Brothers of women with polycystic ovary syndrome: a group with high risk for type 2 diabetes mellitus and cardiovascular diseases studied in Egyptian population.
I Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder affecting 5-10% of reproductive -aged women (1-2), characterized by hyperandrogenism, chronic anovulation, polycystic ovaries along with abdominal obesity and insulin resistance as frequent metabolic traits which in association with other features of the metabolic syndrome can lead to increased risk for type 2 diabetes and cardiovascular disease (CVD). (3-7)
Hyperandrogenemia, insulin resistance and dyslipidemia demonstrate a familial aggregation in the female first degree relatives of women with PCOS, suggesting a genetic basis of the syndrome. However, the exact pattern of inheritance has not yet been determined. (8-10) In addition, a previous study identified one PCOS susceptibility allele in fibrillin-3 gene that is linked to and associated with hyperandrogenemia and markers of insulin resistance in PCOS women. (11)
Male metabolic phenotype in PCOS families is not well defined, while hyperandrogenemia appears to be the male reproductive phenotype. (12) It has been suggested that hyperandrogenemia plays a direct role in the development of associated metabolic abnormalities in female relatives of PCOS women (9,13); these data together with familial clustering of PCOS suggest that male relatives of PCOS women may develop similar metabolic defects and hence may be at increased risk of CVD. The aim of the present study was to assess insulin sensitivity and metabolic parameters in brothers of Egyptian women with PCOS.
SUBJECTS AND METHODS
In total 30 brothers of women with PCOS and 20 male control subjects were recruited in the study. The eligible for the study women were treated at the Outpatient Clinic of Diabetes and Endocrinology and Fertility unit of Mansoura University. The diagnosis of PCOS was made according to Rotterdam Revised Criteria (2004) (14) including oligo and/or anovulation, clinical and/or biochemical hyperandrogenemia and polycystic ovaries by ultrasound with exclusion of patients with hyperprolactinemia, congenital adrenal hyperplasia, known androgen secreting neoplasm, and thyroid disease. The control subjects were healthy men with age and BMI matching to the study group, with no first degree family history of PCOS or diabetes, and without personal history of hypertension. None of the participants was diabetic or had used insulin sensitizing or lipid lowering drugs or any medication known to affect sex hormone metabolism.
All participants were subjected to complete medical and familial history. Weight and height of the subjects were measured while wearing light clothing and no shoes. BMI was calculated as weight (kg) divided by squared height (meter). Waist circumference was measured at the narrowest level between the costal margin and the iliac crest at the end of a normal expiration. Blood pressure was recorded following a 5 minutes rest period in the sitting position.
Blood samples were obtained after overnight fast from all subjects. Fasting plasma glucose levels were determined by enzymatic method. Fasting serum insulin was measured by enzyme immunoassay using MEDGENIX-INS-EASIA kit. (15) The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated according to the formula: fasting glucose (mmol/L) x fasting insulin ([micro]U/ml)/22.5. (16)
Total cholesterol and triglycerides were measured by enzymatic colorimetric tests (Human-Germany). (17) HDL-C was determined by precipitation method (Human-Germany), then LDL-C was calculated by Friedewald equation. (18) C-reactive protein (CRP) was measured by immunoprecipitation assay (Diagnostica Turbox, CRP). (19) Plasminogen activator inhibitor-1 (PAI-1) was measured by ELISA. (20)
Serum testosterone and dehydroepiandrosterone sulfate (DHEA-SO4) were measured by solid phase competitive chemiluminescent enzyme immunoassay, while sex hormone binding globulin (SHBG) was measured by sandwich chemiluminescent enzyme immunoassay (IMMULITE/ IMMULITE 1000 analyzer, SIEMENS Medical Solutions
Diagnostics, Los Angeles, CA, 90045-6900 USA). Free testosterone was measured by direct quantitative determination by enzyme immunoassay (Direct ELISA kit, Diagnostic Biochem Canada Inc).
Statistical analysis was done using SPSS program version 10. To compare between groups, student t-test and Chi-square test were used. Correlation co-efficiency test was used to test for association between variables. P value was considered significant if less than 0.05.
PCOS brothers and control subjects were similar in terms of age and BMI, with no significant differences between the two groups as regards waist to hip ratio or systolic and diastolic blood pressure (Table 1).
Compared with control subjects, brothers had statistically significant higher fasting insulin (10.7+3.54 vs 7.9+2.74, P=0.004), higher HOMA-IR (2.35+1.079 vs 1.77+0.79, P=0.043), higher total cholesterol (186.9+23 vs 165.7+18, P=0.001), higher triglycerides (125.4+35 vs 106.9+27.15, P=0.048), higher LDL-C (112.4+25 vs 92+18, P=0.002) and lower HDL-C (45.6+5.9 vs 49.3+6.2, P=0.03) (Table 2).
PAI-1 and CRP levels were significantly higher in brothers compared to control group (41+12 vs 31.2+6.98, P=0.002 & 2.9+1.07 vs 2.31+0.86, P=0.046 respectively). DHEAS levels were significantly higher in brothers of PCOS women than in control subjects (3063.7+732.9 vs 2599.6+609.1, P=0.023), no significant differences were found between both groups as regard total testosterone, free testosterone, or SHBG levels (Table 3).
Correlation analysis of HOMA-IR in brothers showed positive correlation with BMI (r=0.63, P<0.001), WHR (r=0.68, P<0.001), PAI-1 (r=0.62, P<0.001), CRP (r=0.52, P<0.01), TG (r=0.72, P<0.001) and LDL-C (r=0.43, P=0.02), and negative correlation with HDL-C (r=-0.44, P=0.019) (Table 4).
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders found in humans. The syndrome presents with a wide range of symptoms and longterm health consequences. These include infertility, menstrual disturbances, enlarged cystic ovaries, hirsutism, acne, hormonal imbalance. (21)
Two of the major health consequences of women with PCOS include an increased prevalence of type 2 diabetes mellitus and cardiovascular diseases (CVD). CVD is a major lethal factor, particularly in men and type 2 DM occurs in 4% of men and the risk of death from CVD is thought to rise between 2.5-8 fold in diabetic population. In addition to an impact on mortality, the economic burden of CVD and type 2 DM is substantial. (22)
Any measures to identify at risk populations where appropriate interventions can be applied early to reduce the health and economic burden of CVD and type 2 DM are clearly a priority. Given the familial clustering of PCOS, their brothers would be an ideal group that could be targeted. More importantly, this would be at a young age, as women with PCOS usually present early in their reproductive life. The aim of our study was to focus on the risk of metabolic disorders (CVD and type 2 DM) specifically in brothers of women with PCOS, studying Egyptian participants.
Dyslipidemia (an accepted risk factor for CVD) may be the most common metabolic abnormality in PCOS. Therefore, the first degree relatives of PCOS subjects should be examined for dyslipidemia and treated with hypolipidemic treatment. In our study we found that brothers of women with PCOS have dyslipidemia, there were significant increase in total and LDL-cholesterol levels and in triglycerides levels and significant decrease in HDL-cholesterol compared to control group's men. There were significant positive correlations between HOMA-IR and LDL, TC and TG but significant negative correlation with HDL-C in brothers of women with PCOS. Our above findings were similar to those reported in women with PCOS and are in consistent with the findings of Sam et al. ( 2006)9 who support the hypothesis that some metabolic features of PCOS are heritable and are not sex specific.
Insulin resistance is central to the pathogenesis of type 2 DM and PCOS with strong genetic basis and important implications for the management of both disorders. In our study brothers of women with PCOS showed insulin resistance, hypercoagulability and inflammation as represented by higher fasting insulin, HOMA-IR, PAI-1 and CRP than control, and similar results have recently been reported by Baillargeon and Carpentier in American populations. (23) Also we found significant correlations of HOMA-IR with lipid abnormalities, PAI-1 and CRP. These findings confirm the results of previous studies which suggested that hyperinsulinemia and insulin resistance may be an important marker in family members of PCOS patients. (24,25)
PCOS itself has been accepted as a major risk factor for the development of type 2 DM. DM screening in patients with PCOS is recommended by current American Diabetes Association Guidelines. (26) Taken together, these findings suggest that normal glucose tolerance first degree relatives of women with PCOS can be predicted to be at risk for developing glucose intolerance. Similarly, the family history of heart disease is consistent with those studies which demonstrated several risk factors for heart disease in PCOS women such as obesity, insulin resistance, hyperlipidemia, and raised PAI-1. (5)
Whether insulin resistance in brothers of women with PCOS is genetic, programmed in utero or environmental is unclear. Xita and Tsatsoulis (27), reported a high prevalence of risk factors for cardiovascular disease in brothers but not in fathers of women with PCOS and this is in consistent with the fetal programming hypothesis. The in utero maternal environment from poor nutrition or androgen excess may program children of mothers with PCOS to develop the condition. It is also thought that these factors may interact with common polymorphic variants of genes determining androgen activity or genes that influence the availability of androgen to target tissues in PCOS. (28,29)
Our results suggest that there is a male biochemical reproductive phenotype in PCOS families. Circulating levels of the adrenal androgen DHEAS were significantly increased in brothers of PCOS women compared with control men. There were no other significant changes in reproductive hormone levels in the brothers of PCOS women, which may reflect a genetic defect in steroidogenesis. (30) We did not find elevated testosterone levels in brothers of PCOS women. This might be because testosterone may feedback on the hypothalamic-pituitary axis to modulate its own secretion in women or because the substantially greater male testosterone production rates makes it difficult to discern subtle changes in circulating levels. (31)
In summary, brothers of women with PCOS have a metabolic phenotype consisting of dyslipidemia, insulin resistance, dyscoagulability and low grade inflammation and these results support the finding that, similar to PCOS patients, their first degree relatives also carry an increased risk of CVD and type 2 DM. Given the high prevalence of PCOS, male first degree relatives may represent an important new risk factor for CVD in men and should be considered a well identified group for primary preventive measures. From a point of view that is necessarily adopted by epidemiological studies, our outcomes in Egyptian populations seem to share the picture reported in different parts of the world. In a later phase of our research, we may need to highlight the key differences between the hormone profiles reported in the different continents.
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Fayez El-Kenawy (1), Hala Abd El-Hafez (1), Afaf Abd El-Hafez (1) Mohamed Ghoneim (1), Mohamed Atwa (2)
Departments of Internal Medicine (1) and Clinical Pathology (2) Mansoura University, Egypt
Corresponding author: Dr-Afaf abdel-Hafez Specialized Medical Hospital, Dept of Internal Medicine, Mansoura University, 60 El Gomhoria Street, Mansoura Zipcode 35516, Egypt
Table 1. Clinical data of PCOS brothers and control group. Brothers Control t P (n=30) (n=20) Age 28.4 [+ or -] 6.9 29.9 [+ or -] 7.9 0.728 0.47 BMI 27.7 [+ or -] 5.27 26.08 [+ or -] 5.23 1.115 0.27 WHR 92 [+ or -] 0.044 0.91 [+ or -] 0.042 0.763 0.44 SBP 123.8 [+ or -] 13 120 [+ or -] 9 1.066 0.29 DBP 78 [+ or -] 7.5 75 [+ or -] 8 1.41 0.16 Table 2. Insulin resistance and lipid profile in PCOS brothers and control group. Brothers Control (n=30) (n=20) F. insulin [micro] U/ml 10.7 [+ or -] 3.54 7.9 [+ or -] 2.74 HOMA-IR 2.35 [+ or -] 1.079 1.77 [+ or -] 0.79 T.cholesterol mg/dl 186.9 [+ or -] 23 165.7 [+ or -] 18 LDL-C mg/dl 112.4 [+ or -] 25 92 [+ or -] 18 HDL-C mg/dl 45.6 [+ or -] 5.9 49.3 [+ or -] 6.2 TG mg/dl 125.4 [+ or -] 35 106.9 [+ or -] 27.15 t P F. insulin [micro] U/ml 3.01 0.004 HOMA-IR 2.07 0.043 T.cholesterol mg/dl 3.54 0.001 LDL-C mg/dl 3.2 0.002 HDL-C mg/dl -2.13 0.03 TG mg/dl 2.02 0.048 Table 3. PAI-1, CRP and androgens in PCOS brothers and control group. Brothers Control (n=30) (n=20) PAI-1 ng/ml 41 [+ or -] 12 31.2 [+ or -] 6.98 CRP mg/l 2.9 [+ or -] 1.07 2.31 [+ or -] 0.86 Total T. ng/dl 526.8 [+ or -] 13.4 513.8 [+ or -] 124.8 Free T. ng/dl 243.1 [+ or -] 88.4 228.87 [+ or -] 77.44 SHGB nmol/L 23.25 [+ or -] 9.67 27.43 [+ or -] 9.05 DHEA ng/ml 3063.7 [+ or -] 732.9 2599.6 [+ or -] 609 t P PAI-1 ng/ml 3.303 0.002 CRP mg/l 2.04 0.046 Total T. ng/dl 0.351 0.72 Free T. ng/dl 0.584 0.562 SHGB nmol/L -1.535 0.131 DHEA ng/ml 2.341 0.023 Table 4. Correlation of HOMA-IR with some clinical and biochemical parameters in brothers of PCOS women. r P WHR 0.68 <0.001 BMI 0.63 <0.001 PAI-1 0.62 <0.001 CRP 0.52 <0.01 TG 0.72 <0.001 HDL-C -0.44 0.019 LDL-C 0.43 0.02
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|Title Annotation:||ORIGINAL ARTICLE|
|Author:||El-Kenawy, Fayez; El-Hafez, Hala Abd; El-Hafez, Afaf Abd; Ghoneim, Mohamed; Atwa, Mohamed|
|Publication:||Archives: The International Journal of Medicine|
|Date:||Jan 1, 2009|
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