Clinical, metabolic, and endocrine parameters in response to metformin and lifestyle intervention in women with polycystic ovary syndrome: a randomized, double-blind, and placebo control trial. The impact of metformin, oral contraceptives, and lifestyle modification on polycystic ovary syndrome in obese adolescent women in two randomized, placebo-controlled clinical trials. The effect of combination therapy with metformin and combined oral contraceptives (COC) versus COC alone on insulin sensitivity, hyperandrogenaemia, SHBG and lipids in PCOS patients. Combined lifestyle modification and metformin in obese patients with polycystic ovary syndrome. A randomized, placebo-controlled, double-blind multicentre study. Clinical, metabolic and endocrine parameters in response to metformin in obese women with polycystic ovary syndrome: a randomized, double-blind and placebo-controlled trial. Influence of methyltestosterone postmenopausal therapy on plasma lipids, inflammatory factors, glucose metabolism and visceral fat: a randomized study. A randomized, 48-week, placebo-controlled trial of intensive lifestyle modification and/or metformin therapy in overweight women with polycystic ovary syndrome: a pilot study. Clinical, endocrine and metabolic effects of metformin added to ethinyl estradiol-cyproterone acetate in non-obese women with polycystic ovarian syndrome: a randomized controlled study. Life style changes improve insulin resistance in hyperinsulinaemic subjects: a one-year intervention study of hypertensives and normotensives in Dalby.
The aim of this study was to evaluate the effects of metformin in addition to diet and exercise on endocrine and metabolic disturbances in women with polycystic ovary syndrome (PCOS) in a prospective, double-blind, randomized, placebo (PBO) control trial. Thirty women with insulin resistance and PCOS received lifestyle modification and 1500 mg of metformin or placebo for 4 months. Before and after treatment, body mass index, waist/hip ratio, blood pressure, hirsutism, and menstrual patterns were evaluated. Serum concentrations of gonadotropins, androgens, progesterone, glucose, insulin, and lipids were measured. Lifestyle interventions resulted in similar weight and menstrual cycle's improvements in both groups. A significant reduction in serum fasting insulin, HOMA index, waist and testosterone levels was only observed with metformin. There were no significant changes in androstenedione, dehydroepiandrosterone sulfate, gonadotropins, and lipids levels. No other changes were observed in hirsutism or blood pressure. These findings suggest that metformin has an additive effect to diet and exercise to improve parameters of hyperandrogenism and insulin resistance. Although, a small decrease in body weight trough lifestyle changes could be enough to improve menstrual cycles in insulin-resistant women with PCOS. Polycystic ovary syndrome (PCOS) presents in adolescence, and obesity is a common finding. The benefits and risks of alternate approaches to the management of PCOS in obese adolescent women are not clear.
                We investigated the effects of metformin, oral contraceptives (OCs), and/or lifestyle modification in obese adolescent women with PCOS.
                Two small, randomized, placebo-controlled clinical trials were performed.
                A total of 79 obese adolescent women with PCOS participated.
                In the single treatment trial, subjects were randomized to metformin, placebo, a lifestyle modification program, or OC. In the combined treatment trial, all subjects received lifestyle modification and OC and were randomized to metformin or placebo.
                Serum concentrations of androgens and lipids were measured.
                Lifestyle modification alone resulted in a 59% reduction in free androgen index with a 122% increase in SHBG. OC resulted in a significant decrease in total testosterone (44%) and free androgen index (86%) but also resulted in an increase in C-reactive protein (39.7%) and cholesterol (14%). The combination of lifestyle modification, OC, and metformin resulted in a 55% decrease in total testosterone, as compared to 33% with combined treatment and placebo, a 4% reduction in waist circumference, and a significant increase in HDL (46%).
                In these preliminary trials, both lifestyle modification and OCs significantly reduce androgens and increase SHBG in obese adolescents with PCOS. Metformin, in combination with lifestyle modification and OC, reduces central adiposity, reduces total testosterone, and increases HDL, but does not enhance overall weight reduction. Neither oral contraceptives (COC) nor metformin are an optimal modality for the long-term treatment of polycystic ovary syndrome (PCOS). The aim of this study was to evaluate whether a combination of both is beneficial over COC monotherapy.
                Altogether, 30 women were included in the study and 28 finished the protocol. The patients were randomly assigned to two groups treated with either COC (COC group) or COC and metformin (1500 mg/day) (METOC group) for 6 months. Anthropometric parameters, androgens, lipids, fasting insulin, glucose and sex hormone binding globulin (SHBG) concentrations were measured before and at the end of the sixth cycle of treatment. The insulin sensitivity index was evaluated using the euglycaemic clamp.
                There were no significant changes in anthropometric parameters, fasting glucose or insulin sensitivity in either group. Total testosterone, free androgen index, androstenedione and dehydroepiandrosterone decreased and SHBG increased significantly in both groups. When comparing the effect of both treatments, only a more pronounced decrease in free androgen index was found in the METOC group.
                Adding metformin slightly modified the treatment effect of COC, causing a more significant decrease in the free androgen index but having no additional positive impact on lipids, insulin sensitivity, SHBG or testosterone. The available data do not offer enough evidence to advocate the standard use of combined treatment in PCOS. Whether the combination might be beneficial for specific subgroups of patients is of further interest. It has been reported that women with polycystic ovary syndrome (PCOS) benefit from metformin therapy.
                A randomized, placebo-controlled, double-blind study of obese (body mass index >30 kg/m2), oligo-/amenorrhoeic women with PCOS. Metformin (850 mg) twice daily was compared with placebo over 6 months. All received the same advice from a dietitian. The primary outcome measures were: (i) change in menstrual cycle; (ii) change in arthropometric measurements; and (iii) changes in the endocrine parameters, insulin sensitivity and lipid profile.
                A total of 143 subjects was randomized [metformin (MET) = 69; placebo (PL) = 74]. Both groups showed significant improvements in menstrual frequency [median increase (MET = 1, P < 0.001; PL = 1, P < 0.001)] and weight loss [mean (kg) (MET = 2.84; P < 0.001 and PL = 1.46; P = 0.011)]. However, there were no significant differences between the groups. Logistic regression analysis was used to analyse the independent variables (metformin, percentage of weight loss, initial BMI and age) in order to predict the improvement of menses. Only the percentage weight loss correlated with an improvement in menses (regression coefficient = 0.199, P = 0.047, odds ratio = 1.126, 95% CI 1.001, 1.266). There were no significant changes in insulin sensitivity or lipid profiles in either of the groups. Those who received metformin achieved a significant reduction in waist circumference and free androgen index.
                Metformin does not improve weight loss or menstrual frequency in obese patients with PCOS. Weight loss alone through lifestyle changes improves menstrual frequency. There is still some controversy concerning the effects of metformin in the treatment of Polycystic Ovary Syndrome (PCOS). The aim of this study was to asses the effect of metformin on clinical, metabolic and hormone parameters in obese women with PCOS. Thirty obese, non-diabetic women with PCOS received 500 mg of metformin or placebo, TID, over 90 days. Assessed parameters included body mass index, waist-to-hip ratio, blood pressure, FSH, LH, total testosterone, SHBG, fasting insulinemia, insulin-to-glucose ratio, total, HDL and LDL cholesterol, triglycerides, and menstrual cycles before and after the use of the drugs. Before treatment, patients did not differ in the two groups. After 90 days of metformin use, PCOS women presented significantly lower levels of total testosterone (p = 0.030) and total cholesterol (p = 0.023) compared to the women that used placebo. The other parameters did not differ between the groups. In conclusion, obese women with PCOS may benefit from the use of metformin through the reduction of hyperandrogenemia, total cholesterol, and possibly by restoration of regular menstrual cycles. Further studies with longer follow-ups are necessary to determine cardiovascular and endometrial metformin benefits and insulin-resistance decrease in women with polycystic ovary syndrome. There has been a growing interest in treating postmenopausal women with androgens. However, hyperandrogenemia in females has been associated with increased risk of cardiovascular disease.
                We aimed to assess the effects of androgen replacement on cardiovascular risk factors.
                Thirty-seven postmenopausal women aged 42-62 years that had undergone hysterectomy were prospectively enrolled in a double-blind protocol to receive, for 12 months, percutaneous estradiol (E2) (1 mg/day) combined with either methyltestosterone (MT) (1.25 mg/day) or placebo.
                Along with treatment, we evaluated serum E2, testosterone, sex hormone-binding globulin (SHBG), free androgen index, lipids, fibrinogen, and C-reactive protein; glucose tolerance; insulin resistance; blood pressure; body-mass index; and visceral and subcutaneous abdominal fat mass as assessed by computed tomography.
                A significant reduction in SHBG (P < 0.001) and increase in free testosterone index (P < 0.05; Repeated measures analysis of variance) were seen in the MT group. Total cholesterol, triglycerides, fibrinogen, and systolic and diastolic blood pressure were significantly lowered to a similar extent by both regimens, but high-density lipoprotein cholesterol decreased only in the androgen group. MT-treated women showed a modest rise in body weight and gained visceral fat mass relative to the other group (P < 0.05), but there were no significant detrimental effects on fasting insulin levels and insulin resistance.
                This study suggests that the combination of low-dose oral MT and percutaneous E2, for 1 year, does not result in expressive increase of cardiovascular risk factors. This regimen can be recommended for symptomatic postmenopausal women, although it seems prudent to perform baseline and follow-up lipid profile and assessment of body composition, especially in those at high risk of cardiovascular disease. To obtain data from a pilot randomized trial on the effect of metformin therapy and lifestyle modification on ovulation and androgen concentrations in women with polycystic ovary syndrome (PCOS).
                Prospective, randomized, placebo-controlled pilot trial.
                Academic medical center.
                Thirty-eight overweight or obese women with PCOS.
                All subjects were randomized to one of four 48-week interventions: metformin 850 mg two times per day, lifestyle modification plus metformin 850 mg two times per day, lifestyle modification plus placebo, or placebo alone.
                Recruitment, dropout, and compliance with a long-term lifestyle intervention in PCOS; preliminary estimates of treatment effect on ovulation, as measured by weekly urinary pregnanediol glucuronide, and on total T and free androgen index.
                It was necessary to screen seven women to have one subject randomized. The dropout rate was 39%, with the majority of dropouts occurring within the first 24 weeks. Mean body mass index was >39 mg/kg(2). Modest weight reduction was found in all treatment groups, with the most significant reduction occurring with the combination of metformin and lifestyle intervention. Significant androgen reduction occurred in the combination group only. Ovulation rates did not differ significantly between groups. However, when data were analyzed by presence or absence of weight reduction in subjects, independent of treatment group, the estimated odds ratio for weight loss was 9.0 (95% confidence interval 1.2-64.7) with respect to regular ovulation. If weight loss occurred during metformin therapy, the odds ratio for regular ovulation was 16.2 (95% confidence interval 4.4-60.2).
                Key methodologic issues for a large-scale, randomized trial of lifestyle intervention in PCOS include minimizing early dropout from the lifestyle intervention and including a range of body mass index that is not skewed toward severe obesity. Weight reduction might play the most significant role in restoration of ovulation in obese women with PCOS. Oral contraceptive pills (OC) are usually the first choice of treatment for polycystic ovarian syndrome (PCOS), when fertility is not desired. However, they do not improve, or may even further induce impairment of insulin sensitivity, which is already impaired in women with PCOS. In this prospective, randomized study, we analysed the additional benefits of adding metformin to the OC treatment in non-obese women with PCOS.
                After a baseline work-up including body mass index (BMI), waist:hip ratio (WHR), Ferriman-Gallwey score, ovarian volume, serum gonadotrophin, androgen and sex hormone-binding globulin (SHBG) levels, and fasting lipid, glucose and insulin levels, 40 non-obese women with PCOS were assigned either to the OC or to the OC + metformin treatment by computer-assisted randomization. At the end of the 4 month follow-up period, subjects were re-evaluated.
                The two groups were similar at baseline. After treatment, women in the OC + metformin group had significant decreases in BMI and WHR, and a significant increase in insulin sensitivity, in contrast to those in the OC group, who had insignificant changes in these parameters. Adding metformin also caused significant improvements in serum androstenedione and SHBG levels compared with the OC treatment alone.
                Adding metformin to the OC treatment may improve the insulin sensitivity, and may further suppress the hyperandrogenaemia in non-obese women with PCOS. Insulin resistance and hyperinsulinaemia are, in some prospective studies, linked to an increased cardiovascular risk, at least in men. We tested the hypothesis that hyperinsulinaemia may be reduced by non-pharmacological methods independently of other cardiovascular risk factors.
                In a non-pharmacological intervention study for 1 year three groups of subjects (hypertensives as well as normotensives) were selected after stratification for insulin level at baseline. Half of the hyperinsulinaemic subjects were randomly assigned to active intervention with physical exercise and dietary regulation (HI-A group), the other half were followed passively during the study period (HI-P group). Normo-insulinaemics and hypo(low)-insulinaemics also underwent active intervention (NI-A and LI-A groups, respectively).
                Primary health care in Sweden.
                During the 1-year follow-up subjects in the HI-A group reduced their weight, waist:hip ratio and systolic and diastolic blood pressure, as well as their low:high-density lipoprotein (LDL:HDL)-cholesterol ratio. Glucose levels before and during an oral glucose tolerance test did not change. However, plasma insulin and plasma-C-peptide decreased both in the fasting state and after 1 and 2 h of oral glucose tolerance testing. This decrease was independent of the previously mentioned reduction in weight, waist:hip ratio, blood pressure and LDL:HDL-cholesterol ratio. No reduction in insulin levels was seen in the HI-P, NI-A or LI-A groups, but in the HI-P group there was a slight decrease in fasting plasma-C-peptide levels. In the HI-A group dietary improvements were observed during the study period, with a reduction in energy intake, fat consumption and cholesterol intake. Fibre intake was increased. No major changes were seen in the HI-P group.
                We conclude that in hypertensive and normotensive subjects with hyperinsulinaemia insulin levels can be reduced by active non-pharmacological treatment for 1 year without altering glucose tolerance. This shows that insulin resistance may be lowered by non-pharmacological treatment, which may be of considerable importance, and not only for hypertensives.
Lifestyle intervention improves body composition, hyperandrogenism (high male hormones and clinical effects) and insulin resistance in women with PCOS. There was no evidence of effect for lifestyle intervention on improving glucose tolerance or lipid profiles and no literature assessing clinical reproductive outcomes, quality of life and treatment satisfaction.