Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome

Abdominal obesity and hyperinsulinemia play a key role in the development o f the polycystic ovary syndrome (PCOS). Dietary-induced weight loss and the administration of insulin-lowering drugs, such as metformin, are usually f ollowed by improved hyperandrogenism and related clinical abnormalities. Th is study was carried out to evaluate the effects of combined hypocaloric di et and metformin on body weight, fat distribution, the glucose-insulin syst em, and hormones in a group of 20 obese PCOS women [body mass index (BMI) > 28 kg/m(2)] with the abdominal phenotype (waist to hip ratio >0.80), and a n appropriate control group of 20 obese women who were comparable for age a nd pattern of body fat distribution but without PCOS. At baseline, we measu red sex hormone, sex hormone-binding globulin (SHBG), and leptin blood conc entrations and performed an oral glucose tolerance test and computerized to mography (CT) at the L4-L5 level, to measure sc adipose tissue area (SAT) a nd visceral adipose tissue area. All women were then given a low-calorie di et (1200-1400 kcal/day) alone for one month, after which anthropometric par ameters and CT scan were newly measured. While continuing dietary treatment , PCOS women and obese controls were subsequently placed, in a random order , on metformin (850 mg/os, twice daily) (12 and 8, respectively) or placebo (8 and 12, respectively), according to a double-blind design, for the foll owing 6 months. Blood tests and the CT scan were pel formed in each woman a t the end of the study while they were still on treatment. During the treatment period, 3 women of the control group (all treated with placebo) were excluded because of noncompliance; and 2 PCOS women, both tr eated with metformin, were also excluded because they became pregnant. Ther efore, the women cohort available for final statistical analysis included 1 8 PCOS (10 treated with metformin and 8 with placebo) and 17 control women (8 treated with metformin and 9 with placebo). The treatment was well tolerated. In the PCOS group, metformin therapy impr oved hirsutism and menstrual cycles significantly more than placebo. Baseli ne anthropometric and CT parameters were similar in all groups. Hypocaloric dieting for 1 month similarly reduced BMI values and the waist circumferen ce in both PCOS and control groups, without any significant effect on CT sc an parameters. In both PCOS and control women, however, metformin treatment reduced body weight and BMI significantly more than placebo. Changes in th e waist-to-hip ratio values were similar in PCOS women and controls, regard less of pharmacological treatment. Metformin treatment significantly decrea sed SAT values in both PCOS and control groups, although only in the latter group were SAT changes significantly greater than those observed during th e placebo treatment. On the contrary, visceral adipose tissue area values s ignificantly decreased during metformin treatment in both PCOS and control groups, but only in the former was the effect of metformin treatment signif icantly higher than that of placebo. Fasting insulin significantly decreased in both PCOS women and controls, re gardless of treatment, whereas glucose-stimulated insulin significantly dec reased only in PCOS women and controls treated with metformin. Neither metf ormin or placebo significantly modified the levels of LH, FSH, dehydroepian drosterone sulphate, and progesterone in any group, whereas testosterone co ncentrations decreased only in PCOS women treated with metformin. SHBG conc entrations remained unchanged in all PCOS women; whereas in the control gro up, they significantly increased after both metformin and placebo. Leptin l evels decreased only during metformin treatment in both PCOS and control gr oups. In summary, this study shows that, in PCOS women with abdominal obesity, lo ng-term treatment with metformin added to hypocaloric diet induced, in comp arison with placebo, a greater reduction of body weight and abdominal fat, particularly the visceral depots, and a more consistent decrease of serum i nsulin, testosterone, and leptin concentrations. These changes were associa ted with a more significant improvement of hirsutism and menses abnormaliti es. Moreover, the effects on body weight, insulin, and leptin were similar to those observed in the group of comparable abdominally obese controls, in whom, however, a more pronounced reduction of se fat in the abdominal regi on and an increase of SHBG concentrations were found. These findings, there fore, indicate that hyperinsulinemia and abdominal obesity may have complem entary effects in the pathogenesis of PCOS.