Low-dose pioglitazone and low-dose flutamide added to metformin and oestro-progestagens for hyperinsulinaemic women with androgen excess: add-on benefits disclosed by a randomized double-placebo study over 24 months.
OBJECTIVE
Metformin plus oestro-progestagen is a combination treatment for non-obese women with hyperinsulinaemic androgen excess. We explored whether low-dose pioglitazone (Pio) and flutamide (Flu) has readily detectable add-on effects.
Randomized, double-placebo pilot study over 24 months; 38 women with hyperinsulinaemic androgen excess (mean age 20 years; BMI 23.7 kg/m(2)); all women received metformin and an oestro-progestagen for 24 months, and add-on Flu (62.5 mg/day; 21/28 days) for 18 months. A first randomization was performed at start of the study, for Pio (7.5 mg/day; 21/28 days) vs. Pio-placebo, with a cross-over of Pio subgroups at 18 month. A second randomization was performed at 18 months, for Flu vs. Flu-placebo until 24 months.


RESULTS
Intima media thickness (IMT); body composition by absorptiometry; abdominal fat partitioning by magnetic resonance; circulating glucose, insulin, IGF-I, androgens, LDL : HDL ratio, RBP4, vaspin.


RESULTS
Add-on effects of Pio included a gain of lean mass (mirrored by a loss of fat) and an accelerated lowering of IMT (P <or= 0.001). Add-on effects of flutamide included a further reduction of androgen excess. Between 0 and 18 months, women lost a quarter of their visceral fat (P < 0.001; independently of Pio); beyond 18 months, a rebound of visceral fat occurred in women who had stopped Pio and Flu. Between 0 and 24 months, insulin sensitivity increased, as did circulating RBP-4 and vaspin (all P = 0.001).


CONCLUSIONS
Low-dose Pio and Flu further improve long-term markers - such as IMT, lean mass and visceral fat - when jointly added to a treatment of metformin plus an oestro-progestagen in non-obese women with hyperinsulinaemic androgen excess.
Ibáñez
Lourdes
L
Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain. libanez@hsjdbcn.org
López-Bermejo
Abel
A
Díaz
Marta
M
Enríquez
Goya
G
del Río
Luis
L
de Zegher
Francis
F
D000293:Adolescent; D000726:Androgen Antagonists / Q000008:administration & dosage*; D000728:Androgens / Q000378:metabolism*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005485:Flutamide / Q000008:administration & dosage; D006801:Humans; D006946:Hyperinsulinism / Q000188:drug therapy* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D008687:Metformin / Q000008:administration & dosage; D010865:Pilot Projects; D000077205:Pioglitazone; D011372:Progestins / Q000008:administration & dosage; D045162:Thiazolidinediones / Q000008:administration & dosage*; D055815:Young Adult
D000726:Androgen Antagonists; D000728:Androgens; D007004:Hypoglycemic Agents; D011372:Progestins; D045162:Thiazolidinediones; D005485:Flutamide; D008687:Metformin; D000077205:Pioglitazone