Metabolic Syndrome in Brothers of PCOS Women

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Polycystic ovary syndrome (PCOS), defined by hyperandrogenism, chronic anovulation, and/or polycystic ovary disease is one of the most common endocrinopathies in young women and evidence supports a central role of insulin resistance in the pathophysiology. Although previous studies have found high incidences of familial clustering of PCOS, suggesting that it might be a genetic disease, the lack of a male phenotype has made it difficult to assess the genetic component of this disorder. To date no study has looked at the gold standard of euglycemic-hyperinsulinemic clamp methodology in brothers of PCOS women. Baillargeon and Carpentier studied 17 brothers of women with PCOS and 28 male controls. The male controls selected were of comparable age and BMI as the brothers, and had no first-degree relatives with PCOS. Participants in the study were between 18 to 40 years of age with BMIs between 19-40 kg/m2. The study protocol included anthropometric measurements of waist circumference and fasting blood samples for steroid levels. A standard OGTT was performed 2 days prior to a standard euglycemic-hyperinsulinemic clamp. In a subgroup of participants rates of oxygen consumption were measured during a 40-minute baseline period and during the last 40 minutes of the clamp to determine total body carbohydrate oxidation using indirect calorimetry. Assays obtained included total testosterone, androstenedione, DHEAS, 17 α-hydroxyprogesterone, sex-hormone binding globulin (SHBG), free testosterone, estrogen, progesterone, FSH, LH, thyrotropin, insulin, TSH, and prolactin. In addition C-reactive protein, total cholesterol, triacylglycerol, and HDL cholesterol were measured and LDL cholesterol was calculated. Fibrinogen, plasminogen activator inhibitor (PAI)-1 and factor VIII levels were also measured. For each variable the difference between the groups was adjusted for age and BMI using multiple linear regression analysis.

Age, BMI, waist circumference, and total fat percentage were comparable between the 2 groups as were systolic and diastolic blood pressure. Free testosterone levels, androstenedione, and DHEAS were similar in both groups. Fasting triacylglycerol levels were significantly increased in the brothers, but HDL and LDL cholesterol were comparable. PAI-1 and factor VIII were significantly increased in the brothers as was fasting glucose, 2-hour glucose levels and area under the glucose curve. Those with metabolic syndrome, as defined by the US National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP) III, were 18% in the brothers and 7% in the controls. This difference was not statistically significant. Insulin sensitivity was significantly decreased by 38% in the brothers and insulin stimulated total body carbohydrate oxidation was decreased by 65% in the brothers. After adjustment for age and BMI, the factor VIII levels, 2-hour glucose, as well as AUCglucose and AUCinsulin during the OGTT were still significantly different between the 2 groups, but the differences in triacylglycerol, PAI-1, and fasting glucose were no longer significant. Those individuals with

BMI >26.5 kg/m2 had significantly increased PAI-1 and AUCinsulin and significantly decreased androstenedione and sex hormone binding globulin.
The authors concluded that the brothers of women with PCOS have a significant decrease in insulin sensitivity associated with decreased glucose tolerance and hypercoagulability as evidenced by increased PAI-1 and factor VIII levels. Additionally, insulin stimulated glucose disposal was decreased by 65%. Thus brothers of women with PCOS displayed insulin resistance, glucose intolerance, and many of the characteristics of insulin resistance syndrome. A unique finding of the study was that glucose intolerance in the brothers of women with PCOS is irrespective of their degree of obesity. The authors noted that the limitations of their studies included a somewhat limited recruitment of all brothers since it was not possible to recruit all members of the affected and non-affected families. However, they concluded that their data suggest that brothers of PCOS women may have inherited insulin resistance and metabolic syndrome typical of PCOS and that these young men deserve careful clinical evaluation and long-term follow-up.

Baillargeon JP, Carpentier AC. Brothers of women with polycystic ovary syndrome are characterized by impaired glucose tolerance, reduced insulin sensitivity and related metabolic defects. Diabetologia. 2007;50:2424-32.

Editor’s Comment

Over the past several years pediatric endocrinologists have been evaluating an increasing number of adolescents with PCOS. It is not uncommon for these teenagers to be accompanied by mothers and sisters who also have obvious signs suggestive of PCOS. It is uncommon, at least in this editor’s experience, for brothers of these teenagers to accompany them to the clinic visit. Thus, there is a potentially large group of teenagers and young adults with significant metabolic abnormalities who are not being evaluated and counseled. With the growing epidemic of obesity one is hesitant to suggest that pediatric endocrinologists actively recruit additional overweight adolescents to their clinics. However, the information presented above by Baillargeon and Carpentier suggests that to exclude the discussion of brothers’ health status during the evaluation of girls with PCOS may be a significant omission. It would be of interest to obtain additional clinical information on brothers of adolescents with PCOS. This would appear to be an area for further clinical research.

William A. Clarke, MD

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Last Updated: 04/30/2008