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Dyslipidemia and Metabolic Syndrome in the Sisters of Women with Polycystic Ovary Syndrome

Division of Endocrinology, Metabolism, and Molecular Medicine (S.S., A.D.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; Department of Obstetrics and Gynecology (R.S.L.), Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033; and Division of Endocrinology, Diabetes, and Hypertension (R.B.-L.), Brigham and Women’s Hospital, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Andrea Dunaif, M.D., Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Tarry Building 15-709, Chicago, Illinois 60611-3008. E-mail: a-dunaif{at}northwestern.edu.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Dyslipidemia is a feature of polycystic ovary syndrome (PCOS), but its pathogenesis remains controversial.

Objective: The objective of this study was to test the hypothesis that dyslipidemia is a heritable trait in sisters of women with PCOS.

Design: A case-control design was used.

Setting: The study took place at General Clinical Research Centers in four academic medical centers in the United States.

Patients: The subjects included 385 sisters of women with PCOS with the following reproductive phenotypes: sisters with PCOS (n = 51), sisters with hyperandrogenemia and regular menses (HA) (n = 38), unaffected sisters (n = 143), and unknown phenotypes (n = 153). One hundred twenty-five control women of comparable age, body mass index, and ethnicity to women with PCOS were included.

Interventions: Fasting blood was obtained for measurements of lipid profile, reproductive hormones, glucose, and insulin levels.

Main Outcome Measures: The main outcome measures included lipid and lipoprotein levels and prevalence of metabolic syndrome.

Results: Sisters with PCOS and HA phenotypes had higher total (P 0.001) and low-density lipoprotein cholesterol levels (P 0.01) compared with unaffected sisters and control women. Triglyceride levels were elevated only in sisters with the PCOS phenotype (P < 0.05). The prevalence of metabolic syndrome was increased in sisters with the PCOS (n = 29) and HA (n = 17) phenotypes compared with unaffected sisters (n = 85) (P < 0.001 and P < 0.05, respectively).

Conclusions: Low-density lipoprotein levels are increased in affected sisters of women with PCOS consistent with a heritable trait. The prevalence of metabolic syndrome is increased in affected sisters.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
POLYCYSTIC OVARY SYNDROME (PCOS) affects approximately 7% of reproductive age women (1, 2). It is characterized by disordered gonadotropin secretion and hyperandrogenism (3). Women with PCOS also have metabolic abnormalities such as insulin resistance (4, 5, 6), glucose intolerance (7, 8), and dyslipidemia (9, 10, 11, 12, 13). Increased low-density lipoprotein (LDL) levels are independent of obesity (11, 12, 13), whereas increased triglyceride and decreased high-density lipoprotein (HDL) levels are found primarily in obese women with PCOS (10, 11, 13, 14). Familial aggregation of PCOS is well documented, suggesting a genetic susceptibility to the disorder (15, 16, 17, 18, 19, 20, 21). We have shown previously that there are two affected reproductive phenotypes in the sisters of women with PCOS: 1) chronic anovulation and hyperandrogenemia consistent with the National Institute of Child Health and Human Development diagnostic criteria for PCOS (classical PCOS phenotype) (22), and 2) hyperandrogenemia with regular menses and apparently normal fertility (HA phenotype) (19, 23). Both affected phenotypes have evidence for insulin resistance compared with unaffected sisters and control women (23). This finding is consistent with a genetic susceptibility to insulin resistance that tracks with hyperandrogenemia in families of women with PCOS (23).

It is unknown whether abnormalities in lipids and lipoprotein levels are also inherited in families of women with PCOS. There is some evidence that family members of women with PCOS have dyslipidemia (15, 18). In women with PCOS, hyperandrogenemia plays an important role in the pathogenesis of LDL elevations (24, 25), and, because hyperandrogenemia is present in 50% of sisters, dyslipidemia may also be common in this population. We performed this study to test the hypothesis that there is a genetic susceptibility to dyslipidemia in sisters of women with PCOS and to determine the type of lipid abnormality associated with the various reproductive phenotypes. Furthermore, we examined the prevalence of metabolic syndrome in sisters based on their reproductive phenotype to determine whether PCOS and/or hyperandrogenemia increased the risk for this condition.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Women with PCOS or women with six or fewer menses per year were recruited by advertisements and from the practices of the coauthors. The study was approved by the Institutional Review Boards of Brigham and Woman’s Hospital, Northwestern University Feinberg School of Medicine, Pennsylvania State University College of Medicine, and University of Pennsylvania Medical Center. Written informed consent was obtained from all participants. To qualify as a PCOS index case, a woman had six or fewer menses per year in addition to hyperandrogenemia defined by either total testosterone (T) more than 58 ng/dl (2 nmol/liter) and/or non-SHBG bound T [unbound testosterone (uT)] more than 15 ng/dl (0.5 nmol/liter) levels greater than 2 SD values above the mean value that we have established in reproductively normal women aged 18–40 yr old in the early follicular phase of the menstrual cycle (19, 23). Other causes of anovulation and hyperandrogenemia were excluded by appropriate laboratory tests (19, 23). We limited our analysis to non-Hispanic white women to avoid potential confounding effects of ethnicity on metabolic endpoints (26, 27).

A total of 385 sisters of women with PCOS participated in the study and were assigned reproductive phenotypes as follows: classical PCOS, six or fewer menses per year and elevated T and/or uT levels (n = 51); HA, regular menses every 27–35 d and elevated T and/or uT levels (n = 38); unaffected, regular menses every 27–35 d and normal T, uT, and dehydroepiandrosterone sulfate (DHEAS) levels (n = 143); and unknown (n = 153). Unknown phenotype was assigned if the sisters were on confounding medications or were premenarchal, pregnant, lactating, menopausal, or had a hysterectomy (23). Confounding medications were oral contraceptive agents (28), hypertensive medications (29), and insulin-sensitizing medications (30, 31). There were 25 families who had more than one sister with the same phenotype. To control for the overrepresentation of families with multiple sisters, we averaged the data from sisters with the same phenotype to yield one value per phenotype per family. The findings were unchanged when the sisters’ data were averaged; thus, the results are reported using the individual sister data. Data on reproductive hormones, glucose, and insulin levels for 197 sisters have been reported previously (19, 23).

A total of 125 non-Hispanic white reproductively normal control women with 27- to 35-d menstrual cycles between the ages of 18 and 47 yr were studied. The control women were recruited to be of comparable weight with the probands with PCOS and had the following body weight distribution: 16% nonobese [body mass index (BMI) < 25 kg/m²], 32% overweight (25 kg/m² BMI < 30 kg/m²), and 52% obese (BMI 30 kg/m²). Control women were in good health, sedentary, and did not have a history of hypertension or diabetes mellitus, personally or in a first-degree relative. None of the control women were on any of the confounding medications listed above for at least 1 month (3 months for oral contraceptives) before study.

Sisters were evaluated at one of the four study sites (on-site subjects, n = 146) or in a local clinical laboratory with phlebotomy and blood processing capability (off-site subjects, n = 86). All control women were studied on-site and examined by a physician investigator. Control women had no clinical or biochemical evidence of hyperandrogenism. Standardized forms were used to obtain medical history, including information on exercise habits and tobacco use. Sixty-four percent of subjects provided information on tobacco use, and 89% reported information on exercise history. Height, weight, waist, and hip measurements were determined on all on-site subjects. Blood pressure was determined in the seated position in the right arm as the average of three separate readings obtained 2 min apart after a 5-min rest. For the off-site subjects, the same standardized forms were used to obtain medical history, but the height and weight were self-reported. We have previously validated self-reported height and weight (19, 23).

A fasting morning blood sample was obtained from all subjects as described previously (19, 23). Sisters studied on-site and all control women underwent 75-g oral glucose tolerance test after 3 d of 300 g carbohydrate diet and an overnight fast. Blood was drawn for glucose and insulin at baseline and 2 h after the oral administration of glucose. All control women had normal glucose tolerance by World Health Organization criteria (32). The prevalence of metabolic syndrome in the sisters of women with PCOS was determined according to the Adult Treatment Panel III guidelines (33) based on the presence of three or more of the following features: 1) abdominal obesity (waist circumference of >88 cm; 2) high triglyceride level [150 mg/dl (1.69 mmol/liter)]; 3) low HDL cholesterol level [<50 mg/dl (1.29 mmol/liter)]; 4) high blood pressure (systolic 130 mm Hg or diastolic 85 mm Hg); and 5) high fasting plasma glucose concentration [110 mg/dl (6.1 mmol/liter)]. Metabolic syndrome could only be assessed in sisters studied on-site who had waist and blood pressure measurements (n = 131); these sisters had the following reproductive phenotypes: PCOS (n = 29), HA (n = 17), and unaffected (n = 85).

Assays

Plasma glucose levels were determined by the glucose oxidase technique. Insulin, T, uT, DHEAS, SHBG (19), total and HDL cholesterol, and triglyceride levels were determined as reported previously (13). The LDL cholesterol level was calculated using the Friedewald equation (34).

Data analysis

The homeostatic index of insulin resistance (HOMA IR) was calculated according to the following formula: [fasting glucose (millimoles per liter) x fasting insulin (microunits per milliliter)] ÷ 22.5 (35). Because there were significant differences in age and BMI after the sisters were grouped by phenotype, data were analyzed using analysis of covariance (ANCOVA) adjusted for age and BMI for each continuous variable. Post hoc analysis using least significance difference was applied to determine differences among the groups. Data were log transformed to achieve homogeneity of variance when necessary.

Categorical variables were compared using ² analysis. The prevalence of increased LDL (LDL 130 and 100 mg/dl) and of metabolic syndrome was compared between the various sister phenotypes and control women. The prevalence of each feature of metabolic syndrome was also assessed for affected (PCOS and HA phenotypes) and unaffected sisters. For this analysis, data for sisters with PCOS and HA phenotypes were combined because the number of subjects in the HA group was too small after stratification. The prevalence of metabolic syndrome in the overweight and in obese body weight categories was compared between the sisters with the affected phenotype (n = 14 for overweight and n = 25 for obese) and the unaffected sisters (n = 23 for overweight and n = 18 for obese). Control women were not included in these analyses because we specifically excluded control women with features of the metabolic syndrome, e.g. hypertension.

Linear correlations were assessed by Pearson’s correlation coefficients between affected sisters (PCOS or HA phenotypes) and their proband sisters for total, LDL, and HDL cholesterol and triglyceride levels. Multivariate regression analyses were performed to assess the predictors of total and LDL cholesterol, as well as triglyceride levels in affected sisters, with age, BMI, uT levels, and HOMA IR as independent variables. The regression analysis was repeated with addition of tobacco and exercise history as independent variables because the sample size was smaller for this analysis. Statistical analyses were performed using SAS 8.2 (SAS Institute, Inc., Cary, NC) and SPSS 12.0 (SPSS, Inc., Chicago, IL) data analysis softwares. Data are presented as the untransformed mean ± 1 SD.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Sisters with the PCOS and HA phenotypes were younger than unaffected sisters and control women (Table 1). Sisters with the PCOS phenotype were heavier than sisters with HA phenotype and unaffected sisters but were similar in BMI to control women by design (Table 1). Levels of total T and uT as well as DHEAS were significantly higher in sisters with HA and PCOS phenotypes compared with unaffected sisters and control women, as we reported previously (Table 1) (19). Insulin and glucose/insulin were significantly higher in sisters with PCOS and HA phenotypes compared with unaffected sisters and control women, as reported previously (Table 1) (23). HOMA IR was significantly higher in sisters with the PCOS phenotype compared with both control women and unaffected sisters (Table 1) and was also significantly higher in sisters with the HA phenotype compared with control women (Table 1). HOMA IR tended to be higher (P = 0.06) in sisters with the PCOS phenotype compared with sisters with the HA phenotype.

View larger version (29K): [in this window] [in a new window]   FIG. 1. Sisters with the PCOS and HA phenotypes had significantly higher (***, P 0.001) total cholesterol levels compared with unaffected sisters (UA) and control women (top left). Total triglyceride levels were significantly higher (*, P < 0.05) in sisters with the PCOS phenotype compared with sisters with the HA phenotype, unaffected sisters, and control women (top right). Sisters with the PCOS and HA phenotypes had significantly higher (**, P 0.01) LDL levels compared with unaffected sisters and control women (bottom left). HDL cholesterol levels did not differ significantly among the groups (bottom right). Black bars, Sisters with PCOS phenotype; gray bars, sisters with HA phenotype; white bars, unaffected sisters; and hatched bars, control women. To convert total, LDL, and HDL cholesterol to millimoles per liter, multiply by 0.02586; to convert total triglyceride to millimoles per liter, multiply by 0.01138.

Prevalence of metabolic syndrome

The prevalence of metabolic syndrome was significantly increased in sisters with the PCOS (52%) and the HA (23%) phenotypes compared with the unaffected sisters (7%) (P < 0.001 and P < 0.05, respectively) (Fig. 2). There was a trend (P = 0.07) toward an increase in prevalence of metabolic syndrome in sisters with the PCOS phenotype compared with sisters with the HA phenotype (Fig. 2). Low HDL (<50 mg/dl) was the most common abnormality in affected sisters, followed by high waist circumference (>88 cm) (Table 2).

View larger version (13K): [in this window] [in a new window]   FIG. 2. Sisters with PCOS (n = 29) and HA (n = 17) phenotypes had significantly higher (***, P < 0.001 for PCOS vs. unaffected sisters; *, P < 0.05 HA vs. unaffected sisters) prevalence of metabolic syndrome compared with unaffected sisters (n = 85). There was a trend toward higher (P = 0.07) prevalence of metabolic syndrome in sisters with PCOS phenotype compared with sisters with HA phenotype. Black bars, Sisters with PCOS phenotype; gray bars, sisters with HA phenotype; white bars, unaffected sisters.

View larger version (12K): [in this window] [in a new window]   FIG. 3. The prevalence of metabolic syndrome was significantly higher (*, P < 0.05) in overweight affected sisters (PCOS and HA phenotypes, n = 14) compared with unaffected sisters (n = 23). There was a trend toward higher (P = 0.07) prevalence of metabolic syndrome in obese affected sisters (n = 25) compared with unaffected sisters (n = 18). Black bars, Affected sisters; white bars, unaffected sisters.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Elevations in LDL levels have been found in PCOS independent of obesity (12, 13). The androgen receptor antagonist flutamide significantly decreased LDL levels in women with PCOS without weight loss or improvements in insulin sensitivity (24, 25). In contrast, insulin sensitizing agents did not decrease LDL levels in affected women (25, 30). These observations suggest that hyperandrogenemia rather than insulin resistance is important in the pathogenesis of LDL elevations in women with PCOS (12, 24, 25). Our finding that LDL levels were similarly elevated in both groups of hyperandrogenemic sisters is consistent with an important role for androgens in the pathogenesis of this defect.

Triglyceride levels were elevated only in sisters with the PCOS phenotype. Sisters with the PCOS phenotype tended to be more insulin resistant than sisters with the HA phenotype by HOMA IR. Furthermore, HOMA IR was the only predictor of triglyceride levels in affected sisters, whereas BMI was not a predictor. These findings suggest that insulin resistance may have contributed to elevated triglyceride levels in sisters with the PCOS phenotype. These findings are similar to our previous cross-sectional studies in which only obese women with PCOS, who are the most profoundly insulin resistant (37), had elevated triglyceride levels compared with both nonobese women with PCOS and weight-comparable control women (11, 13). It remains likely that additional factors associated with PCOS contributed to triglyceride elevations because HOMA IR accounted for only 17% of the variance in triglyceride levels in sisters with the PCOS phenotype.

Metabolic syndrome was more prevalent in sisters with the PCOS and HA phenotypes than in unaffected sisters, and it tended to be more prevalent in sisters with the PCOS phenotype compared with those with the HA phenotype. Unaffected sisters are an ideal control group for the prevalence of metabolic syndrome because they share the same genetic and environmental background as their affected sisters but do not have elevated androgen levels. In affected sisters of women with PCOS, the prevalence of metabolic syndrome began to increase in overweight sisters (25 kg/m² BMI < 30 kg/m²) compared with unaffected sisters. However, these findings should be interpreted with caution because samples sizes were relatively small when the sisters were stratified by both affected status and body weight.

The most common feature of metabolic syndrome in affected sisters was low HDL levels. However, affected sisters were significantly more obese than unaffected sisters, which may account for the differences in prevalence of low HDL levels. In our previous cross-sectional studies of women with PCOS, we have found that low HDL levels were associated with obesity rather than PCOS (11, 13). Fifty percent of the control women in our study were obese, which most likely accounted for the low mean HDL levels in this population because similar levels of HDL have been reported in obese reproductively normal non-Hispanic white women (38).

In summary, we have shown that the affected sisters of women with PCOS have elevated LDL levels. This abnormality is associated with hyperandrogenemia rather than irregular menses. These findings are similar to those reported in their proband sisters consistent with a heritable trait. However, because hyperandrogenemia is a heritable trait and LDL elevations track with this abnormality, it is not possible to determine whether these findings reflect a causal association or are closely linked genetic traits. In affected sisters, the prevalence of metabolic syndrome is increased at lower body weights compared with unaffected sisters. This finding suggests that hyperandrogenemia and adiposity have a synergistic effect to increase the risk for metabolic syndrome. Insofar as the affected sisters are more obese, they are also at risk for low HDL levels in addition to increased LDL levels. Affected sisters of women with PCOS have two risk factors for cardiovascular disease: increased LDL levels and an increased prevalence of features of the metabolic syndrome, in particular low HDL levels. Whether these risk factors translate into an actual increase in cardiovascular events requires prospective studies. Nevertheless, screening the sisters of women with PCOS for metabolic abnormalities should be considered.

	Footnotes

 
This work was supported by National Institutes of Health Grants U54 HD34449, P50 HD44405, K12 RR017707, M01 RR00048, M01 RR10732, and M01 RR02635.

First Published Online May 17, 2005

¹ S.S. and R.S.L. contributed equally to this work.

Abbreviations: BMI, Body mass index; DHEAS, dehydroepiandrosterone sulfate; HA, hyperandrogenemia phenotype; HDL, high-density lipoprotein; HOMA IR, homeostatic index of insulin resistance; LDL, low-density lipoprotein; PCOS, polycystic ovary syndrome; T, testosterone; uT, unbound T.

Received November 11, 2004.

Accepted May 9, 2005.

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