Ethinylestradiol-drospirenone, flutamide-metformin, or both for adolescents and women with hyperinsulinemic hyperandrogenism: opposite effects on adipocytokines and body adiposity

J Clin Endocrinol Metab. 2004 Apr;89(4):1592-7. doi: 10.1210/jc.2003-031281.


Hyperinsulinemic hyperandrogenism with anovulation, the so-called polycystic ovary syndrome (PCOS), is the most frequent endocrine disorder of young women. One of the stigmata of PCOS is a deficit of lean mass and an excess of fat, in particular, abdominal fat, even in the absence of obesity. Adiponectin and IL-6 are among the adipocytokines that have recently been related to abdominal fat excess, insulin resistance states, and cardiovascular disease risk. We studied the effects of two new treatment options, ethinylestradiol-drospirenone and flutamide-metformin, and of their combination on adipocytokinemia and body adiposity in adolescents and women with PCOS. Adolescents with PCOS (n = 32; age, approximately 15 yr; body mass index, approximately 22 kg/m(2)) were randomly assigned to receive the oral contraceptive (OC) ethinylestradiol-drospirenone, or the low-dose generic duo of flutamide (62.5 mg/d) plus metformin (850 mg/d). Young women with PCOS (n = 22; age, approximately 19 yr; body mass index, approximately 22 kg/m(2)) were randomized to receive the same OC, either alone or with flutamide-metformin. Fasting blood glucose, serum insulin, lipids, androgens, IL-6, adiponectin, and body composition (by absorptiometry) were assessed at the start, and after 3 and/or 9 months. At the start, serum concentrations of the proinflammatory IL-6 were high, and those of the antiinflammatory adiponectin were low; body composition was adipose in each subpopulation. Abnormal adipocytokine levels, hypertriglyceridemia, and body adiposity diverged further from the norm in adolescents on OC; in contrast, girls on flutamide-metformin reverted all study indices toward normal, lost part of their fat excess, and reduced their lean mass deficit. In comparison to the girls on OC, those on flutamide-metformin lost a mean of approximately 4 kg of fat and gained approximately 4 kg of lean mass. Similarly, abnormal adipocytokine levels and adiposity were aggravated in women on OC alone and improved in women on OC plus flutamide-metformin; within 9 months, the latter subgroup lost a mean of approximately 3 kg of fat and gained approximately 3 kg of lean mass, in comparison to women on OC alone. In conclusion, young and nonobese PCOS patients were found to be in a low-grade, chronic inflammation state, and to have a body adiposity that evolves according to the balance of circulating adipocytokines and lipids, rather than to androgen excess or fasting hyperinsulinemia. Monotherapy with ethinylestradiol-drospirenone may not be a prime choice for PCOS, given its inefficacy to attenuate abnormal adipocytokine levels and body adiposity; ethinylestradiol-drospirenone plus flutamide-metformin, however, is a first OC combination that was found capable of reverting both the adipocytokine balance and the body composition toward normal, and that may therefore improve the long-term cardiovascular perspectives of women with PCOS.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Adiponectin
  • Adipose Tissue / pathology
  • Adolescent
  • Adult
  • Androgen Antagonists / therapeutic use
  • Androstenes / therapeutic use
  • Drug Therapy, Combination
  • Estrogens / therapeutic use*
  • Ethinyl Estradiol / therapeutic use
  • Female
  • Flutamide / therapeutic use
  • Hormone Antagonists / therapeutic use*
  • Humans
  • Hyperandrogenism / drug therapy*
  • Hyperandrogenism / etiology
  • Hyperandrogenism / metabolism
  • Hyperinsulinism / drug therapy*
  • Hyperinsulinism / etiology
  • Hyperinsulinism / metabolism
  • Hypoglycemic Agents / therapeutic use*
  • Intercellular Signaling Peptides and Proteins*
  • Interleukin-6 / metabolism
  • Metformin / therapeutic use
  • Mineralocorticoid Receptor Antagonists / therapeutic use
  • Polycystic Ovary Syndrome / complications*
  • Proteins / metabolism


  • Adiponectin
  • Androgen Antagonists
  • Androstenes
  • Estrogens
  • Hormone Antagonists
  • Hypoglycemic Agents
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-6
  • Mineralocorticoid Receptor Antagonists
  • Proteins
  • Ethinyl Estradiol
  • Flutamide
  • Metformin
  • drospirenone