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.
BACKGROUND
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.


METHODS
We conducted a prospective, randomized, placebo-controlled trial at a medical center.


METHODS
Of 80 overweight-obese women with PCOS, 76 completed the study.


METHODS
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).


METHODS
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.
Gambineri
Alessandra
A
Division of Endocrinology, Department of Internal Medicine, S. Orsola-Malpighi Hospital, Via Massarenti 9, 40138 Bologna, Italy.
Patton
Laura
L
Vaccina
Antonella
A
Cacciari
Mauro
M
Morselli-Labate
Antonio Maria
AM
Cavazza
Carla
C
Pagotto
Uberto
U
Pasquali
Renato
R
D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D004038:Diet, Reducing; D004359:Drug Therapy, Combination; D002149:Energy Intake; D005260:Female; D005485:Flutamide / Q000008:administration & dosage / Q000627:therapeutic use*; D012739:Gonadal Steroid Hormones / Q000097:blood; D006801:Humans; D007333:Insulin Resistance; D008687:Metformin / Q000008:administration & dosage / Q000627:therapeutic use*; D009765:Obesity / Q000150:complications* / Q000378:metabolism; D011085:Polycystic Ovary Syndrome / Q000188:drug therapy* / Q000378:metabolism; D011446:Prospective Studies; D012738:Sex Hormone-Binding Globulin / Q000032:analysis
D012739:Gonadal Steroid Hormones; D012738:Sex Hormone-Binding Globulin; D005485:Flutamide; D008687:Metformin