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Glucose Intolerance, Insulin Resistance, and Hyperandrogenemia in First Degree Relatives of Women with Polycystic Ovary Syndrome

Department of Internal Medicine, Division of Endocrinology and Metabolism (B.O.Y., M.B.); Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility (H.Y.); and Department of Pediatrics, Endocrinology Unit (H.O.), Faculty of Medicine, Hacettepe University, 06100 Sihhiye, Ankara, Turkey

Address all correspondence and requests for reprints to: Dr. Bülent O. Yildiz, Emeklisubayevleri 2, C. 23 C Blok 15/3, 06580 Yucetepe, Ankara, Turkey. E-mail: yildizbo{at}yahoo.com.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Polycystic ovary syndrome (PCOS) is associated with hyperinsulinemia, insulin resistance (IR), increased risk of glucose intolerance, and type 2 diabetes. Family studies have indicated a genetic susceptibility to PCOS. The aims of this study were 1) to assess glucose tolerance status, gonadotropins, and androgens in first degree relatives of patients with PCOS; and 2) to assess IR in normal glucose tolerant (NGT) family members. One hundred two family members of 52 patients with PCOS [Mothers_PCOS (n = 34; mean age, 46.5 yr; mean body mass index (BMI), 28.8 kg/m²), Fathers_PCOS (n = 24; mean age, 50.4 yr; mean BMI, 27.5 kg/m²), Sisters_PCOS (n = 19; mean age, 25.1 yr; mean BMI, 22.9 kg/m²), and Brothers_PCOS (n = 25; mean age, 23.7 yr; mean BMI, 22.5 kg/m²)] and 82 unrelated healthy control subjects without a family history of diabetes or PCOS (4 age- and weight-matched subgroups, i.e. Control_MothersPCOS, Control_FathersPCOS, Control_SistersPCOS, and Control_BrothersPCOS) were studied. Glucose and insulin (at baseline and during a 75-g, 2-h oral glucose tolerance test) were measured. IR was assessed by fasting insulin (FI), fasting glucose to insulin ratio (FGI), homeostatic model assessment (HOMA IR), and area under the curve for insulin during the oral glucose tolerance test (AUC_insulin) in NGT Mothers_PCOS, Fathers_PCOS, Sisters_PCOS, Brothers_PCOS, and matched control subgroups. Including the prestudy-diagnosed 3 mothers and 2 fathers with diabetes, diabetes and impaired glucose tolerance (IGT) were noted in 16% and 30% of Mothers_PCOS and 27% and 31% of Fathers_PCOS, respectively. There was no diabetes in Sisters_PCOS and Brothers_PCOS. IGT was found in 5% of Sisters_PCOS. Impaired fasting glucose was found in 3% of Mothers_PCOS and 4% of Brothers_PCOS. The analysis of NGT family members showed that Mothers_PCOS had higher FI (P < 0.05), HOMA IR (P < 0.05), and AUC_insulin (P < 0.01) and lower FGI (P < 0.05) than Control_MothersPCOS, whereas all IR parameters were comparable between Fathers_PCOS and their matched control subgroup. Sisters_PCOS had higher FI (P < 0.05), HOMA IR (P < 0.01), and AUC_insulin (P < 0.05) and lower FGI (P < 0.01), and Brothers_PCOS had higher AUC_insulin (P < 0.01) than their matched control subgroups, respectively. Mothers_PCOS had higher testosterone levels than Control_MothersPCOS (P < 0.01 and P < 0.05 for pre- and postmenopausal women, respectively). Sisters_PCOS had higher LH (P < 0.01), testosterone (P < 0.001), androstenedione (P < 0.01), and dehydroepiandrosterone sulfate (P < 0.05) levels than Control_SistersPCOS. There was no difference in gonadotropin and androgen levels in Fathers_PCOS compared with Control_FathersPCOS or in Brothers_PCOS compared with Control_BrothersPCOS.

Our results suggest that 1) first degree relatives of patients with PCOS may be at high risk for diabetes and glucose intolerance; 2) NGT female family members have insulin resistance; and 3) mothers and sisters of PCOS patients have higher androgen levels than control subjects. We propose that the high risks of these impairments warrant screening in first degree relatives of patients with PCOS.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
POLYCYSTIC OVARY SYNDROME (PCOS) is a common endocrine disorder, affecting approximately 4–8% of reproductive-aged women; it is characterized by hyperandrogenism and chronic anovulation (1, 2, 3, 4). PCOS is associated with an increased risk for metabolic complications, including type 2 diabetes, hypertension, dyslipidemia, and cardiovascular disease (5). Women with PCOS are at substantially higher risk for impaired glucose tolerance (IGT) and type 2 diabetes, with combined prevalence rates of 35–40% for glucose intolerance (6, 7). Insulin resistance (IR) and hyperinsulinemia play important roles in the pathogenesis of PCOS (8). In addition, ß-cell insulin secretory defects are present in women with PCOS (9, 10), which are most evident among a subset of patients who have a first degree relative with type 2 diabetes (9).

Familial aggregation of PCOS consistent with a genetic etiology has been well documented (11). Family studies of PCOS investigated mainly ovarian morphology, menstrual irregularities, and symptoms of hyperandrogenism and hyperandrogenemia (12, 13, 14, 15, 16, 17, 18, 19).

Norman et al. (20), studying the families of five patients with PCOS, reported that increased insulin levels were common among first degree relatives. Colilla et al. (21) noted that there was a heritable component of ß-cell dysfunction in families of women with PCOS. Recently, Legro et al. reported that affected sisters of women with PCOS (who fulfill criteria for the diagnosis of PCOS, and those with hyperandrogenemia) had high insulin levels and low fasting glucose to insulin ratios (22), and the brothers of women with PCOS had increased dehydroepiandrosterone (DHEAS) levels (23).

It is likely that PCOS represents a complex multifactorial trait, inherited similarly to type 2 diabetes. First degree relatives of patients with type 2 diabetes have a high lifetime risk of developing diabetes (24). Although limited, the available evidence raises the hypothesis that first degree relatives of women with PCOS may also have increased risk of glucose intolerance.

The primary aim of the present study was to evaluate glucose tolerance status and gonadotropin and androgen levels in first degree relatives of patients with PCOS. We also aimed to assess IR in normal glucose tolerant (NGT) family members.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

A total of 52 consecutive patients with PCOS were recruited. The diagnosis of PCOS was based on elevated serum total or free testosterone levels and peripubertal onset oligomenorrhea (6 menses/yr) or amenorrhea. Cushing’s syndrome, nonclassical 21-hydroxylase deficiency, hyperprolactinemia, thyroid dysfunction, and androgen-secreting tumors were excluded, according to the recommendations of the NICHHD consensus conference on PCOS (8). Three patients had diabetes, and 2 patients had IGT, as determined by a 2-h, 75-g oral glucose tolerance test (OGTT) (25).

After obtaining permission from patients with PCOS, an attempt was made to contact all first degree relatives. Of the available and living 51 mothers, 52 fathers, 34 sisters, and 45 brothers, 37 mothers (73%), 26 fathers (50%), 19 sisters (56%), and 25 brothers (56%) agreed to participate in the study. Three mothers and 2 fathers had previously diagnosed type 2 diabetes, and a total of 102 first degree relatives [Mothers_PCOS (n = 34), Fathers_PCOS (n = 24), Sisters_PCOS (n = 19), and Brothers_PCOS (n = 25)] were studied. Of the 19 sisters, 1 family had 2 sisters, and of the 25 brothers, 4 families had 2 brothers in the study. Four age- and weight-matched subgroups including unrelated healthy subjects without a family history of diabetes and PCOS were formed to serve as the controls. These control subgroups were defined as Control_MothersPCOS (n = 24), Control_FathersPCOS (n = 12), Control_SistersPCOS (n = 31), and Control_BrothersPCOS (n = 15). The female control subjects had no personal history of PCOS, i.e. regular cycles and normal androgen levels. Eleven (32%) women in the Mothers_PCOS and 8 (33%) women in the Control_MothersPCOS groups were postmenopausal. All women in the Sisters_PCOS and Control_SistersPCOS groups were premenopausal. None of the women in the Control_MothersPCOS and Control_SistersPCOS groups had hirsutism (Ferriman-Gallwey score, <8) (26) or acne on physical examination. All women in the Control_SistersPCOS group and all premenopausal women in the Control_MothersPCOS group had regular menses every 27–35 d.

All medications, including oral contraceptives, known to alter sex hormone metabolism or insulin action and/or kinetics had been discontinued for at least 3 months before enrollment in the study. The Institutional Review Board of Hacettepe University Medical School approved all the studies, and each subject gave informed consent.

Study protocol

One of study investigators (B.O.Y.) evaluated all subjects using standardized forms, which included medical history and physical examination. Weight, height, waist and hip circumferences (waist: midway between the lower rib margin and the iliac crest, hip: widest circumference over the great trochanters) were measured. The body mass index [BMI; weight (kilograms)/height (meters)²] and waist to hip ratio (WHR) were calculated. An OGTT was performed between 0800–1000 h after a 3-d, 300-g carbohydrate diet and an overnight fast of 10–14 h. A 75-g oral glucose load was administered, and blood samples for glucose and insulin determinations were collected through an iv cannula at 0, 30, 60, 90, and 120 min. Additional baseline blood samples were obtained for LH, FSH, testosterone (T), and DHEAS determinations in all subjects and for estradiol (E₂) and androstenedione (A) measurements in female subjects. Blood sampling was performed between d 4 and 7 of the menstrual cycle in all women with regular cycles.

Assay methods

Blood samples were centrifuged immediately, and serum was stored at -20 C until assayed. Plasma glucose was measured by the glucose oxidase technique (Roche Molecular Biochemicals, Mannheim, Germany). Insulin, LH, FSH, E₂, T, A, and DHEAS were measured by RIA using commercially available kits. (ICN Biomedicals, Inc., Costa Mesa, CA). The intra- and interassay coefficients of variation for insulin were 4.2% and 8.4%, respectively; for LH they were 2.4% and 7.3%, respectively; for FSH they were 4.0% and 5.9%, respectively; for E₂ they were 5.5% and 5.5%, respectively; for T they were 9.6% and 11.6%, respectively; for A they were 4.3% and 6.0%, respectively; for DHEAS they were 9.0% and 9.5%, respectively.

Data analysis

Glucose tolerance was assessed by American Diabetes Association criteria (25). First degree relatives without impaired fasting glucose (IFG), IGT, or diabetes were termed NGT. In NGT first degree relatives and in all control subgroups, the insulin area under the curve during the OGTT (AUC_insulin) and fasting glucose to insulin ratio (FGI) were calculated. Homeostatic model assessment (HOMA) (27) is applied by using the formula below:

Statistical analysis

Data analysis was performed using the 9.0 PC package (SPSS, Inc., Chicago, IL). All parameters are shown as the mean ± SD. In families with multiple sisters or brothers, the data for sisters or brothers were averaged to produce one mean value per family. The t test and Mann-Whitney U test were used when appropriate. P < 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The prevalence of any degree of glucose intolerance including the prestudy-diagnosed 3 mothers with type 2 diabetes was 49% (18 of 37) in the Mothers_PCOS group. Diabetes, IGT, and IFG alone were found in 6 of 37 (16%), 11 of 37 (30%), and 1 of 37 (3%) subjects in the Mothers_PCOS group, respectively. One patient with IGT in this group had also IFG. Three newly diagnosed diabetic patients in this group had normal fasting plasma glucose values during the OGTT.

The prevalence of any degree of glucose intolerance including the prestudy-diagnosed 2 fathers with type 2 diabetes was 58% (15 of 26) in the Fathers_PCOS group. Diabetes and IGT were diagnosed in 7 of 26 (27%), and 8 of 26 (31%) subjects in the Fathers_PCOS group, respectively. Of the 5 newly diagnosed diabetic patients, 1 had normal fasting plasma glucose, 2 had IFG, and 2 had fasting plasma glucose levels in diabetic range.

Diabetes was not present in the Sisters_PCOS and Brothers_PCOS groups. IGT was noted in 1 of 19 (5%) subjects in the Sisters_PCOS group, and IFG was diagnosed in 1 of 25 (4%) subjects n the Brothers_PCOS group.

The clinical and hormonal characteristics of Mothers_PCOS and Control_MothersPCOS groups are summarized in Table 1. The data are given for pre- and postmenopausal women separately. Both pre- and postmenopausal women in the Mothers_PCOS group had significantly higher WHR (P < 0.05 for both) and T (P < 0.01 and P < 0.05, respectively) values than the respective control subgroups of Control_MothersPCOS. All other parameters were comparable between the two groups as well as between postmenopausal women in the Mothers_PCOS and postmenopausal women in the Control_MothersPCOS. There was a nonsignificant tendency toward increased LH levels in premenopausal women in the Mothers_PCOS group compared with the respective controls.

The clinical and hormonal characteristics of Fathers_PCOS, Control_FathersPCOS, Brothers_PCOS, and Control_BrothersPCOS groups are summarized in Table 3. The mean anthropometric measurements and all androgen levels were comparable between Fathers_PCOS and Control_FathersPCOS groups as well as between Brothers_PCOS and Control_BrothersPCOS groups. There was a nonsignificant tendency toward increased DHEAS values in the Brothers_PCOS compared with controls.

NGT subjects were compared with controls in a separate analysis (Tables 4 and 5). The NGT Mothers_PCOS group had significantly higher WHR (P < 0.05), fasting insulin (FI; P < 0.05), HOMA IR (P < 0.05), and AUC_insulin (P < 0.01) and lower FGI (P < 0.05) values than the Control_MothersPCOS group. The NGT Sisters_PCOS group had significantly higher WHR (P < 0.01), FI (P < 0.05), HOMA IR (P < 0.01), and AUC_insulin (P < 0.05) and lower FGI (P < 0.01) values than the Control_SistersPCOS group (Table 4).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In the present study the first degree relatives of women with PCOS had an increased prevalence of glucose intolerance and IR. Furthermore, the mothers and sisters of women with PCOS had higher androgen levels compared with the respective control groups. The combined prevalence rates for IGT and diabetes were 46% in the mothers and 58% in the fathers of women with PCOS. These figures were reported as 19.1% and 17% for women and men in similar age groups, respectively, in a population-based study from Turkey (28). Of note, all patients with IGT and 8 of 13 (62%) patients with diabetes were undiagnosed before the study, and of all those with newly diagnosed diabetes, 50% had normal fasting plasma glucose values. These findings emphasize that mothers and fathers of women with PCOS have a high risk of glucose intolerance, and in this group, OGTT should be considered to identify those who have impaired glucose homeostasis.

Age, BMI, WHR, and a first degree relative with glucose intolerance are reported to be the risk factors for glucose intolerance in PCOS, identical to the factors in other populations (29). Of interest, we could not find any difference in the mean age, BMI, WHR, or androgen levels between subjects with NGT and subjects with any degree of glucose intolerance in both the Mothers_PCOS and Fathers_PCOS groups. Therefore, key factors in the development of glucose intolerance in our study population remain to be determined.

Studies evaluating phenotypes in PCOS families demonstrated that hyperandrogenemia is a common finding in female first degree relatives of women with PCOS. Kahsar-Miller et al. (18) reported the rates of PCOS in mothers and sisters of patients with PCOS as 24% and 32%, respectively. The mean T, free T, and DHEAS values in affected first degree relatives were higher than those in controls (18). Legro et al. (19) showed that 22% of reproductive-aged sisters of women with PCOS fulfilled the diagnostic criteria of PCOS, whereas 24% had increased T and DHEAS values with regular menstrual cycles. Our data demonstrated that the mean T value in both pre- and postmenopausal women in the Mothers_PCOS group and the mean values of all androgens measured as well as mean LH value in the Sisters_PCOS group were significantly higher than those in the matched control groups, respectively. The prevalence rates for PCOS in sisters and mothers of patients with PCOS were 16% and 8%, respectively. Our study and those by Kahsar-Miller et al. (18) and Legro et al. (19) showed that female first degree relatives of patients with PCOS in different populations may have increased androgen levels compared with healthy controls. Women with hyperandrogenemia have an increased risk of developing type 2 diabetes, hypertension, and cardiovascular disease. Compelling evidence suggests that androgens are powerful predictors of serious disease (30, 31). In the present study the Mothers_PCOS and Sisters_PCOS groups had significantly higher WHR values than healthy controls. It is also well recognized that the android pattern of fat distribution, characterized by increased WHR, is closely associated with cardiovascular disease and type 2 diabetes (32, 33). All of these data are consistent with the idea that mothers and sisters of women with PCOS may have metabolic derangements that will increase the risk of glucose intolerance and cardiovascular disease.

The mean values of gonadotropins and all androgens measured in our study were similar in Fathers_PCOS and Control_FathersPCOS groups. There has been a paucity of data in the literature regarding the androgen levels of fathers of women with PCOS. Our results are similar to the preliminary study by Norman et al. (20), which noted that the fathers of PCOS patients did not have increased androgen levels. In our study the Brothers_PCOS group had similar gonadotropin and androgen values compared with the Control_BrothersPCOS group. Mean DHEAS appeared to be higher in the Brothers_PCOS group, but the difference was not significant. Legro et al. (23) reported that the brothers of women with PCOS had significantly higher DHEAS levels than controls, whereas T, free T, and SHBG values were similar in the two groups. The Brothers_PCOS group in our study was younger and had lower BMI values than the subjects in that report. The lack of difference in DHEAS levels between the brothers of women with PCOS and controls in our study may also result from type 2 error due to the relatively small sample size and the high variation.

The analyses of NGT family members in our study suggest that NGT mothers and sisters of women with PCOS have IR. The increased AUC_insulin values in brothers of women with PCOS may also indicate IR. We could not find statistically significant differences in the insulin levels between Fathers_PCOS and Brothers_PCOS groups and their respective controls; however, these results might be due to type 2 error, because of the small sample size and the relatively large variation in insulin levels.

Our findings confirm the results of the preliminary study by Norman et al. (20), which suggested that hyperinsulinemia may be an important marker in family members of PCOS patients. IR is central to the pathogenesis of both type 2 diabetes and PCOS, with a strong genetic basis and important implications for the management of both disorders. IR and hyperinsulinemia are common antecedents of IGT and type 2 diabetes (34, 35). NGT first degree relatives of type 2 diabetic families are at increased risk of developing diabetes and have been studied to identify early metabolic abnormalities. IR and insulin secretory dysfunction have been found in these subjects (35). Taken together, these findings suggest that NGT first degree relatives of women with PCOS can be predicted to be at risk for development of glucose intolerance.

PCOS itself has been accepted as a major risk factor for the development of type 2 diabetes (36). Diabetes screening in patients with PCOS is recommended according to the current American Diabetes Association guidelines (36). Although limited, the available evidence suggests that first degree relatives of PCOS patients may also have a high risk of glucose intolerance.

The failure of all family members of the 52 PCOS patients to participate is a limitation of our study. Selection bias due to phenotypic and metabolic differences between those family members who did and did not participate could not be ruled out.

We conclude that the first degree relatives of women with PCOS may form a specific subset of the population with increased prevalence of glucose intolerance and type 2 diabetes. Mothers and sisters of patients with PCOS have higher androgen levels than healthy controls, and NGT family members have insulin resistance. Further large scale, controlled family studies are warranted to delineate the risk of glucose intolerance and other metabolic complications as well as to propose screening and preventive strategies.

	Footnotes

 
This work was supported in part by a grant from the Scientific and Technical Research Council of Turkey.

Abbreviations: A, Androstenedione; AUC, area under the curve; BMI, body mass index; DHEAS, dehydroepiandrosterone; E₂, estradiol; FGI, fasting glucose to insulin ratio; FI, fasting insulin; HOMA, homeostatic model assessment; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; IR, insulin resistance; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; PCOS, polycystic ovary syndrome; T, testosterone; WHR, waist to hip ratio.

Received September 26, 2002.

Accepted February 10, 2003.

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