title: Ethinylestradiol-drospirenone, flutamide-metformin, or both for adolescents and women with hyperinsulinemic hyperandrogenism: opposite effects on adipocytokines and body adiposity.
abstract: 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.
authors.affiliation: Endocrinology Unit, Hospital Sant Joan de Déu (L.I), University of Barcelona, 08950 Esplugues, Barcelona, Spain. libanez@hsjdbcn.org
authors.forename: Lourdes
authors.initials: L
authors.lastname: Ibáñez
authors.forename: Francis
authors.initials: F
authors.lastname: de Zegher
mesh_terms: D052242:Adiponectin; D000273:Adipose Tissue / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000726:Androgen Antagonists / Q000627:therapeutic use; D000736:Androstenes / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D004967:Estrogens / Q000627:therapeutic use*; D004997:Ethinyl Estradiol / Q000627:therapeutic use; D005260:Female; D005485:Flutamide / Q000627:therapeutic use; D006727:Hormone Antagonists / Q000627:therapeutic use*; D006801:Humans; D017588:Hyperandrogenism / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D006946:Hyperinsulinism / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6 / Q000378:metabolism; D008687:Metformin / Q000627:therapeutic use; D000451:Mineralocorticoid Receptor Antagonists / Q000627:therapeutic use; D011085:Polycystic Ovary Syndrome / Q000150:complications*; D011506:Proteins / Q000378:metabolism
chemical_list: D052242:Adiponectin; D000726:Androgen Antagonists; D000736:Androstenes; D004967:Estrogens; D006727:Hormone Antagonists; D007004:Hypoglycemic Agents; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D000451:Mineralocorticoid Receptor Antagonists; D011506:Proteins; D004997:Ethinyl Estradiol; D005485:Flutamide; D008687:Metformin; C035144:drospirenone