardiology/American Heart Association (ACC/AHA) criteria. *P<.01 for SAH versus normal blood pressure. Age and body mass index (BMI) were used as covariates in the model. The variables of interest are expressed as means in the y-axis. Two-way analysis of covariance (ANCOVA). DBP ¼ diastolic blood pressure; PCOS ¼ polycystic ovary syndrome; SBP ¼ systolic blood pressure. Marchesan. High blood pressure criteria and PCOS. Fertil Steril 2018.
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FIGURE 2
Correlations of homeostasis model assessment insulin resistance (HOMA-IR), total T (TT), and free androgen index (FAI) with systolic and diastolic blood pressure in the overall group of participants. (A) Systolic blood pressure (SBP). r ¼ 0.36; P<.01 (left panel), r ¼ 0.16; P¼.01 (middle panel), r ¼ 0.16; P<.01 (right panel); (B) Diastolic blood pressure (DBP). r ¼ 0.36; P<.01 (left panel), r ¼ 0.22; P<.01 (middle panel), r ¼ 0.33; P<.01 (right panel) Spearman rank correlation test. Marchesan. High blood pressure criteria and PCOS. Fertil Steril 2018.
We also observed that IR markers were more pronounced in SAH than in normal blood pressure in all groups, that is, women with c-PCOS, ov-PCOS, and controls. Indeed, IR-related compensatory hyperinsulinemia may influence blood pressure through an autonomic nervous system imbalance (30, 31), increased renal sodium reabsorption, and decreased nitric oxide production (32– 34) in distinct populations. Regarding PCOS phenotypes, we have previously shown that patients with c-PCOS present subclinical autonomic dysfunction in comparison with controls, and that women with ov-PCOS present intermediate heart rate variability indexes in relation to c-PCOS and control groups (10). In addition, a recent study (15) reported that, within a normotensive range, hyperinsulinemia could influence 24-hour ambulatory blood pressure levels in women with PCOS. Taken together, our data and previous results (17, 35–38) suggest a possible role for the more striking IR-related metabolic derangements found in the classic phenotype in cardiovascular imbalance. In the present study, a positive correlation was observed between T and free androgen index with both SBD and DBP. However, T levels did not vary in different PCOS phenoVOL. 111 NO. 3 / MARCH 2019
types or controls according to blood pressure status (SAH or normal blood pressure). In fact, hyperandrogenism has been implicated in blood pressure dysregulation in patients with PCOS (13, 14). However, recent evidence suggests that the higher risk for SAH in women with PCOS is linked to metabolic abnormalities, such as IR and adipose tissue dysfunction, rather than to hyperandrogenism per se (4, 6, 35–37). Patients with PCOS, especially with the classic phenotype, are exposed to cardiovascular risk factors for a long period of their lives. Investigators have demonstrated that longer exposure to the vascular effects of SAH entails a greater risk for cardiovascular outcomes. A recent study (38) analyzing data from the Framingham Original Cohort (including 790 women, or 63.1% of the cohort) found that individuals in the community generally maintained SBP <120– 125 mmHg. Above that level, a rapid SBP increase toward overt SAH was noted. Thus, a resting SBP that chronically exceeds the range of 120–125 mmHg may signal incipient SAH irrespective of age. Our patients with c-PCOS presented higher blood pressure levels than controls and had a higher prevalence of other metabolic derangements associated with 583
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FIGURE 3
(A) Frequency of overweight, obesity, and metabolic abnormalities in women with polycystic ovary syndrome (PCOS) and with systemic arterial hypertension (SAH) versus normal blood pressure (NBP) according to 2017 American College of Cardiology/American Heart Association (ACC/ AHA) and Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) criteria. BMI ¼ body mass index; HDL ¼ high-density lipoprotein; TG ¼ triglyceride. (B) Prevalence ratios (PR) and 95% confidence intervals (CI) for metabolic parameters in women with PCOS in the presence of SAH versus normal blood pressure according to 2017 ACC/AHA and JNC7 criteria. Marchesan. High blood pressure criteria and PCOS. Fertil Steril 2018.
cardiovascular risk. That indicates the need for earlier intervention, especially for the classic phenotype. Because most of our hypertensive patients with PCOS would be classified as stage I hypertension, the main intervention would be lifestyle modification, which could also help improve other obesity-related clinical manifestations of PCOS. One strength of the present study was testing. For the first time there was the usefulness of applying the new cutoffs for blood pressure levels to a subgroup of young women at higher cardiovascular risk. In this sense, another strength was the use of a sample stratified according to the main PCOS phenotypes, highlighting the link between higher blood pressure levels and more pronounced IR in women with c-PCOS. Conversely, a limitation was that euglycemic hyperinsulinemic clamping, the gold standard for assessment of IR, was not used. Never-
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theless, HOMA-IR is well correlated with the clamp (39), and has been shown to be significantly and independently associated with risk of cardiovascular disease. The fact that all our samples were from hyperandrogenic women, regardless of PCOS phenotype, is another limitation. This prevented us from analyzing the performance of the 2017 ACC/AHA criteria in women with the normoandrogenic PCOS phenotype (phenotype D). However, the prevalence of cardiovascular risk factors and metabolic co-morbidities in normoandrogenic women with PCOS has been reported to be lower than in the other phenotypes (40, 41). In conclusion, in the presence of SAH, more pronounced IR was observed in the c-PCOS phenotype compared with women with ov-PCOS and controls. In the three groups, women with SAH had higher IR than their normal blood
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Fertility and Sterility® pressure counterparts. The 2017 ACC/AHA criteria for SAH were useful to identify a subgroup of patients with PCOS and with a higher risk profile considering other cardiometabolic alterations. These findings should prompt an earlier intervention—initially a recommendation for lifestyle changes—in the group of PCOS with SBP R130 mmHg or DBP R 80 mmHg. Further longitudinal studies are needed to determine whether these interventions would contribute to blood pressure control in this group and to decrease cardiovascular morbidity and mortality in the long term. Acknowledgments: The authors thank Fernanda Missio Mario, Kristhiane Di Domenico, and Denusa Wiltgen for their support with data collection.
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Mioni R, Ca AD, Turra J, Azzolini S, Xamin N, Bleve L, et al. Hyperinsulinemia and obese phenotype differently influence blood pressure in young normotensive patients with polycystic ovary syndrome. Endocrine 2017;55:625–34. Whelton PK, Carey RM, Aronow WS, Casey DE, Collins KJ, Dennison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Hypertension 2018;71:e13–115. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560–72. SPRINT Research Group, Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373:2103–16. Muntner P, Carey RM, Gidding S, Jones DW, Taler SJ, Wright JT, et al. Potential U.S. population impact of the 2017 ACC/AHA high blood pressure guideline. J Am Coll Cardiol 2018;71:109–18. Toscani MK, Mario FM, Radavelli-Bagatini S, Wiltgen D, Matos MC, Spritzer PM. Effect of high-protein or normal-protein diet on weight loss, body composition, hormone, and metabolic profile in southern Brazilian women with polycystic ovary syndrome: a randomized study. Gynecol Endocrinol 2011;27:925–30. Wiltgen D, Benedetto IG, Mastella LS, Spritzer PM. Lipid accumulation product index: a reliable marker of cardiovascular risk in polycystic ovary syndrome. Hum Reprod 2009;24:1726–31. Group REA-SPCW. Revised 2003 consensus on diagnostic criteria and longterm health risks related to polycystic ovary syndrome. Fertil Steril 2004;81: 19–25. Toscani M, Migliavacca R, Sisson de Castro JA, Spritzer PM. Estimation of truncal adiposity using waist circumference or the sum of trunk skinfolds: a pilot study for insulin resistance screening in hirsute patients with or without polycystic ovary syndrome. Metabolism 2007;56:992–7. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499–502. Brum IS, Spritzer PM, Paris F, Maturana MA, Audran F, Sultan C. Association between androgen receptor gene CAG repeat polymorphism and plasma testosterone levels in postmenopausal women. J Soc Gynecol Investig 2005;12:135–41. Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care 2004;27:1487–95. Dickerson EH, Cho LW, Maguiness SD, Killick SL, Robinson J, Atkin SL. Insulin resistance and free androgen index correlate with the outcome of controlled ovarian hyperstimulation in non-PCOS women undergoing IVF. Hum Reprod 2010;25:504–9. Hirschberg AL. Polycystic ovary syndrome, obesity and reproductive implications. Womens Health (Lond) 2009;5:529–40 [quiz 41–2]. Bilal M, Haseeb A, Rehman A. Relationship of polycystic ovarian syndrome with cardiovascular risk factors. Diabetes Metab Syndr 2018;12:375–80. Pal GK, Adithan C, Ananthanarayanan PH, Pal P, Nanda N, Thiyagarajan D, et al. Association of sympathovagal imbalance with cardiovascular risks in young prehypertensives. Am J Cardiol 2013;112:1757–62. Emdin M, Gastaldelli A, Muscelli E, Macerata A, Natali A, Camastra S, et al. Hyperinsulinemia and autonomic nervous system dysfunction in obesity: effects of weight loss. Circulation 2001;103:513–9. Brands MW, Manhiani MM. Sodium-retaining effect of insulin in diabetes. Am J Physiol Regul Integr Comp Physiol 2012;303:R1101–9. Li L, Garikepati RM, Tsukerman S, Tiwari S, Ecelbarger CM. Salt sensitivity of nitric oxide generation and blood pressure in mice with targeted knockout of the insulin receptor from the renal tubule. Am J Physiol Regul Integr Comp Physiol 2012;303:R505–12. Nakamura M, Yamazaki O, Shirai A, Horita S, Satoh N, Suzuki M, et al. Preserved Na/HCO3 cotransporter sensitivity to insulin may promote hypertension in metabolic syndrome. Kidney Intern 2015;87:535–42.
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Wiltgen D, Spritzer PM. Variation in metabolic and cardiovascular risk in women with different polycystic ovary syndrome phenotypes. Fertil Steril 2010;94:2493–6. Jovanovic VP, Carmina E, Lobo RA. Not all women diagnosed with PCOS share the same cardiovascular risk profiles. Fertil Steril 2010;94:826–32. Spritzer PM, Lecke SB, Satler F, Morsch DM. Adipose tissue dysfunction, adipokines, and low-grade chronic inflammation in polycystic ovary syndrome. Reproduction 2015;149:R219–27. Niiranen TJ, Henglin M, Claggett B, Muggeo VMR, McCabe E, Jain M, et al. Trajectories of blood pressure elevation preceding hypertension onset: an analysis of the Framingham Heart Study Original Cohort. JAMA Cardiol 2018;3:427.
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Fertility and Sterility® Definicion de tension arterial elevada de la ACC/AHA de 2017: implicaciones en mujeres con síndrome de ovario poliquístico Objetivo: evaluar la asociaci on de marcadores de resistencia a la insulina, índice de masa corporal (IMC), edad y niveles de andr ogenos con hipertension arterial sistemica (HAS) definida de acuerdo con los criterios del Colegio Americano de Cardiología/Asociaci on Americana del Corazon (ACC/AHA) de 2017 en el síndrome de ovario poliquístico (SOP); y determinar el riesgo de alteraciones metab olicas en presencia de HAS definida seg un los criterios tanto de ACC/AHA 2017 como del Comite Nacional Conjunto sobre Prevenci on, Detecci on, Evaluaci on y Tratamiento de la Tensi on Arterial Elevada (JNC7) en mujeres con SOP. ~o: Estudio transversal. Disen Entorno: Centro de investigaci on. Paciente(s): Muestras de biobanco obtenidas de 233 mujeres con SOP y 70 controles sin disfunci on ovulatoria hirsuta. Intervencion(es): Evaluacion metab olica, hormonal y bioquímica. Principal(es) medida(s) de resultado(s): Estado de la tensi on arterial seg un los criterios de ACC/AHA y JNC7 de 2017 y la prevalencia de alteraciones metab olicas. Resultado(s): La prevalencia de HAS entre mujeres con SOP fue del 65% (n¼152) considerando los criterios ACC/AHA del 2017 y del 26,6% (n¼62) considerando los criterios JNC7. Las 90 mujeres cuyo estado de HAS se modific o seg un los criterios de ACC/AHA del 2017 se clasificaron como HAS (tensi on arterial sist olica 130-139 mmHg y/o tensi on arterial diast olica 80-89 mmHg), requiriendo s olo terapia no farmacologica (cambios en el estilo de vida). La prevalencia de HAS en el grupo control fue del 41,1% (n¼29) seg un los criterios del 2017 de ACC/AHA y del 12,8% (n¼9) seg un los criterios de JNC7. En todos los grupos, la HAS estuvo asociada con un mayor estudio del modelo homeostatico y de los niveles de insulina comparados con la tensi on arterial normal (p< 0,01). En mujeres con SOP, la tasa de riesgo de glucosa R 100 mg/dL (tasa de prevalencia 3,88, intervalo de confianza 95% [IC] 1,30-11,55), lipoproteína de alta densidad (HDL) < 50 mg/dL (tasa de prevalencia 2,13, IC 95% 1,45-3,12) y trigliceridos R 150 mg/dL (tasa de prevalencia 3,39; IC 95% 1,56 – 7,35) fue mayor con HAS comparado con la tensi on arterial normal cuando se aplicaron los criterios ACC/AHA del 2017, y no aument oo aument o ligeramente cuando se aplicaron los criterios de JNC7 (glucosa R 100 mg/dL, tasa de prevalencia 1,38, IC 95% 0,99-1,91), HDL < 50 mg/dL (tasa de prevalencia 1,1, IC 95% 0,99-1,37) y trigliceridos R 150 mg/dL (tasa de prevalencia 1,48, IC 95% 1,13-1,94). Conclusion(es): El riesgo de comorbilidades cardiometabolicas aument o en mujeres con HAS definidas por los criterios de ACC/AHA del 2017. Los puntos de corte bajos para la tensi on arterial anormal parecen apropiados para las mujeres SOP, brindando una herramienta de detecci on simple para las comorbilidades cardiometab olicas y una oportunidad para la prevenci on primaria precoz.
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SUPPLEMENTAL FIGURE 1
Frequency of overweight, obesity, and metabolic abnormalities in control women with SAH versus normal blood pressure according to 2017 American College of Cardiology/American Heart Association (ACC/AHA) and Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) criteria. BMI ¼ body mass index; HDL ¼ high-density lipoprotein; NBP ¼ normal blood pressure; SAH ¼ systemic arterial hypertension; TG ¼ triglyceride. Marchesan. High blood pressure criteria and PCOS. Fertil Steril 2018.
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Objective: To assess the association of insulin resistance markers, body mass index (BMI), age, and androgen levels with systemic arterial hypertension (SAH) defined according to 2017 American College of Cardiology/American Heart Association (ACC/AHA) criteria in polycystic ovary syndrome (PCOS); and to determine the risk of metabolic abnormalities in the presence of SAH defined by both the 2017 ACC/AHA and Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) criteria in women with PCOS. Design: Cross-sectional study. Setting: Research center. Patient(s): Biobanked samples obtained from 233 women with PCOS and 70 controls without hirsute, ovulatory dysfunction. Intervention(s): Metabolic, hormonal, and biochemical assessment. Main Outcome Measure(s): Blood pressure status according to 2017 ACC/AHA and JNC7 criteria and prevalence of metabolic abnormalities. Result(s): The prevalence of SAH among women with PCOS was 65% (n ¼ 152) using 2017 ACC/AHA criteria and 26.6% (n ¼ 62) considering JNC7 criteria. The 90 women whose SAH status was changed by 2017 ACC/AHA criteria were categorized as stage 1 SAH (systolic blood pressure 130–139 mmHg and/or diastolic blood pressure 80–89 mmHg), requiring nonpharmacologic therapy only (lifestyle changes). The prevalence of SAH in the control group was 41.4% (n ¼ 29) according to 2017 ACC/AHA criteria and 12.8% (n ¼ 9) according to JNC7 criteria. In all groups, SAH was associated with higher homeostasis model assessment and insulin levels compared with normal blood pressure (P< .01). In women with PCOS, the risk ratio for glucose R100 mg/dL (prevalence ratio 3.88, 95% confidence interval [CI] 1.30–11.55), high-density lipoprotein (HDL) <50 mg/dL (prevalence ratio 2.13, 95% CI 1.45– 3.12), and triglycerides R150 mg/dL (prevalence ratio 3.39, 95% CI 1.56–7.35) was higher with SAH versus normal blood pressure when 2017 ACC/AHA criteria were applied, and did not increase or increased slightly when JNC7 criteria were applied (glucose R100 mg/dL, prevalence ratio 1.38, 95% CI 0.99–1.91), HDL <50 mg/dL (prevalence ratio 1.1, 95% CI 0.99–1.37), and triglycerides R150 mg/dL (prevalence ratio 1.48, 95% CI 1.13–1.94). Conclusion(s): The risk of cardiometabolic co-morbidities was increased in women with SAH defined by 2017 ACC/AHA criteria. Lower cutoffs for abnormal blood pressure seem appropriate for women with PCOS, providing a simple screening tool for cardiometabolic co-morbidities and an opportunity for early primary prevention. (Fertil SterilÒ 2019;111:579–87. Ó2018 by American Society for Reproductive Medicine.) El resumen está disponible en Español al final del artículo. Key Words: Hypertension, polycystic ovary syndrome, androgen, insulin resistance, cardiovascular diseases Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertilityand-sterility/posts/40659-26689
Received July 20, 2018; revised and accepted November 21, 2018. L.B.M. has nothing to disclose. P.M.S. has nothing to disclose. gico (grant INCT/CNPq/FAPERGS: 465482/2014-7). Supported by the Conselho Nacional de Desenvolvimento Científico e Tecnolo Reprint requests: Poli Mara Spritzer, M.D., Ph.D., Division of Endocrinology, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350 Porto Alegre, RS, Brazil (E-mail: [email protected]). Fertility and Sterility® Vol. 111, No. 3, March 2019 0015-0282/$36.00 Copyright ©2018 American Society for Reproductive Medicine, Published by Elsevier Inc. https://doi.org/10.1016/j.fertnstert.2018.11.034 VOL. 111 NO. 3 / MARCH 2019
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W
omen with polycystic ovary syndrome (PCOS) face increased cardiovascular risk when compared with healthy women of the same age. Polycystic ovary syndrome, otherwise characterized by an association between hyperandrogenism and ovulatory dysfunction, is also often associated with obesity (1, 2), lipid abnormalities (3, 4), insulin resistance (IR) (5), and high blood pressure/systemic arterial hypertension (SAH) (6–8). The mechanism underlying the increased prevalence of SAH in PCOS has been linked to a series of factors such as obesity in and of itself (9), heart autonomic dysfunction (10–12), hyperandrogenism (13, 14), and IR (15). The American College of Cardiology/American Heart Association (ACC/AHA) has recently issued a new guideline for the diagnosis and management of high blood pressure/ SAH (16), proposing more stringent cutoffs for high blood pressure compared with the previous cutoffs recommended by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC7 report (17). The 2017 ACC/AHA guideline, which was mainly based on observational data and was influenced, at least in part, by the Randomized Trial of Intensive versus Standard Blood-Pressure Control (SPRINT) trial (18), led to a substantial increase in the prevalence of SAH in the American general population (19). The SPRINT trial (18) compared intensive versus standard blood pressure control in patients aged 50 years or older with increased blood pressure and at least one additional cardiovascular risk factor. The study's intensive control arm targeted a systolic blood pressure (SBP) of <120 mmHg, whereas the standard control arm targeted a SBP of <140 mm Hg. The intervention was interrupted early after a median follow-up of 3.26 years owing to a significantly lower rate of the primary composite outcome (myocardial infarction, acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes) in the intensive control group compared with the standard control group. The impact of the 2017 ACC/AHA cutoffs for young adult populations at higher cardiovascular risk has not yet been established. Therefore, the aims of the present study were [1] to assess the association of IR markers, body mass index (BMI), age, and androgen levels with blood pressure levels and SAH status according to 2017 ACC/AHA criteria in PCOS; and [2] to determine the prevalence of metabolic abnormalities, such as dysglycemia, dyslipidemia, obesity, and central adiposity, in the presence of SAH as defined by both 2017 ACC/AHA and JNC7 criteria in women with PCOS.
None of the PCOS or control women had received any drugs known to interfere with hormone and metabolic variables (i.e., oral contraceptive [OC] pills, antiandrogens, metformin, fibrates, statins) for at least 3 months before the samples were collected. Diabetic and pregnant women, as well as those presenting other causes of hyperandrogenism were excluded. In accordance with the Rotterdam criteria, 180 women were classified as having classic PCOS (c-PCOS [A þ B phenotypes]), defined by biochemical and/or clinical hyperandrogenism and oligomenorrhetc and amenorrheic cycles, <9 cycles/year, with or without polycystic ovary (PCO) appearance at ultrasound. The other 53 women were classified as having ovulatory PCOS (ov-PCOS [C phenotype]), characterized by hyperandrogenism, with or without PCO appearance at ultrasound, and regular ovulatory menstrual cycles confirmed by luteal phase P>3.8 ng/mL (22).
Measurements In addition to the samples for biochemical tests, information was available on weight, height, waist circumference (waist measured at the midpoint between the lower rib margin and the iliac crest) (23), and blood pressure (measured after a 10-minute rest, in the sitting position, with feet on the floor and the arm supported at heart level). Body mass index was calculated as weight in kilograms divided by squared height in meters.
Hormonal and Metabolic Assessment Samples were obtained between days 2 and 10 of the menstrual cycle, or on any day if the patient was amenorrheic. All samples were obtained between 8 and 10 AM. Blood samples were drawn after an overnight 12-hour fast for determination of plasma cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. Low-density lipoprotein (LDL) cholesterol was estimated indirectly with the formula LDL ¼ total cholesterol - HDL - triglycerides/5 (24). Glucose and insulin were measured before and 2 hours after the ingestion of a 75-g oral glucose load. Blood samples were also drawn for measurement of sex hormone-binding globulin (SHBG) and total T. Free androgen index was estimated by dividing total T (nmol/L) by SHBG (nmol/L) 100 (25). Homeostasis model assessment index of IR (HOMA-IR index) was calculated by multiplying insulin (mIU/mL) by glucose (mmol/L) and dividing this product by 22.5 (26). The cutoff point to define IR was arbitrarily defined as a HOMA-IR index R2.5 (27).
MATERIALS AND METHODS Study Design and Participants
Assays
This is a cross-sectional study of biobanked samples (stored in aliquots at -80 C) obtained from 233 women with PCOS and 70 women without hirsute, ovulatory dysfunction (regular cycles and luteal phase P>3.8 ng/mL), who were prospectively recruited and participated in studies conducted at our research center from 2008 to 2012 (10, 20, 21). The study protocol was approved by the local Research Ethics Committee, and written informed consent was obtained from all subjects at the time of recruitment.
Total cholesterol, HDL cholesterol, triglycerides, and glucose were determined using a colorimetric-enzymatic method (Siemens Advia System). Insulin, LH, SHBG, and DHEAS serum concentrations were measured with electrochemiluminescent immunoassays (Roche diagnostic) with sensitivity of 0.20 mIU/mL, 0.10 mIU/mL, 0.35 nmol/L, and 0.10 mg/dL, respectively, intra-assay coefficient of variation (CV) of <3% and interassay CV of <5%. Serum total T (sensitivity <0.10 ng/mL) levels were measured in a subgroup of patients
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Statistics for Windows, version 20 (IBM Corp.). Data were considered to be significant at P< .05.
Definitions of SAH
RESULTS
The SAH was defined as SBP R130 mmHg or diastolic blood pressure (DBP) R80 mmHg (16). In addition, for comparative analyses, the previous JNC7 criteria (17) for SAH were also considered (SBP R140 mmHg or DBP R90 mmHg).
Statistical Analysis The Shapiro-Wilk normality test and descriptive statistics were used to evaluate the distribution of data. Results are presented as means SD, or median and interquartile range. Correlations between variables were performed by twotailed Spearman rank correlation test considering the nonGaussian distribution of variables. For the other analyses, non-Gaussian variables were log-transformed for statistical analysis and reported after being back-transformed into their original units of measure. Metabolic variables were adjusted for BMI and age by analysis of covariance (ANCOVA) and Bonferroni test. For comparisons between categorical variables c2 tests were used. Two-way ANCOVA, with age and BMI as covariates, was used for testing the interaction between SAH and PCOS phenotypes with IR and T. Prevalence ratios were determined for metabolic disturbances in hypertensive and normotensive women with PCOS, according to 2017 ACC/AHA or JNC7 blood pressure cutoffs. All analyses were performed using the IBM SPSS
Clinical, hormonal, and metabolic characteristics of women with c-PCOS, ov-PCOS, and controls are summarized in Table 1. Women with the c-PCOS phenotype were younger than controls (P< .01). The BMI, SBP, and DBP levels were higher in women with c-PCOS (P< .01) and T levels differed significantly among the three groups (P< .01). Metabolic variables were higher in women with c-PCOS, even after adjustment for age and BMI, except for fasting glucose and HDL, which were similar in all groups. The prevalence of obesity, defined as BMI R30 kg/m2, was similar in the control (43.9%) and PCOS (52.8%) groups, with no statistical difference. The prevalence of SAH among women with PCOS was 65% (n ¼ 152) and 26.6% (n ¼ 62), considering 2017 ACC/ AHA and JNC7 criteria. The group of 90 women with PCOS whose SAH status changed with application of the 2017 ACC/AHA criteria were categorized as stage 1 SAH (SBP 130–139 mmHg and/or DBP 80–89 mmHg), requiring only nonpharmacologic therapy (lifestyle changes). Also, when applying 2017 ACC/AHA criteria, the frequency of SAH in women with c-PCOS was significantly higher than those with ov-PCOS and in the control group (Table 1). Overall age- and sex-adjusted SAH prevalence in women has been previously estimated as 43% with 2017 ACC/AHA criteria (16).
TABLE 1 Clinical, hormonal, and metabolic profile of patients with classic polycystic ovary syndrome, ovulatory polycystic ovary syndrome, and controls at the time of sample collection. Clinical, hormonal, and metabolic profile Age (y) BMI (kg/m2) FGS SBP (mmHg) DBP (mmHg) DHEAS (mg/dL) T (ng/mL)d SHBG (nmol/L) FAId Glucose (mg/dL) Glucose 120 (mg/dL) Insulin (mU/L) HOMA-IR index Total cholesterol (mg/dL) HDL (mg/dL) LDL (mg/dL) Triglycerides (mg/dL) SAH 2017 ACC/AHA % (n) SAH JNC7 % (n)
Classic PCOS (n [ 180) a
25 (21–29) 32.52 7.41a 11 (8–16)a 120 (115–130)a 80 (75–90)a 198.4 (130.8–281.1)a 1.0 (0.69–1.23)a 24.35 (17.36–36.3)a 14.8 (8.34–22.55)a 90 (83–96) 110.5 (96–133.25)a 19.57 (11.9–33.6)a 4.28 (2.52–7.63)a 190.26 43.2a 45 (40–55) 117.4 37.5a 109 (70–157)a 70 (126)a 29.4 (53)a
Ovulatory PCOS (n [ 53) a,b
26.5 (21–31) 25.69 6.14b 13 (10–17.75)a 115 (110–130)b 78 (68.5–80)b 246 (132.9–366.2)a 0.48 (0.4–0.73)b 36.5 (23.35–48.85)b 4.67 (3.53–8.32)b 85 (79.5–91) 97 (82–116.5)b 11.95 (6.6–17.5)b 2.5 (1.45–3.92)b 170.3 29b 53 (46–59) 99.75 26b 74 (55–109)b 49.1 (26)b 17 (9)a
Controls (n [ 70) b
29 (26–34) 28.71 5.71b 3 (0–5)b 110 (108–120)b 72.5 (69.5–80)b 154.2 (100.15–204)b 0.26 (0.19–0.39)c 39.1 (29.93–58.15)b 2.15 (1.27–3.77)c 88 (83.25–93.75) 93.5 (85.25–107.7)b 9.05 (6.07–12.61)b 2.01 (1.34–2.79)b 169 30.8b 50 (45–57) 100.4 26.7b 66.5 (50–100.5)b 41.4 (29)b 12.8 (9)b
P value < .01 < .01 < .01 < .01 < .01 < .01 < .01 < .01 < .01 .07e < .01e < .01e < .01e < .01e .08e < .001e < .001e < .001 .01
Note: Values are expressed as mean SD, median (25–75 interquartile range), or % and number. a,b,c Statistical difference by analysis of variance (ANOVA) and Bonferroni tests (continuous variables) and c2 test (categorical variables). dT and FAI were reanalyzed in a subgroup of samples (125 classic PCOS, 31 ovulatory PCOS, and 33 controls) in which T was measured by radioimmunoassay. eP value adjusted for age and BMI. ACC/AHA ¼ American College of Cardiology/American Heart Association; BMI ¼ body mass index; DBP ¼ diastolic blood pressure; FAI ¼ free androgen index; FGS ¼ Ferriman Gallwey score; Glucose 120 ¼ plasma glucose value 120 minutes after a standard dose of 75 g of oral glucose; HDL ¼ high-density lipoprotein cholesterol; JNC7 ¼ Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; LDL ¼ low-density lipoprotein cholesterol; PCOS ¼ polycystic ovary syndrome; SAH ¼ systemic arterial hypertension; SBP ¼ systolic blood pressure; SHBG ¼ sex hormone binding globulin. Marchesan. High blood pressure criteria and PCOS. Fertil Steril 2018.
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ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY Figure 1 shows the association of HOMA-IR, insulin, and T levels with 2017 ACC/AHA blood pressure status (normal blood pressure or SAH) in the three groups (c-PCOS, ovPCOS, and controls), using age and BMI as covariates. The HOMA-IR, insulin, and T levels were more elevated in patients with c-PCOS and patients with ov-PCOS presented intermediate values between those found for c-PCOS and controls. In all groups, SAH was associated with higher HOMA-IR and insulin levels compared with normal blood pressure, with no interaction between blood pressure status and groups (P< .01). The T levels did not differ between normal blood pressure and SAH groups, and there was no interaction with groups (P¼ .18). The HOMA-IR, T, and free androgen index correlation with SBP and DBP levels in all groups combined (Fig. 2). The HOMA-IR was positively correlated with SBP and DBP levels. Androgen levels presented a weak correlation with SBP and a moderate one with DBP. Figure 3A presents the frequency of waist circumference >88 cm, dysglycemia, BMI R25 and R30 kg/m2, and lipid abnormalities in women with PCOS and with SAH or normal blood pressure according to 2017 ACC/AHA and JNC7 criteria. The prevalence of metabolic abnormalities was high in women with PCOS and with SAH regardless of the defining criteria. However, these metabolic disturbances were more frequent in participants with normal blood pressure defined by JNC7 criteria than in those with normal blood pressure according to the 2017 ACC/AHA guidelines. Also, the risk ratio for these abnormalities in the presence of SAH versus normal blood pressure ranged from around 2 for BMI R25 kg/m2 to 3.8 times for glucose R100 mmol/L when 2017 ACC/AHA criteria were applied (Fig. 3B), and around 1.4 times when JNC7 criteria were applied. No significant increase in risk was detected for glucose R100 mmol/L and
HDL<50 mmHg (Fig. 3B) in a patient with normal blood pressure by the JNC7 criteria. The absolute number of control women with SAH was low according to both criteria, as well as the frequency of metabolic abnormalities (Supplemental Fig. 1 and Supplemental Table 1, available online). Except for BMI R25 kg/m2 (prevalance ratio 1.64, 95% confidence interval 1.12–2.4) in women with SAH defined according to the 2017 ACC/AHA criteria, no other clinically relevant risk factors were found for SAH in the control group, regardless of blood pressure criteria (Supplemental Table 1).
DISCUSSION In the present study, we found that the risk of cardiometabolic co-morbidities was higher in women with SAH as defined by the 2017 ACC/AHA criteria. In this group, the prevalence of dysglycemia and hypertriglyceridemia was more than three times higher than in the PCOS group with normal blood pressure. In contrast, when using the JCN7 cutoffs for SAH, the risk for metabolic abnormalities became less important in this population. This is possibly explained by the classification of a part of the group at risk for metabolic co-morbidities into the normal blood pressure category by the JCN7 cutoffs. The status of these women was changed to SAH when the 2017 ACC/AHA cutoffs were applied. These data suggest that lower cutoffs for abnormal blood pressure, as recently proposed by the ACC/ AHA, could be especially relevant and appropriate for women with PCOS, a subgroup of patients with a higher number of cardiovascular risk factors compared with the general population (1, 4–8, 28, 29), and provide a simple screening tool for cardiometabolic co-morbidities and the opportunity to introduce early primary prevention strategies. To our knowledge, this is the first study to assess the impact of the new SAH definition in a population with PCOS.
FIGURE 1
Association of homeostasis model assessment insulin resistance (HOMA-IR), insulin, and T levels with phenotypes and systemic arterial hypertension (SAH) according to 2017 American College of Cardiology/American Heart Association (ACC/AHA) criteria. *P<.01 for SAH versus normal blood pressure. Age and body mass index (BMI) were used as covariates in the model. The variables of interest are expressed as means in the y-axis. Two-way analysis of covariance (ANCOVA). DBP ¼ diastolic blood pressure; PCOS ¼ polycystic ovary syndrome; SBP ¼ systolic blood pressure. Marchesan. High blood pressure criteria and PCOS. Fertil Steril 2018.
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FIGURE 2
Correlations of homeostasis model assessment insulin resistance (HOMA-IR), total T (TT), and free androgen index (FAI) with systolic and diastolic blood pressure in the overall group of participants. (A) Systolic blood pressure (SBP). r ¼ 0.36; P<.01 (left panel), r ¼ 0.16; P¼.01 (middle panel), r ¼ 0.16; P<.01 (right panel); (B) Diastolic blood pressure (DBP). r ¼ 0.36; P<.01 (left panel), r ¼ 0.22; P<.01 (middle panel), r ¼ 0.33; P<.01 (right panel) Spearman rank correlation test. Marchesan. High blood pressure criteria and PCOS. Fertil Steril 2018.
We also observed that IR markers were more pronounced in SAH than in normal blood pressure in all groups, that is, women with c-PCOS, ov-PCOS, and controls. Indeed, IR-related compensatory hyperinsulinemia may influence blood pressure through an autonomic nervous system imbalance (30, 31), increased renal sodium reabsorption, and decreased nitric oxide production (32– 34) in distinct populations. Regarding PCOS phenotypes, we have previously shown that patients with c-PCOS present subclinical autonomic dysfunction in comparison with controls, and that women with ov-PCOS present intermediate heart rate variability indexes in relation to c-PCOS and control groups (10). In addition, a recent study (15) reported that, within a normotensive range, hyperinsulinemia could influence 24-hour ambulatory blood pressure levels in women with PCOS. Taken together, our data and previous results (17, 35–38) suggest a possible role for the more striking IR-related metabolic derangements found in the classic phenotype in cardiovascular imbalance. In the present study, a positive correlation was observed between T and free androgen index with both SBD and DBP. However, T levels did not vary in different PCOS phenoVOL. 111 NO. 3 / MARCH 2019
types or controls according to blood pressure status (SAH or normal blood pressure). In fact, hyperandrogenism has been implicated in blood pressure dysregulation in patients with PCOS (13, 14). However, recent evidence suggests that the higher risk for SAH in women with PCOS is linked to metabolic abnormalities, such as IR and adipose tissue dysfunction, rather than to hyperandrogenism per se (4, 6, 35–37). Patients with PCOS, especially with the classic phenotype, are exposed to cardiovascular risk factors for a long period of their lives. Investigators have demonstrated that longer exposure to the vascular effects of SAH entails a greater risk for cardiovascular outcomes. A recent study (38) analyzing data from the Framingham Original Cohort (including 790 women, or 63.1% of the cohort) found that individuals in the community generally maintained SBP <120– 125 mmHg. Above that level, a rapid SBP increase toward overt SAH was noted. Thus, a resting SBP that chronically exceeds the range of 120–125 mmHg may signal incipient SAH irrespective of age. Our patients with c-PCOS presented higher blood pressure levels than controls and had a higher prevalence of other metabolic derangements associated with 583
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FIGURE 3
(A) Frequency of overweight, obesity, and metabolic abnormalities in women with polycystic ovary syndrome (PCOS) and with systemic arterial hypertension (SAH) versus normal blood pressure (NBP) according to 2017 American College of Cardiology/American Heart Association (ACC/ AHA) and Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) criteria. BMI ¼ body mass index; HDL ¼ high-density lipoprotein; TG ¼ triglyceride. (B) Prevalence ratios (PR) and 95% confidence intervals (CI) for metabolic parameters in women with PCOS in the presence of SAH versus normal blood pressure according to 2017 ACC/AHA and JNC7 criteria. Marchesan. High blood pressure criteria and PCOS. Fertil Steril 2018.
cardiovascular risk. That indicates the need for earlier intervention, especially for the classic phenotype. Because most of our hypertensive patients with PCOS would be classified as stage I hypertension, the main intervention would be lifestyle modification, which could also help improve other obesity-related clinical manifestations of PCOS. One strength of the present study was testing. For the first time there was the usefulness of applying the new cutoffs for blood pressure levels to a subgroup of young women at higher cardiovascular risk. In this sense, another strength was the use of a sample stratified according to the main PCOS phenotypes, highlighting the link between higher blood pressure levels and more pronounced IR in women with c-PCOS. Conversely, a limitation was that euglycemic hyperinsulinemic clamping, the gold standard for assessment of IR, was not used. Never-
584
theless, HOMA-IR is well correlated with the clamp (39), and has been shown to be significantly and independently associated with risk of cardiovascular disease. The fact that all our samples were from hyperandrogenic women, regardless of PCOS phenotype, is another limitation. This prevented us from analyzing the performance of the 2017 ACC/AHA criteria in women with the normoandrogenic PCOS phenotype (phenotype D). However, the prevalence of cardiovascular risk factors and metabolic co-morbidities in normoandrogenic women with PCOS has been reported to be lower than in the other phenotypes (40, 41). In conclusion, in the presence of SAH, more pronounced IR was observed in the c-PCOS phenotype compared with women with ov-PCOS and controls. In the three groups, women with SAH had higher IR than their normal blood
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Fertility and Sterility® pressure counterparts. The 2017 ACC/AHA criteria for SAH were useful to identify a subgroup of patients with PCOS and with a higher risk profile considering other cardiometabolic alterations. These findings should prompt an earlier intervention—initially a recommendation for lifestyle changes—in the group of PCOS with SBP R130 mmHg or DBP R 80 mmHg. Further longitudinal studies are needed to determine whether these interventions would contribute to blood pressure control in this group and to decrease cardiovascular morbidity and mortality in the long term. Acknowledgments: The authors thank Fernanda Missio Mario, Kristhiane Di Domenico, and Denusa Wiltgen for their support with data collection.
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Fertility and Sterility® Definicion de tension arterial elevada de la ACC/AHA de 2017: implicaciones en mujeres con síndrome de ovario poliquístico Objetivo: evaluar la asociaci on de marcadores de resistencia a la insulina, índice de masa corporal (IMC), edad y niveles de andr ogenos con hipertension arterial sistemica (HAS) definida de acuerdo con los criterios del Colegio Americano de Cardiología/Asociaci on Americana del Corazon (ACC/AHA) de 2017 en el síndrome de ovario poliquístico (SOP); y determinar el riesgo de alteraciones metab olicas en presencia de HAS definida seg un los criterios tanto de ACC/AHA 2017 como del Comite Nacional Conjunto sobre Prevenci on, Detecci on, Evaluaci on y Tratamiento de la Tensi on Arterial Elevada (JNC7) en mujeres con SOP. ~o: Estudio transversal. Disen Entorno: Centro de investigaci on. Paciente(s): Muestras de biobanco obtenidas de 233 mujeres con SOP y 70 controles sin disfunci on ovulatoria hirsuta. Intervencion(es): Evaluacion metab olica, hormonal y bioquímica. Principal(es) medida(s) de resultado(s): Estado de la tensi on arterial seg un los criterios de ACC/AHA y JNC7 de 2017 y la prevalencia de alteraciones metab olicas. Resultado(s): La prevalencia de HAS entre mujeres con SOP fue del 65% (n¼152) considerando los criterios ACC/AHA del 2017 y del 26,6% (n¼62) considerando los criterios JNC7. Las 90 mujeres cuyo estado de HAS se modific o seg un los criterios de ACC/AHA del 2017 se clasificaron como HAS (tensi on arterial sist olica 130-139 mmHg y/o tensi on arterial diast olica 80-89 mmHg), requiriendo s olo terapia no farmacologica (cambios en el estilo de vida). La prevalencia de HAS en el grupo control fue del 41,1% (n¼29) seg un los criterios del 2017 de ACC/AHA y del 12,8% (n¼9) seg un los criterios de JNC7. En todos los grupos, la HAS estuvo asociada con un mayor estudio del modelo homeostatico y de los niveles de insulina comparados con la tensi on arterial normal (p< 0,01). En mujeres con SOP, la tasa de riesgo de glucosa R 100 mg/dL (tasa de prevalencia 3,88, intervalo de confianza 95% [IC] 1,30-11,55), lipoproteína de alta densidad (HDL) < 50 mg/dL (tasa de prevalencia 2,13, IC 95% 1,45-3,12) y trigliceridos R 150 mg/dL (tasa de prevalencia 3,39; IC 95% 1,56 – 7,35) fue mayor con HAS comparado con la tensi on arterial normal cuando se aplicaron los criterios ACC/AHA del 2017, y no aument oo aument o ligeramente cuando se aplicaron los criterios de JNC7 (glucosa R 100 mg/dL, tasa de prevalencia 1,38, IC 95% 0,99-1,91), HDL < 50 mg/dL (tasa de prevalencia 1,1, IC 95% 0,99-1,37) y trigliceridos R 150 mg/dL (tasa de prevalencia 1,48, IC 95% 1,13-1,94). Conclusion(es): El riesgo de comorbilidades cardiometabolicas aument o en mujeres con HAS definidas por los criterios de ACC/AHA del 2017. Los puntos de corte bajos para la tensi on arterial anormal parecen apropiados para las mujeres SOP, brindando una herramienta de detecci on simple para las comorbilidades cardiometab olicas y una oportunidad para la prevenci on primaria precoz.
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SUPPLEMENTAL FIGURE 1
Frequency of overweight, obesity, and metabolic abnormalities in control women with SAH versus normal blood pressure according to 2017 American College of Cardiology/American Heart Association (ACC/AHA) and Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) criteria. BMI ¼ body mass index; HDL ¼ high-density lipoprotein; NBP ¼ normal blood pressure; SAH ¼ systemic arterial hypertension; TG ¼ triglyceride. Marchesan. High blood pressure criteria and PCOS. Fertil Steril 2018.
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