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Effects of metformin in adolescents with polycystic ovary syndrome undertaking lifestyle therapy: a pilot randomized double-blind study

2011; Elsevier BV; Volume: 95; Issue: 8 Linguagem: Inglês

10.1016/j.fertnstert.2011.05.048

ISSN

1556-5653

Autores

Gwinnett Ladson, William C. Dodson, Stephanie Sweet, Anthony E. Archibong, Allen R. Kunselman, Laurence M. Demers, Peter A. Lee, Nancy I. Williams, PonJola Coney, Richard S. Legro,

Tópico(s)

Growth Hormone and Insulin-like Growth Factors

Resumo

Our small study does not support the addition of metformin to the lifestyle of adolescents. Although there are favorable trends toward hyperandrogenism with metformin, these must be balanced against the increased rate of gastrointestinal side effects. However, other treatments were associated with an improved quality of life. Our small study does not support the addition of metformin to the lifestyle of adolescents. Although there are favorable trends toward hyperandrogenism with metformin, these must be balanced against the increased rate of gastrointestinal side effects. However, other treatments were associated with an improved quality of life. Adolescents with polycystic ovary syndrome (PCOS) are difficult to manage clinically because of the lack of well-designed studies showing treatment safety and efficacy. In addition, this is a vulnerable population, so studies must be balanced to withstand increased scrutiny. Adolescents may be less compliant with recommended therapies because of immaturity. However, this population represents an enormous opportunity to intervene early in the ontogeny of PCOS, especially when linked to obesity. Randomized studies of metformin in girls with premature pubarche show delays in pubertal development and a relative protection against developing PCOS post menarche (1Ibanez L. Valls C. Ong K. Dunger D.B. de Zegher F. Metformin therapy during puberty delays menarche, prolongs pubertal growth, and augments adult height: a randomized study in low-birth-weight girls with early-normal onset of puberty.J Clin Endocrinol Metab. 2006; 91: 2068-2073Crossref PubMed Scopus (98) Google Scholar, 2Ibanez L. Valls C. Marcos M.V. Ong K. Dunger D.B. De Zegher F. Insulin sensitization for girls with precocious pubarche and with risk for polycystic ovary syndrome: effects of prepubertal initiation and postpubertal discontinuation of metformin treatment.J Clin Endocrinol Metab. 2004; 89: 4331-4337Crossref PubMed Scopus (102) Google Scholar). Treatments such as metformin have been studied extensively in adolescents with type 2 diabetes and found to have a safe risk–benefit ratio (3Jones K.L. Arslanian S. Peterokova V.A. Park J.S. Tomlinson M.J. Effect of metformin in pediatric patients with type 2 diabetes: a randomized controlled trial.Diabetes Care. 2002; 25: 89-94Crossref PubMed Scopus (319) Google Scholar). There are fewer data in adolescents with PCOS. Lifestyle therapy in obese women with PCOS has become, at least according to expert opinion, a cornerstone (4Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop GroupConsensus on infertility treatment related to polycystic ovary syndrome.Fertil Steril. 2008; 89: 505-522Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar, 5Moran L.J. Pasquali R. Teede H.J. Hoeger K.M. Norman R.J. Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society.Fertil Steril. 2009; 92: 1966-1982Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar). In addition, the addition of metformin has been associated with increased weight loss when combined with lifestyle interventions (6Nieuwenhuis-Ruifrok A.E. Kuchenbecker W.K. Hoek A. Middleton P. Norman R.J. Insulin sensitizing drugs for weight loss in women of reproductive age who are overweight or obese: systematic review and meta-analysis.Hum Reprod Update. 2009; 15: 57-68Crossref PubMed Scopus (89) Google Scholar). We sought to establish the risk–benefit ratio of lifestyle therapy combined with and without metformin therapy over 6 months in obese adolescent females with PCOS and designed a trial very similar to our recent trial in adults (7Ladson G. Dodson W.C. Sweet S.D. Archibong A.E. Kunselman A.R. Demers L.M. et al.The effects of metformin with lifestyle therapy in polycystic ovary syndrome: a randomized double-blind study.Fertil Steril. 2011; 95 (e1–7): 1059-1066Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). We hypothesized that the combination of lifestyle and metformin would be superior to lifestyle alone in improving serum testosterone levels, an important biomarker of PCOS. The IRBs of the Meharry Medical College and Penn State College of Medicine approved the study. Subjects aged 13–18 years and with a BMI >27 kg/m2 were enrolled between 2004 and 2008 and all gave written informed consent. We used the 1990 NIH/NICHD PCOS diagnostic criteria to identify subjects (8Zawadski J.K. Dunaif A. Diagnostic criteria for polycystic ovary syndrome; towards a rational approach.in: Dunaif A. Givens J.R. Haseltine F.P. Merriam G.R. Polycystic ovary syndrome. Blackwell Scientific, Boston1992: 377-384Google Scholar): chronic anovulation, defined as spontaneous intermenstrual periods of ≥45 days or a total of ≤8 menses per year, and hyperandrogenism defined as an elevated total testosterone (>50 ng/dL) or a free androgen index (FAI = ratio of testosterone/sex hormone–binding globulin (SHBG) (100)) >1.5 (9Katcher H.I. Kunselman A.R. Dmitrovic R. Demers L.M. Gnatuk C.L. Kris-Etherton P.M. et al.Comparison of hormonal and metabolic markers after a high-fat, Western meal versus a low-fat, high-fiber meal in women with polycystic ovary syndrome.Fertil Steril. 2009; 91: 1175-1182Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar). Other causes were excluded by appropriate tests. Subjects were in good general health and off confounding medications. The a priori primary outcome was the change in serum testosterone level. The study was powered to detect a 25% absolute difference in serum testosterone levels using a two-sided test having a type I error of 5% with at least 80% power and assumed projected subject dropout rate of 15%. On the basis of a log-normal distribution and a 30% coefficient of variation, 50 subjects per treatment arm were required. Subjects were randomized for this double-blind study in a 1:1 allocation ratio using a computer-generated random number table with permuted blocks and stratified by center and prior metformin exposure status after a baseline visit. All subjects received the lifestyle intervention (and described in more detail in the Supplemental Materials and Methods, available online) (7Ladson G. Dodson W.C. Sweet S.D. Archibong A.E. Kunselman A.R. Demers L.M. et al.The effects of metformin with lifestyle therapy in polycystic ovary syndrome: a randomized double-blind study.Fertil Steril. 2011; 95 (e1–7): 1059-1066Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). A combined intervention of diet and exercise was employed with the goal of achieving an average weight loss of at least 7% from initial body weight over 6 months, with a prescription of 150 minutes/week of exercise combined with a low-calorie diet (10Knowler W.C. Barrett-Connor E. Fowler S.E. Hamman R.F. Lachin J.M. Walker E.A. et al.Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.N Engl J Med. 2002; 346: 393-403Crossref PubMed Scopus (7121) Google Scholar). The exercise program consisted of supervised and nonsupervised components (without polar heart rate monitoring in adolescents) to maximize flexibility and acceptance of the intervention (7Ladson G. Dodson W.C. Sweet S.D. Archibong A.E. Kunselman A.R. Demers L.M. et al.The effects of metformin with lifestyle therapy in polycystic ovary syndrome: a randomized double-blind study.Fertil Steril. 2011; 95 (e1–7): 1059-1066Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). Subjects were given the opportunity to attend a fitness facility operated by the research team at least 2 sessions per week. Metformin hydrochloride was obtained as a powder (Spectrum Chemical Manufacturing), formulated with a 500-mg dose of drug per capsule with identical placebo capsules by the Investigational Pharmacies in a double-blind fashion (7Ladson G. Dodson W.C. Sweet S.D. Archibong A.E. Kunselman A.R. Demers L.M. et al.The effects of metformin with lifestyle therapy in polycystic ovary syndrome: a randomized double-blind study.Fertil Steril. 2011; 95 (e1–7): 1059-1066Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 11Hoeger K.M. Kochman L. Wixom N. Craig K. Miller R.K. Guzick D.S. 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.Fertil Steril. 2004; 82: 421-429Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). Medication was initiated in a step-up fashion every 5 days, from one tablet a day to four. This dose was maintained as tolerated throughout the remainder of the study. The patients were seen monthly and underwent submaximal exercise testing on a stationary bicycle. Hirsutism was assessed using the modified Ferriman-Galwey score (12Hatch R. Rosenfield R.L. Kim M.H. Tredway D. Hirsutism: implications, etiology, and management.Am J Obstet Gynecol. 1981; 140: 815-830Abstract Full Text PDF PubMed Google Scholar). Facial lesions counts of open and closed comedones (noninflammatory lesions) were obtained from the forehead, left, and right cheeks, nose, and chin (13Thiboutot D. Zaenglein A. Weiss J. Webster G. Calvarese B. Chen D. An aqueous gel fixed combination of clindamycin phosphate 1.2% and benzoyl peroxide 2.5% for the once-daily treatment of moderate to severe acne vulgaris: assessment of efficacy and safety in 2813 patients.J Am Acad Dermatol. 2008; 59: 792-800Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). Serum was obtained for hormone measurements. Testosterone was measured by RIA (14Legro R.S. Chiu P. Kunselman A.R. Bentley C.M. Dodson W.C. Dunaif A. Polycystic ovaries are common in women with hyperandrogenic chronic anovulation but do not predict metabolic or reproductive phenotype.J Clin Endocrinol Metab. 2005; 90: 2571-2579Crossref PubMed Scopus (53) Google Scholar) and SHBG was determined by chemiluminescence using a Siemens Immulite platform. In addition, at baseline and study completion after 6 months, subjects completed a quality-of-life survey, a 75-g oral glucose tolerance test, a transabdominal ovarian ultrasound, and a dual-energy x-ray absorptiometry (DXA) scan using a total-body scan and dual hip scans with the fan-beam mode of a Hologic QDR-4500W (Hologic Inc.). Subregion analysis of visceral and central abdominal fat was modeled (15Carey D.G. Jenkins A.B. Campbell L.V. Freund J. Chisholm D.J. Abdominal fat and insulin resistance in normal and overweight women: direct measurements reveal a strong relationship in subjects at both low and high risk of NIDDM.Diabetes. 1996; 45: 633-638Crossref PubMed Google Scholar). The validated PCOS Questionnaire, measuring health-related quality of life in women with PCOS, includes five domains (16Cronin L. Guyatt G. Griffith L. Wong E. Azziz R. Futterweit W. et al.Development of a health-related quality-of-life questionnaire (PCOSQ) for women with polycystic ovary syndrome (PCOS).J Clin Endocrinol Metab. 1998; 83: 1976-1987Crossref PubMed Scopus (95) Google Scholar). Each domain score is graded on a scale of 1 (poorest function) to 7 (optimal). Linear mixed-effects models were fit to continuous outcomes to compare metformin to placebo with respect to the change from baseline measurement (17Field A.E. Coakley E.H. Must A. Spadano J.L. Laird N. Dietz W.H. et al.Impact of overweight on the risk of developing common chronic diseases during a 10-year period.Arch Int Med. 2001; 161: 1581-1586Crossref PubMed Google Scholar). The number of bleeding episodes and the adverse event rates were compared between the two treatment arms using Poisson regression models. All analyses followed the intention-to-treat principle and we reported mean ± SD. No adjustments for multiple hypothesis testing were performed because all outcomes, other than the primary, were considered to be exploratory. All hypothesis tests were two-sided and all analyses performed using SAS software (version 9.1, SAS Institute Inc.). We screened 28 patients and randomized 22 (20 Caucasian and 2 African American) (Supplemental Fig. 1). The two treatment groups were similar at baseline for all parameters. Mean age for MET was 16.1 ± 1.5 years versus 15.4 ± 1.2 years for PBO, mean BMI was 37.1 ± 5.8 for MET versus 35.9 ± 6.6 for PBO (Supplemental Table 1). On ultrasonographic exam, all subjects in the MET group had polycystic ovaries by consensus criteria (18Balen A.H. Laven J.S. Tan S.L. Dewailly D. Ultrasound assessment of the polycystic ovary: international consensus definitions.Hum Reprod Update. 2003; 9: 505-514Crossref PubMed Scopus (749) Google Scholar) and 9 subjects in the PBO group (2 girls in PBO did not have ultrasound visualization of their ovaries). Thus, all girls who were fully phenotyped met all of the Rotterdam criteria for PCOS. Only four subjects dropped out of the study (1 for MET and 3 for PBO). The addition of metformin to lifestyle resulted in a significant decrease in serum testosterone and FAI at 3 months compared with baseline and lifestyle alone, and at 6 months compared with baseline (Fig. 1A and B). Further, there was a significant reduction in acne, a marker of hyperandrogenism, at every visit compared with baseline in the MET group (Fig. 1C), and no significant change in weight (Fig. 1D). Moreover, there were no changes in waist measurement, blood pressure, hirsutism scores, lipid parameters, VO2max, or in ovarian volume or maximum follicle size during the study (Supplemental Table 2). There was no difference in the number of menstrual bleeding episodes in the MET group compared with the PBO group (rate ratio [RR] = 1.7, 95% CI = 0.7, 3.9, P=.22). There were significantly more adverse events in the MET group compared with the PBO group for stomach or abdominal pain (RR = 3.6, 95% CI = 1.0, 12.8, P=.05) and diarrhea (RR = 4.5, 95% CI = 1.5, 13.2, P=.01). There were no serious adverse events in either group. Our trial in adolescents showed no benefit of MET over PBO on our primary outcome of serum testosterone levels at 6 months (though it did at 3 months); however, we did note improvements in acne, a peripheral marker of hyperandrogenism at various time points in both groups. In comparison with our larger study in adults (7Ladson G. Dodson W.C. Sweet S.D. Archibong A.E. Kunselman A.R. Demers L.M. et al.The effects of metformin with lifestyle therapy in polycystic ovary syndrome: a randomized double-blind study.Fertil Steril. 2011; 95 (e1–7): 1059-1066Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar), this study had a much higher retention rate, although the sample size was small (82% retention in adolescents and 33% retention in adults). This higher retention rate could be due to support of the parents, our relative lack of minority participation (compared with our adult study), or the more streamlined protocol in adolescents with less monitoring of diet and exercise and lack of daily urine collections. Also, the favorable improvements in overall quality of life (compared with baseline) in both treatment groups, may have supported further participation in the study (19Harris-Glocker M. Davidson K. Kochman L. Guzick D. Hoeger K. Improvement in quality-of-life questionnaire measures in obese adolescent females with polycystic ovary syndrome treated with lifestyle changes and oral contraceptives, with or without metformin.Fertil Steril. 2010; 93: 1016-1019Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar). Our data suggest that the benefits of our interventions waned from 3 to 6 months, and the diminished compliance with our lifestyle recommendations was probably a factor as we noted no improvement in VO2max in either group. We failed to recruit our projected sample size, so our findings are somewhat surprising given our limited sample size. The primary barrier to recruitment was the number of subjects interested in the study, as patients who consented to screening were likely to participate in the study. There are few studies of combined lifestyle and insulin-sensitizing therapy in adolescents with PCOS. Our findings are consistent with the largest and most similar study performed in adolescents (20Hoeger K. Davidson K. Kochman L. Cherry T. Kopin L. Guzick D.S. The impact of metformin, oral contraceptives, and lifestyle modification on polycystic ovary syndrome in obese adolescent women in two randomized, placebo-controlled clinical trials.J Clin Endocrinol Metab. 2008; 93: 4299-4306Crossref PubMed Scopus (192) Google Scholar). In a preliminary single therapy trial reported in this paper, lifestyle modification over 24 weeks showed a significant improvement in free androgen index (through SHBG increase) and no change in hirsutism as in our study (nor would this be expected in 6 months), but did not track acne changes. Similarly, the present study noted no changes in weight or waist circumference at the completion of 24 weeks. In a second trial in this same paper (20Hoeger K. Davidson K. Kochman L. Cherry T. Kopin L. Guzick D.S. The impact of metformin, oral contraceptives, and lifestyle modification on polycystic ovary syndrome in obese adolescent women in two randomized, placebo-controlled clinical trials.J Clin Endocrinol Metab. 2008; 93: 4299-4306Crossref PubMed Scopus (192) Google Scholar), Hoeger et al. compared metformin with lifestyle plus oral contraceptives to placebo with lifestyle plus oral contraceptives and found in the lifestyle plus metformin arm a significant decrease in both weight and waist, whereas our subjects gained weight albeit minimal. We noted, again as in the adults (7Ladson G. Dodson W.C. Sweet S.D. Archibong A.E. Kunselman A.R. Demers L.M. et al.The effects of metformin with lifestyle therapy in polycystic ovary syndrome: a randomized double-blind study.Fertil Steril. 2011; 95 (e1–7): 1059-1066Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar), a significant decrease in AUC glucose after our lifestyle intervention, with no effect in the metformin group. We noted an increase in bone mineral content with metformin and lifestyle compared with lifestyle alone, similar to that in our adult trial (7Ladson G. Dodson W.C. Sweet S.D. Archibong A.E. Kunselman A.R. Demers L.M. et al.The effects of metformin with lifestyle therapy in polycystic ovary syndrome: a randomized double-blind study.Fertil Steril. 2011; 95 (e1–7): 1059-1066Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). Our study does not support the addition of metformin to lifestyle in adolescents. Although there are favorable trends toward less hyperandrogenism with metformin, these must be balanced against the increased rate of gastrointestinal side effects. However, both treatments were associated with improved quality of life. Our study also suggests that multicenter trials will be needed to achieve adequate sample sizes to thoroughly answer this vital therapeutic question. We acknowledge the excellent coordination and oversight to this long-term study provided by Barbara Dailey and Joy Vassel at Meharry Medical College and Patsy Rawa at Penn State College of Medicine, and the nursing staff of the GCRC at Penn State Hershey Medical Center. We wish to also acknowledge the contributions to the analyses of Christy Stetter in the Department of Public Health Sciences at Penn State. Finally we are grateful to the subjects who choose to participate in our study. All subjects received the lifestyle intervention. A combined intervention of diet and exercise was employed with the goal of achieving an average weight loss of at least 7% of initial body weight over 6 months. This weight loss target mimics that of the Diabetes Prevention Program (DPP) (1Knowler W.C. Barrett-Connor E. Fowler S.E. Hamman R.F. Lachin J.M. Walker E.A. et al.Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.N Engl J Med. 2002; 346: 393-403Crossref PubMed Scopus (14204) Google Scholar), with a prescription of 150 minutes/week of exercise combined with a low-calorie diet. Before beginning the dietary intervention, subjects were instructed to maintain a 3-day food log. The number of calories to maintain current body weight was assessed by combining the analysis of the 3-day diet records (Nutritionist V, First Databank) with the results of the Harris Benedict equation multiplied by an activity factor of 1.3. The target level of calorie intake was calculated as the daily calories required to maintain weight minus 500 kcal. The food exchange system was utilized to attain this target intake. The target macronutrient composition was 55% carbohydrate, 30% fat, and 15% protein. This system was implemented and monitored with monthly meetings between the subjects and a registered dietitian. The exercise program consisted of supervised and nonsupervised components to maximize flexibility and acceptance of the intervention. Subjects were given the opportunity to attend at least 2 sessions per week at a fitness facility run by the research team. Workouts consisted of a 5-minute warm-up period followed by a 30- to 45-minute workout at 60%–75% of predicted maximal heart rate using one of several modes, that is, stair stepper, stationary bike, elliptical machine, treadmill, or dancing to music. A personal trainer trained in fitness assessment supervised workouts and performed monthly reviews with the subjects. Problems of compliance were addressed by the study coordinator. Unsupervised: Because logistics precluded frequent visits to the training facility, subjects were responsible for performing aerobic activity on their own to achieve a total exercise time of 150 minutes/week (including supervised sessions). Subjects completed a daily physical activity log once per month. Subjects were counseled monthly about ways to increase their nonpurposeful activity and corroborate the records of workouts from the heart rate monitor. Metformin hydrochloride was obtained as a powder (Spectrum Chemical Manufacturing) and formulated with the appropriate dose of drug into capsules with identically appearing placebo capsules (2Hoeger K.M. Kochman L. Wixom N. Craig K. Miller R.K. Guzick D.S. 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.Fertil Steril. 2004; 82: 421-429Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar). Drug and placebo were packaged and labeled according to subject number by the Investigational Pharmacies in a double-blind fashion. Medication was initiated in a step-up fashion every 5 days, from one tablet a day to four. This dose was maintained as tolerated throughout the remainder of the study. Hirsutism was assessed by trained study personnel using the modified Ferriman-Galwey score (3Hatch R. Rosenfield R.L. Kim M.H. Tredway D. Hirsutism: implications, etiology, and management.Am J Obstet Gynecol. 1981; 140: 815-830Abstract Full Text PDF PubMed Scopus (824) Google Scholar). Facial lesions counts of open and closed comedones (noninflammatory lesions) were obtained from the forehead, left and right cheeks, nose, and chin by trained study personnel (4Thiboutot D. Zaenglein A. Weiss J. Webster G. Calvarese B. Chen D. An aqueous gel fixed combination of clindamycin phosphate 1.2% and benzoyl peroxide 2.5% for the once-daily treatment of moderate to severe acne vulgaris: assessment of efficacy and safety in 2813 patients.J Am Acad Dermatol. 2008; 59: 792-800Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar). Before beginning the exercise program and at each monthly visit during the study, subjects underwent a submaximal test of aerobic capacity to determine fitness levels (5Golding L.A. Myers C.R. Sinning W.E. Y's way to fitness: the complete guide to fitness testing and instruction. Human Kinetics, Champaign, IL1989Google Scholar). This test involves riding a stationary bike at several different workloads for a total of 6–12 minutes while the heart rate is monitored with a polar heart rate monitor at regular intervals. Body composition data were determined by dual energy x-ray absorptiometry (DXA) using a Hologic QDR-4500W (Hologic Inc.). Each participant underwent a total-body scan and dual hip scans using the fan-beam mode at baseline and at the completion of the study. Subregion analysis of visceral and central abdominal fat were modeled (6Carey D.G. Jenkins A.B. Campbell L.V. Freund J. Chisholm D.J. Abdominal fat and insulin resistance in normal and overweight women: direct measurements reveal a strong relationship in subjects at both low and high risk of NIDDM.Diabetes. 1996; 45: 633-638Crossref PubMed Google Scholar). Levels of LH, FSH, DHEAS, and sex hormone binding globulin (SHBG) were determined by chemiluminescence using the Siemens Immulite platform. Testosterone was measured by RIA (7Legro R.S. Chiu P. Kunselman A.R. Bentley C.M. Dodson W.C. Dunaif A. Polycystic ovaries are common in women with hyperandrogenic chronic anovulation but do not predict metabolic or reproductive phenotype.J Clin Endocrinol Metab. 2005; 90: 2571-2579Crossref PubMed Scopus (92) Google Scholar) and non-SHBG testosterone (uT) by ammonium sulfate precipitation (8Vermeulen A. Verdonck L. Kaufman J.M. A critical evaluation of simple methods for the estimation of free testosterone in serum.J Clin Endocrinol Metab. 1999; 84: 3666-3672Crossref PubMed Google Scholar). A 75-g oral glucose tolerance test (OGTT) with glucose and insulin levels obtained at 0, 30, 60, 90, and 120 minutes after challenge was performed after an overnight fast (9Legro R.S. Kunselman A.R. Dodson W.C. Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women.J Clin Endocrinol Metabol. 1999; 84: 165-169Crossref PubMed Scopus (1516) Google Scholar). Fasting glucose (FBG), insulin (FI), and lipids were determined as previously reported (7Legro R.S. Chiu P. Kunselman A.R. Bentley C.M. Dodson W.C. Dunaif A. Polycystic ovaries are common in women with hyperandrogenic chronic anovulation but do not predict metabolic or reproductive phenotype.J Clin Endocrinol Metab. 2005; 90: 2571-2579Crossref PubMed Scopus (92) Google Scholar). The insulinogenic index, a measure of early phase insulin secretion, was defined as (30 minute glucose–FBG) divided by (30 minute insulin–FI) (10Phillips D.I. Clark P.M. Hales C.N. Osmond C. Understanding oral glucose tolerance: comparison of glucose or insulin measurements during the oral glucose tolerance test with specific measurements of insulin resistance and insulin secretion [see comments].Diabet Med. 1994; 11: 286-292Crossref PubMed Scopus (554) Google Scholar). The insulin sensitivity index was calculated using the formula of Matsuda and Defronzo (10,000/the square root of [(FBG)(FI)][(mean OGTT glucose)(mean OGTT insulin)] (11Matsuda M. DeFronzo R.A. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp.Diabetes Care. 1999; 22: 1462-1470Crossref PubMed Scopus (4215) Google Scholar). A transvaginal (if sexually active) or transabdominal (if not) ultrasound of the pelvis was performed (7Legro R.S. Chiu P. Kunselman A.R. Bentley C.M. Dodson W.C. Dunaif A. Polycystic ovaries are common in women with hyperandrogenic chronic anovulation but do not predict metabolic or reproductive phenotype.J Clin Endocrinol Metab. 2005; 90: 2571-2579Crossref PubMed Scopus (92) Google Scholar). Volume of the ovary was calculated using the formula for a prolate ellipsoid (length × height × width × (π/6)) (7Legro R.S. Chiu P. Kunselman A.R. Bentley C.M. Dodson W.C. Dunaif A. Polycystic ovaries are common in women with hyperandrogenic chronic anovulation but do not predict metabolic or reproductive phenotype.J Clin Endocrinol Metab. 2005; 90: 2571-2579Crossref PubMed Scopus (92) Google Scholar). The validated PCOS health-related quality of life questionnaire includes five domains: emotional, body hair, infertility, weight, and menstrual problems (12Cronin L. Guyatt G. Griffith L. Wong E. Azziz R. Futterweit W. et al.Development of a health-related quality-of-life questionnaire (PCOSQ) for women with polycystic ovary syndrome (PCOS).J Clin Endocrinol Metab. 1998; 83: 1976-1987Crossref PubMed Scopus (225) Google Scholar). Each domain score is graded on a scale of 1 (poorest function) to 7 (optimal), with a change of 0.5 approximating the minimal important difference, the smallest change in score that women think is important in their daily lives. Linear mixed-effects models were fit to continuous outcomes, such as total testosterone or the free androgen index, to compare metformin to placebo with respect to the change from baseline measurement (13Field A.E. Coakley E.H. Must A. Spadano J.L. Laird N. Dietz W.H. et al.Impact of overweight on the risk of developing common chronic diseases during a 10-year period.Archives of Internal Medicine. 2001; 161: 1581-1586Crossref PubMed Scopus (1182) Google Scholar). The linear mixed-effects model is an extension of multiple linear regression and allows for estimation of the within-subject and between-subject correlations in this longitudinal trial. Contrasts were constructed to compare metformin to placebo for the change in an outcome from the randomization visit to the end of therapy. Adverse event rates were compared between the two treatment arms using Possion regression models. All analyses followed the intention-to-treat principle whereby data from all participants were analyzed according to the assigned treatment group. No adjustments for multiple hypothesis testing were performed as all outcomes other than the primary are considered exploratory. All statistical tests are two-sided and all analyses were performed using SAS software (version 9.1, SAS Institute Inc.) with graphics constructed using S-plus (version 8.0, TIBCO Software Inc.). Supplemental Table 1Baseline descriptives of study participants.MetforminPlacebonMean (SD)nMean (SD)Biometric Age (y)1116.1 (1.5)1115.4 (1.2) Weight (kg)1195.7 (16.7)1195.3 (21.7) BMI (kg/m2)1137.1 (5.8)1135.9 (6.6) Waist (cm)1142.3 (6.1)1141.0 (5.5) Ferriman-Gallwey score1116.3 (10.3)1123.4 (8.5) Total acne lesion count119.5 (14.9)117.6 (5.5) Systolic blood pressure (mm Hg)11120.9 (12.5)11117.2 (12.5) Diastolic blood pressure (mm Hg)1170.2 (7.4)1169.4 (7.6)Hormones Testosterone (ng/dL)1187.7 (46.2)1173.4 (25.0) SHBG (nmol/L)920.0 (11.6)1115.8 (7.8) FAI923.9 (21.7)1120.4 (12.3) Progesterone (ng/mL)91.8 (2.6)111.4 (2.1) Estradiol (pg/mL)439.7 (35.0)821.1 (3.8) LH (mIU/mL)98.9 (5.0)117.8 (3.4) FSH (mIU/mL)94.6 (1.7)115.0 (2.0) LH/FSH ratio92.1 (1.5)111.6 (0.8)Lipid parameters Cholesterol (mg/dL)10144.4 (23.8)11158.6 (32.7) HDL (mg/dL)1029.6 (8.2)1129.7 (11.2) LDL (mg/dL)1096.6 (26.3)11107.0 (35.1) Triglycerides (mg/dL)1091.4 (27.6)11109.7 (57.5)Glycemic parameters from OGTT Fasting glucose (mg/dL)1181.8 (5.8)1184.7 (7.1) Fasting insulin (μU/mL)1016.3 (11.5)917.9 (14.9) HOMA insulin resistance103.3 (2.3)93.9 (3.4) AUC glucose (μU min/mL)1113772 (2133)1113875 (3076) AUC insulin (mg min/dL)1012533 (7013)915629 (13036) Insulinogenic index102.4 (1.5)92.5 (1.3) Insulin sensitivity index103.6 (1.9)94.5 (4.2)Ultrasound parameters Left ovarian volume (cm3)1112.1 (5.7)99.9 (4.9) Right ovarian volume (cm3)1111.5 (7.7)910.3 (4.4) Total ovarian volume (cm3)1123.6 (10.6)1018.2 (8.0) Largest follicle diameter (mm)118.5 (6.4)510.6 (6.2)DXA parameters Total area (cm2)111970 (136)111970 (223) Total BMC (g)112287 (244)112206 (339) Total BMD (g/cm2)111.16 (0.08)111.12 (0.06) Total mass (g)1193994 (16148)1193289 (20846) Total lean (g)1154806 (8222)1153177 (8268) Total fat (g)1139188 (9157)1140111 (13207) Central abdominal fat (g)33526 (1922)63151 (1178) Abdominal fat (g)34717 (1832)67105 (2733) Central-to-total body fat ratio30.11 (0.07)60.08 (0.01) Central-to-abdominal fat ratio31.01 (1.03)60.45 (0.02) % body fat1141.4 (3.9)1142.1 (5.0)Submaximal testing Estimated VO2max1124.0 (3.8)1124.3 (5.3)PCOS QOL parameters Domain: Emotion mean score113.93 (1.31)114.97 (1.68) Domain: Body hair mean score114.40 (2.18)113.58 (1.41) Domain: Weight mean score112.42 (1.50)113.09 (1.94) Domain: Infertility mean score114.16 (1.67)115.59 (1.74) Domain: Menstrual problems mean score114.58 (1.36)114.18 (1.46) Overall physical well-being113.55 (1.92)114.27 (1.42) Overall emotional well-being114.00 (1.73)114.00 (1.73) Overall general well-being113.91 (1.81)114.82 (1.25)Note: AUC = area under the curve; BMI = body mass index; BMC = bone mineral content; BMD = bone mineral density; HDL = high-density lipoprotein; HOMA = Homeostatic Model Assessment; LDL = low-density lipoprotein; OGTT = oral glucose tolerance test; QOL = quality of life; SHBG = sex hormone–binding globulin. Open table in a new tab Supplemental Table 2Effects of treatment after 6 months.MetforminPlaceboDifference (metformin-placebo)Mean change (95% CI)P valueMean change (95% CI)P valueMean change (95% CI)P valueBiometric Waist (inches)−1.0 (−2.7, 0.6)0.22−0.5 (−2.3, 1.4)0.60−0.5 (−2.3, 1.2)0.53 Total acne lesion count−7.0 (−13.7, −0.2)0.04−6.8 (−14.5, 0.9)0.08−0.2 (−9.0, 8.6)0.97 Systolic blood pressure (mm Hg)−4.8 (−10.9, 1.3)0.11−5.6 (−12.4, 1.1)0.090.9 (−7.1, 8.9)0.82 Diastolic blood pressure (mm Hg)1.3 (−4.3, 6.9)0.63−3.7 (−10.2, 2.8)0.255.0 (−1.5, 11.4)0.12Hormones Testosterone (ng/dL)−25.0 (−49.9, −0.1)0.05−4.1 (−31.6, 23.5)0.75−20.9 (−50.3, 8.4)0.15 SHBG (nmol/L)0.0 (−5.5, 5.5)1.002.4 (−3.8, 8.7)0.40−2.4 (−6.7, 1.8)0.23 FAI−8.2 (−15.8, −0.6)0.04−2.2 (−10.3, 5.9)0.56−6.0 (−15.9, 3.8)0.20 Progesterone (ng/mL)−0.4 (−1.7, 0.8)0.46−0.3 (−1.5, 1.0)0.67−0.2 (−2.0, 1.6)0.82 Estradiol (pg/mL)20.6 (−3.9, 45.2)0.08−1.9 (−22.1, 18.2)0.8122.6 (−10.3, 55.4)0.14 LH (mIU/mL)1.3 (−4.3, 7.0)0.610.3 (−6.4, 7.1)0.911.0 (−4.3, 6.2)0.69 FSH (mIU/mL)−0.6 (−3.0, 1.7)0.56−0.7 (−3.4, 1.9)0.560.1 (−2.2, 2.4)0.93Lipid parameters Cholesterol (mg/dL)−9.4 (−27.9, 9.0)0.28−6.4 (−27.1, 14.2)0.51−3.0 (−18.1, 12.1)0.67 HDL (mg/dL)0.6 (−9.2, 10.4)0.893.8 (−8.1, 15.7)0.50−3.2 (−11.7, 5.3)0.42 LDL (mg/dL)−7.8 (−32.1, 16.5)0.49−1.2 (−28.9, 26.5)0.93−6.6 (−26.4, 13.1)0.47 Triglycerides (mg/dL)−11.2 (−46.2, 23.7)0.49−29.5 (−69.8, 10.7)0.1318.3 (−11.3, 47.9)0.20Glycemic parameters from OGTT Fasting glucose (mg/dL)−2.0 (−7.7, 3.7)0.47−0.9 (−7.0, 5.2)0.75−1.1 (−9.4, 7.3)0.79 Fasting insulin (μU/mL)−4.8 (−14.1, 4.6)0.27−11.2 (−23.6, 1.2)0.076.4 (−3.2, 16.1)0.16 HOMA insulin resistance−0.0 (−1.2, 1.1)0.96−1.2 (−2.7, 0.3)0.111.1 (−0.9, 3.1)0.22 AUC glucose (μU min/mL)373 (−549, 1296)0.40−1095 (−2074, −115)0.031468 (118, 2818)0.04 AUC insulin (mg min/dL)−2603 (−18719, 13512)0.72−10496 (−30641, 9649)0.267892 (−7528, 23312)0.27 Insulinogenic index−0.6 (−1.3, 0.2)0.12−0.3 (−1.3, 0.8)0.58−0.3 (−1.6, 1.0)0.61 Insulin sensitivity index1.7 (−2.0, 5.4)0.321.0 (−3.7, 5.8)0.640.7 (−5.6, 7.0)0.81Ultrasound parameters Left ovarian volume (cm3)−2.1 (−7.2, 3.0)0.350.2 (−6.2, 6.5)0.94−2.3 (−7.5, 2.9)0.32 Right ovarian volume (cm3)0.6 (−6.8, 8.0)0.860.6 (−8.1, 9.3)0.880.0 (−6.8, 6.9)1.00 Total ovarian volume (cm3)−2.5 (−12.1, 7.0)0.572.7 (−8.5, 13.9)0.61−5.2 (−14.1, 3.7)0.22 Largest follicle diameter (mm)−2.8 (−7.0, 1.5)0.16−5.9 (−13.7, 1.9)0.113.1 (−5.3, 11.6)0.38DXA parameters Total area (cm2)3.7 (−60.6, 68.1)0.905.0 (−68.7, 78.7)0.89−1.2 (−49.7, 47.2)0.96 Total BMC (g)57.6 (13.1, 102.1)0.0220.7 (−30.5, 71.8)0.4036.9 (−0.5, 74.4)0.05 Total BMD (g/cm2)0.023 (−0.022, 0.069)0.280.004 (−0.045, 0.053)0.860.019 (−0.014, 0.053)0.23 Total mass (g)−5146 (−10414, 123)0.05−4450 (−10540, 1641)0.14−696 (−5186, 3794)0.74 Total lean (g)−2035 (−4078, 8)0.05−1515 (−3920, 890)0.20−520 (−2101, 1061)0.49 Total fat (g)−1768 (−6129, 2592)0.39−1767 (−6423, 2888)0.42−1 (−3217, 3215)1.00 % body fat0.9 (−1.7, 3.5)0.471.2 (−1.8, 4.2)0.41−0.3 (−1.9, 1.3)0.70PCOS QOL Parameters Domain: Emotion mean score1.98 (0.67, 3.29)0.0061.91 (0.45, 3.37)0.010.07 (−1.11, 1.24)0.91 Domain: Body hair mean score0.77 (−0.65, 2.19)0.260.63 (−0.90, 2.16)0.390.14 (−0.93, 1.22)0.78 Domain: Weight mean score2.13 (0.54, 3.71)0.012.39 (0.55, 4.23)0.01−0.27 (−1.63, 1.09)0.68 Domain: Infertility mean score1.53 (0.40, 2.66)0.012.19 (0.99, 3.40)0.002−0.66 (−1.63, 0.31)0.16 Domain: Menstrual Problems Mean Score1.46 (−0.10, 3.02)0.060.99 (−0.80, 2.78)0.250.47 (−0.83, 1.78)0.44 Overall physical well-being1.30 (−0.10, 2.69)0.071.34 (−0.52, 3.20)0.14−0.04 (−1.25, 1.17)0.94 Overall emotional well-being1.54 (−0.28, 3.35)0.092.41 (0.33, 4.50)0.03−0.88 (−2.40, 0.64)0.23 Overall general well-being1.42 (0.48, 2.35)0.0061.48 (0.33, 2.63)0.02−0.06 (−0.88, 0.76)0.87Note: AUC = area under the curve; BMI = body mass index; BMC = bone mineral content; BMD = bone mineral density; HDL = high-density lipoprotein; HOMA = Homeostatic Model Assessment; LDL = low-density lipoprotein; OGTT = oral glucose tolerance test; QOL = quality of life; SHBG = sex hormone–binding globulin. Open table in a new tab Note: AUC = area under the curve; BMI = body mass index; BMC = bone mineral content; BMD = bone mineral density; HDL = high-density lipoprotein; HOMA = Homeostatic Model Assessment; LDL = low-density lipoprotein; OGTT = oral glucose tolerance test; QOL = quality of life; SHBG = sex hormone–binding globulin. Note: AUC = area under the curve; BMI = body mass index; BMC = bone mineral content; BMD = bone mineral density; HDL = high-density lipoprotein; HOMA = Homeostatic Model Assessment; LDL = low-density lipoprotein; OGTT = oral glucose tolerance test; QOL = quality of life; SHBG = sex hormone–binding globulin.

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