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Treatment with Flutamide, Metformin, and Their Combination Added to a Hypocaloric Diet in Overweight-Obese Women with Polycystic Ovary Syndrome: A Randomized, 12-Month, Placebo-Controlled Study
Abstract
CONTEXT: The few controlled trials performed so far indicate that the addition of metformin and/or flutamide to a hypocaloric diet in obese women with polycystic ovary syndrome (PCOS) effectively influences different phenotypic aspects of the syndrome. All these studies are, however, characterized by a short to medium period of treatment. OBJECTIVE: Our objective was to investigate the long-term effects of these therapies. DESIGN AND SETTING: We conducted a prospective, randomized, placebo-controlled trial at a medical center. PATIENTS: Of 80 overweight-obese women with PCOS, 76 completed the study. INTERVENTIONS: Patients were placed on a hypocaloric diet for the first month and then on a hypocaloric diet plus placebo, metformin (850 mg, orally, twice a day), flutamide (250 mg, orally, twice a day), or metformin plus flutamide for the subsequent 12 months (20 subjects in each group). MAIN OUTCOME MEASURES: We assessed clinical features, computerized tomography measurement of fat distribution, androgens, lipids, and fasting and glucose-stimulated glucose and insulin levels at baseline and after 6 and 12 months of treatment. RESULTS: After 6 months, compared with placebo, flutamide further decreased visceral/sc fat mass (P = 0.044), androstenedione (P < 0.001), dehydroepiandrosterone sulfate (P < 0.001), and hirsutism score (P < 0.001), whereas metformin further increased frequency of menstruation (P = 0.039). After 12 months, flutamide maintained the effects observed after 6 months on visceral/sc fat mass (P = 0.033) and androstenedione (P < 0.001), whereas it produced an additional decrease in dehydroepiandrosterone sulfate (P = 0.020) and hirsutism score (P = 0.019); metformin further improved the menstrual pattern (P = 0.013). Moreover, after 12 months, flutamide improved more than placebo the menstrual pattern (P = 0.008), glucose-stimulated glucose levels (P = 0.041), insulin sensitivity (P < 0.001), and low-density lipoprotein cholesterol levels (P = 0.003), whereas metformin decreased glucose-stimulated insulin levels (P = 0.014). The combination of the two drugs maintained the specific effect of each of the compounds, without any additive or synergistic effect. CONCLUSIONS: These findings add relevance to the usefulness of metformin and flutamide in the treatment of dieting overweight-obese PCOS women and provide a rationale for targeting different therapeutic options according to the required outcomes in the long term.
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“Duration of follow-up, except for two studies (Hoeger et al. , 2004; Gambineri et al. , 2006), was 6 months or shorter.”
From Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis (2015) · cites this paper as Gambineri et al. , 2006
In the citing paper
“In addition, IGT was seen in three (15%) subjects on lifestyle + metformin and two (11%) on lifestyle + placebo at baseline which decreased to two (10%) and 0 respectively at 12 months.”
From Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis (2015) · cites this paper as Gambineri et al. , 2006
In the citing paper
“In Gambineri et al. (2006), IFG was seen in three (15%) subjects on lifestyle + metformin and two (11%) on lifestyle + placebothat were unchanged at study end (12 months).”
From Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis (2015) · cites this paper as Gambineri et al. , 2006
In the citing paper
“Data on BMI, testosterone, SHBG, FAI, menstruation, fasting glucose, glucose AUC and insulin AUC were also available from two studies with durations of 12 months and 48 weeks (Hoeger et al. , 2004; Gambineri et al. , 2006).”
From Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis (2015) · cites this paper as Gambineri et al., 2006
In the citing paper
“Insulin resistance was assessed in five of nine studies comparing lifestyle + metformin with lifestyle + placebo (Pasquali et al. , 2000; Hoeger et al. , 2004; Gambineri et al. , 2006; Ladson et al. , 2011a, b).”
From Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis (2015) · cites this paper as Gambineri et al. , 2006
In the citing paper
“IFG or IGT was assessed in five of nine studies comparing lifestyle + metformin with lifestyle + placebo (Hoeger et al. , 2004, 2008; Vanky et al. , 2004; Gambineri et al. , 2006; Otta et al. , 2010).”
From Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis (2015) · cites this paper as Gambineri et al. , 2006
In the citing paper
“The number of menstrual cycles from 6 to 12 months was greater in the lifestyle + metformin compared with lifestyle + placebo groups (MD 1.38, 95% CI 0.47-2.29, P ¼ 0.003).”
From Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis (2015) · cites this paper as Gambineri et al., 2006
In the citing paper
“There were two (10%) subjects with both IFG and IGT on lifestyle + metformin and one (5%) on lifestyle + placebo at baseline, which were all normal at 12 months (Gambineri et al. , 2006).”
From Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis (2015) · cites this paper as Gambineri et al. , 2006
In the citing paper
“Body composition as assessed by computed tomography(CT)atL4-5wasprovided in two (Pasquali et al. , 2000; Gambineri et al. , 2006) of nine studies comparing lifestyle + metformin with lifestyle + placebo.”
From Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis (2015) · cites this paper as Gambineri et al. , 2006
In the citing paper
“27 100.0%-92.49 [-164.14,-20.84]”
From Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis (2015) · cites this paper as Gambineri et al., 2006
In the citing paper
“Gambineri and colleagues reported that metformin was better than placebo plus diet for menstrual pattern after 6 ( P =0.03) and 12 months ( P =0.003)”
From Assessment and management of polycystic ovary syndrome: Summary of an evidence-based guideline (2011) · cites this paper as [211]
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Polycystic Ovary Syndrome: Definition, Aetiology, Diagnosis and Treatment
Escobar-Morreale, H. F. (2018) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2018.24 · Cited by 2,083
Fauser, B. C. J. M., Tarlatzis, B. C., Rebar, R. W., Legro, R. S., Balen, A. H., Lobo, R., Carmina, E., Chang, J., Yildiz, B. O., Laven, J. S. E., et al. (2012) · Fertility and Sterility · doi:10.1016/j.fertnstert.2011.09.024 · Cited by 1,976
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Joham, A. E., Norman, R. J., Stener-Victorin, E., Legro, R. S., Franks, S., Moran, L. J., Boyle, J., & Teede, H. J. (2022) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(22)00163-2 · Cited by 838
Metadata
- Authors
- Gambineri, A., Patton, L., Vaccina, A., Cacciari, M., Morselli-Labate, A. M., Cavazza, C., Pagotto, U., & Pasquali, R.
- Affiliations
- IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
- Division of Endocrinology, Department of Internal Medicine, and Center for Applied Biomedical Research, S. Orsola-Malpighi Hospital, University of Bologna, 40138 Bologna, Italy
- Corresponding author
- Pasquali, Renato
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2006-10-01
- Volume
- 91
- Issue
- 10
- Pages
- 3970-3980
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2014108789
- Cited by
- 221
- References
- 48
- Citations by year
- 2026: 4 · 2025: 14 · 2024: 3 · 2023: 8 · 2022: 11 · 2021: 11 · 2020: 12 · 2019: 7 · 2018: 14 · 2017: 10 · 2016: 7 · 2015: 20 · 2014: 12 · 2013: 10 · 2012: 9
- FWCI
- 17.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Keywords
- polycystic ovary syndrome, flutamide, metformin, hypocaloric diet, obesity, overweight women, long-term treatment outcomes, visceral fat, androgen levels, hirsutism, menstrual pattern, insulin sensitivity, glucose-stimulated insulin secretion, lipid profile, body fat distribution, combination therapy, weight loss, insulin resistance, androgen receptor antagonists
- MeSH terms
- Adipose Tissue, Adult, Energy Intake, Diet, Reducing, Drug Therapy, Combination, Female, Flutamide, Humans, Insulin Resistance, Metformin, Obesity, Polycystic Ovary Syndrome, Prospective Studies, Sex Hormone-Binding Globulin, Gonadal Steroid Hormones
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