Ethinyl estradiol-cyproterone acetate versus low-dose pioglitazone-flutamide-metformin for adolescent girls with androgen excess: divergent effects on CD163, TWEAK receptor, ANGPTL4, and LEPTIN expression in subcutaneous adipose tissue.
OBJECTIVE
The aim was to compare the effects of a traditional therapy (an oral estroprogestagen) to those of a novel treatment (a low-dose combination of generics) in adolescent girls with androgen excess.


METHODS
In an open-label trial over 1 yr, 34 adolescents (age, 16 yr; body mass index, 23 kg/m2) with hyperinsulinemic androgen excess and without pregnancy risk were randomized to receive daily ethinyl estradiol-cyproterone acetate (EE-CA; Diane 35 Diario) or a low-dose combination of pioglitazone 7.5 mg/d, flutamide 62.5 mg/d, and metformin 850 mg/d (PioFluMet). Markers of androgen excess, C-reactive protein, high molecular weight adiponectin, lipids, carotid intima media thickness, body composition (absorptiometry), abdominal fat partitioning (magnetic resonance imaging), and gene expression in longitudinal biopsies of sc adipose tissue at the abdominal level (RT-PCR) were assessed at baseline and after 1 yr.


RESULTS
EE-CA and low-dose PioFluMet reduced androgen excess comparably, but had divergent effects on C-reactive protein, high molecular weight adiponectin, lipids, carotid intima media thickness, lean mass, abdominal and visceral fat, and on the expression of CD163, leptin, TNF-like weak inducer of apoptosis receptor, and angiopoietin-like protein 4, respectively, related to macrophage activation, fat accretion, inflammation, and lipoprotein metabolism in adipose tissue. All these divergences pointed to a healthier condition on low-dose PioFluMet.


CONCLUSIONS
EE-CA and PioFluMet are similarly effective in reversing androgen excess over 1 yr, but low-dose PioFluMet is superior in reversing inflammatory, metabolic, and cardiovascular anomalies that are often associated with androgen excess.
Endocrinology Unit, Department of Obstetrics and Gynecology, Hospital Sant Joan de Déu, University of Barcelona, Passeig de Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain.
Marta
M
Díaz
Matilde R
MR
Chacón
Abel
A
López-Bermejo
Elsa
E
Maymó-Masip
Cristina
C
Salvador
Joan
J
Vendrell
Francis
F
de Zegher
Lourdes
L
Ibáñez
D050153:Abdominal Fat / Q000502:physiology; D000293:Adolescent; D000726:Androgen Antagonists / Q000008:administration & dosage; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000378:metabolism; D001823:Body Composition / Q000502:physiology; D017373:Cyproterone Acetate / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004997:Ethinyl Estradiol / Q000008:administration & dosage*; D005260:Female; D005485:Flutamide / Q000008:administration & dosage*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D017588:Hyperandrogenism / Q000188:drug therapy* / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D020738:Leptin / Q000235:genetics / Q000378:metabolism; D008687:Metformin / Q000008:administration & dosage*; D000077205:Pioglitazone; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D050151:Subcutaneous Fat / Q000187:drug effects / Q000502:physiology; D000074050:TWEAK Receptor; D045162:Thiazolidinediones / Q000008:administration & dosage*; D000098902:CD163 Antigen
C474772:ANGPTL4 protein, human; D000726:Androgen Antagonists; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D004338:Drug Combinations; D007004:Hypoglycemic Agents; D020738:Leptin; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; D045162:Thiazolidinediones; D004997:Ethinyl Estradiol; D017373:Cyproterone Acetate; C032640:Cyproterone acetate, ethinyl estradiol drug combination; D005485:Flutamide; D008687:Metformin; D000077205:Pioglitazone