title: Low-dose flutamide-metformin therapy reverses insulin resistance and reduces fat mass in nonobese adolescents with ovarian hyperandrogenism.
abstract: Ovarian hyperandrogenism is a common disorder often presenting post menarche with anovulatory oligomenorrhea and signs of androgen excess. Associated hyperinsulinemic insulin resistance, dyslipidemia, and central fat excess herald long-term disease risk. Combined antiandrogen (flutamide 250 mg/d) and insulin-sensitizing (metformin) therapy has beneficial effects, in particular on dyslipidemia and androgen excess in young women. We studied the effects of low-dose flutamide-metformin combination on metabolic variables and body composition in adolescent girls with ovarian hyperandrogenism. Thirty teenage girls (age range, 13.6-18.6 yr) with hyperinsulinemic hyperandrogenism participated in a 12-month pilot study with a 3-month off-treatment phase and a 9-month treatment phase (randomized sequence) on combined flutamide (125 mg/d) and metformin (1275 mg/d). Body composition was assessed by dual-energy x-ray absorptiometry; endocrine-metabolic state and ovulation rate were screened every 3 months. Insulin sensitivity was assessed by homeostasis model assessment (HOMA). Overnight GH and LH profiles were obtained pretreatment and after 6 months on treatment (n = 8). Over the 3-month pretreatment control phase (n = 14) all study indices were unchanged. Flutamide-metformin treatment (n = 30) was followed within 3 months by marked decreases in hirsutism score and serum androgens, by a more than 50% increase in insulin sensitivity and by a less atherogenic lipid profile (all P < 0.0001). After 9 months on flutamide-metformin, body fat decreased by 10%, with a preferential 20% loss of abdominal fat; conversely lean body mass increased, and total body weight remained unchanged; ovulation rate increased from 7-87% after 9 months. Baseline GH hypersecretion and elevated serum IGF-1 normalized after 6 months on flutamide-metformin. Within 3 months post treatment (n = 16), a rebound was observed for all assessed indices. In conclusion, in teenage girls with ovarian hyperandrogenism, low-dose combined flutamide-metformin therapy attenuated a spectrum of abnormalities, including insulin resistance and hyperlipidemia. Improved insulin sensitivity and reduced androgen activity led to a marked redistribution of body fat and lean mass, resulting in a more feminine body shape.
authors.affiliation: Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona, Barcelona 08950, Spain. libanez@hsjdbcn.org
authors.forename: Lourdes
authors.initials: L
authors.lastname: Ibáñez
authors.forename: Ken
authors.initials: K
authors.lastname: Ong
authors.forename: Angela
authors.initials: A
authors.lastname: Ferrer
authors.forename: Rakesh
authors.initials: R
authors.lastname: Amin
authors.forename: David
authors.initials: D
authors.lastname: Dunger
authors.forename: Francis
authors.initials: F
authors.lastname: de Zegher
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects* / Q000473:pathology; D000726:Androgen Antagonists / Q000008:administration & dosage*; D002648:Child; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005485:Flutamide / Q000008:administration & dosage*; D006801:Humans; D017588:Hyperandrogenism / Q000188:drug therapy* / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007333:Insulin Resistance; D008687:Metformin / Q000008:administration & dosage*; D010865:Pilot Projects; D011085:Polycystic Ovary Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D011897:Random Allocation; D016896:Treatment Outcome
chemical_list: D000726:Androgen Antagonists; D007004:Hypoglycemic Agents; D005485:Flutamide; D008687:Metformin