Combined low-dose pioglitazone, flutamide, and metformin for women with androgen excess.
OBJECTIVE
One of the treatments for hyperinsulinemic hyperandrogenism in nonobese women is combined androgen receptor blockade (with flutamide; Flu), insulin sensitization (with metformin; Met) plus an estroprogestagen contraceptive. We tested whether adding low-dose pioglitazone (Pio; 7.5 mg/d) confers more benefit.


METHODS
The study was conducted at a university hospital.


METHODS
This double-blind study enrolled 38 young women with hyperinsulinemic hyperandrogenism [mean body mass index (BMI) 24 kg/m(2)], all of whom started on Flu (62.5 mg/d) and Met (850 mg/d) plus a transdermal estroprogestagen, each for 21 of 28 d over 6 months. Patients were randomly assigned to receive, in addition, placebo (n=19) or Pio (n=19; 7.5 mg/d) for the same 21 of 28 d over 6 months.


RESULTS
BMI, waist to hip ratio, hirsutism score, fasting endocrine-metabolic markers, body composition, abdominal fat (visceral vs. sc), and carotid intima-media thickness were measured at study start and after 6 months.


RESULTS
PioFluMet reduced intima-media thickness more than FluMet and lowered glucose, IGF-I, and C-reactive protein more as well as the ratio of low-density lipoprotein to high-density lipoprotein cholesterol and the ratio of neutrophils to lymphocytes. PioFluMet treatment was followed by a leaner body composition and a loss of visceral fat (both P < 0.001). In the total group, the changes included not only decreases in waist to hip ratio, hirsutism score, and testosterone (all P < 0.001) but also minor drops in alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, and lactate dehydrogenase (all P < 0.005), indicating absence of hepatotoxicity; BMI remained unchanged. Clinical side effects were not detected.


CONCLUSIONS
In this proof-of-concept study, addition of Pio to FluMet plus an estroprogestagen led to improvements in the endocrine-metabolic condition, in low-grade inflammation, in total and visceral adiposity, and in markers of cardiovascular health.
Ibáñez
Lourdes
L
Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona, Passeig de Sant Joan de Déu 2, 08950 Esplugues, Barcelona, Spain. libanez@hsjdbcn.org
López-Bermejo
Abel
A
del Rio
Luis
L
Enríquez
Goya
G
Valls
Carme
C
de Zegher
Francis
F
D000273:Adipose Tissue / Q000502:physiology; D000293:Adolescent; D000328:Adult; D000726:Androgen Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001823:Body Composition / Q000502:physiology; D015992:Body Mass Index; D002339:Carotid Arteries / Q000000981:diagnostic imaging; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005485:Flutamide / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005951:Glucose Tolerance Test; D006728:Hormones / Q000097:blood; D006801:Humans; D017588:Hyperandrogenism / Q000188:drug therapy* / Q000378:metabolism; D006946:Hyperinsulinism / Q000150:complications; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood; D008687:Metformin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014463:Ultrasonography
D000726:Androgen Antagonists; D006728:Hormones; D007004:Hypoglycemic Agents; D008055:Lipids; D045162:Thiazolidinediones; D005485:Flutamide; D008687:Metformin; D000077205:Pioglitazone