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Low-dose flutamide-metformin therapy for hyperinsulinemic hyperandrogenism in nonobese adolescents and women

2006; Elsevier BV; Volume: 86; Linguagem: Inglês

10.1016/j.fertnstert.2006.03.006

1556-5653

Lourdes Ibáñez, Francis de Zegher,

Lipid metabolism and disorders

Hyperinsulinemic hyperandrogenism is the core of polycystic ovary syndrome (PCOS), and, accordingly, low-dose flutamide-metformin proved so far to be a most effective approach to normalize the broad spectrum of PCOS anomalies in nonobese adolescents and young women. For safety reasons, it is wise to combine flutamide-metformin with a contraceptive, for example, an oral or transdermal estroprogestagen. Hyperinsulinemic hyperandrogenism is the core of polycystic ovary syndrome (PCOS), and, accordingly, low-dose flutamide-metformin proved so far to be a most effective approach to normalize the broad spectrum of PCOS anomalies in nonobese adolescents and young women. For safety reasons, it is wise to combine flutamide-metformin with a contraceptive, for example, an oral or transdermal estroprogestagen. Hyperinsulinemic hyperandrogenism is the core of so-called polycystic ovary syndrome (PCOS), which is a prevalent endocrine-metabolic disorder of adolescents and young women characterized by a variable spectrum of other anomalies, including anovulation, dyslipidemia, body adiposity, and low-grade inflammation (1Kirchengast S. Huber J. Body composition characteristics and body fat distribution in lean women with polycystic ovary syndrome.Hum Reprod. 2001; 16: 1255-1260Crossref PubMed Scopus (233) Google Scholar, 2Boulman N. Levy Y. Leiba R. Shachar S. Linn R. Zinder O. Blumenfeld Z. Increased C-reactive protein levels in the polycystic ovary syndrome a marker of cardiovascular disease.J Clin Endocrinol Metab. 2004; 89: 2160-2165Crossref PubMed Scopus (251) Google Scholar, 3Orio Jr, F. Palomba S. Cascella T. De Simone B. Di Biase S. Russo T. et al.Early impairment of endothelial structure and function in young normal-weight women with polycystic ovary syndrome.J Clin Endocrinol Metab. 2004; 89: 4588-4593Crossref PubMed Scopus (273) Google Scholar). Abdominal fat excess, endothelial dysfunction, and impaired insulin sensitivity have each been related to circulating levels of adiponectin and proinflammatory markers such as interleukin-6, tumor necrosis factor α, C-reactive protein, and the neutrophil count. This state of low-grade inflammation and body adiposity is thought to contribute to premature cardiovascular disease in women with hyperinsulinemic hyperandrogenism (3Orio Jr, F. Palomba S. Cascella T. De Simone B. Di Biase S. Russo T. et al.Early impairment of endothelial structure and function in young normal-weight women with polycystic ovary syndrome.J Clin Endocrinol Metab. 2004; 89: 4588-4593Crossref PubMed Scopus (273) Google Scholar, 4Tarkun I. Arslan B.C. Canturk Z. Turemen E. Sahin T. Duman C. Endothelial dysfunction in young women with polycystic ovary syndrome relationship with insulin resistance and low-grade chronic inflammation.J Clin Endocrinol Metab. 2004; 89: 5592-5596Crossref PubMed Scopus (230) Google Scholar). At present, there is no approved therapy for PCOS. A first step in the classic treatment approach is to give an oral contraceptive (OC), even to young teenagers. Although OCs reduce the hyperandrogenemia, they correct neither the low-grade inflammation, the adipose body composition, nor most of the other endocrine-metabolic anomalies (5Diamanti-Kandarakis E. Baillargeon J.P. Iuorno M.J. Jakubowicz D.J. Nestler J.E. A modern medical quandary polycystic ovary syndrome, insulin resistance, and oral contraceptive pills.J Clin Endocrinol Metab. 2003; 88: 1927-1932Crossref PubMed Scopus (149) Google Scholar). Recently, independent teams found that major endocrine-metabolic benefits can be achieved by combining flutamide (Flu, a generic androgen-receptor blocker) and metformin (Met, a generic insulin sensitizer) in both nonobese and obese women with PCOS (6Ibáñez L. Valls C. Ferrer A. Ong K. Dunger D. de Zegher F. Additive effects of insulin-sensitizing and antiandrogen treatment in young, nonobese women with hyperinsulinism, hyperandrogenism, dyslipidemia and anovulation.J Clin Endocrinol Metab. 2002; 87: 2870-2874Crossref PubMed Scopus (106) Google Scholar, 7Gambineri A. Pelusi C. Genghini S. Morselli-Labate A.M. Cacciari M. Pagotto U. Pasquali R. Effect of flutamide and metformin administered alone or in combination in dieting obese women with polycystic ovary syndrome.Clin Endocrinol. 2004; 60: 241-249Crossref PubMed Scopus (174) Google Scholar). Randomized studies indicate that low-dose Flu-Met normalizes the adolescent PCOS spectrum more than OC. In young women, the PCOS spectrum was found to be more normalized by OC plus Flu-Met than by OC alone (8Ibáñez L. de Zegher F. Ethinylestradiol-drospirenone, flutamide-metformin, or both for adolescents and young women with hyperinsulinemic hyper-androgenism opposite effects on adipocytokines and body adiposity.J Clin Endocrinol Metab. 2004; 89: 1592-1597Crossref PubMed Scopus (147) Google Scholar, 9Ibáñez L. Valls C. de Zegher F. Discontinuous flutamide-metformin plus an oral or a transdermal contraceptive in patients with hyperinsulinemic hyperandrogenism normalizing effects on C-reactive protein, tumor necrosis factor-α and the neutrophil/lymphocyte ratio.Hum Reprod. 2006; 21: 451-456Crossref PubMed Scopus (24) Google Scholar); Table 1 lists the relative efficacy of these treatments for a series of PCOS features. Available experience (for up to 5 yrs) indicates that low-dose flutamide is not hepatotoxic in young and nonobese patients with PCOS (10Ibáñez L. Jaramillo A. Ferrer A. de Zegher F. Absence of hepatotoxicity after long-term, low-dose flutamide in hyperandrogenic girls and young women.Hum Reprod. 2005; 20: 1833-1836Crossref PubMed Scopus (47) Google Scholar).TABLE 1Relative efficacies of flutamide (Flu) plus metformin (Met) as compared with oral contraceptives (OC) alone or in combination in adolescents and young women with hyperinsulinemic hyperandrogenism.Most normalizing therapyOC vs. [Flu-Met] in adolescentsOC vs. [OC + Flu-Met] in young womenHyperandrogenemiacomparablecomparableReduced insulin sensitivityFlu-MetOC + Flu-MetDyslipidemia High LDLFlu-MetOC + Flu-Met Low HDLFlu-MetOC + Flu-Met High triglyceridesFlu-MetOC + Flu-MetAnovulation(Flu-Met)Body Adiposity Low Lean MassFlu-MetOC + Flu-Met High Fat MassFlu-MetOC + Flu-MetProinflammatory state High IL-6, TNF-α, and/or CRPFlu-MetOC + Flu-Met Low adiponectinFlu-MetOC + Flu-Met High neutrophil countFlu-MetOC + Flu-MetNote: LDL = low-density lipoprotein; HDL = high-density lipoprotein; IL-6 = interleukin-6; TNF-α = tumor necrosis factor α; CRP = C-reactive protein.Ibáñez and de Zegher. Flutamide-metformin for PCOS. Fertil Steril 2006. Open table in a new tab Note: LDL = low-density lipoprotein; HDL = high-density lipoprotein; IL-6 = interleukin-6; TNF-α = tumor necrosis factor α; CRP = C-reactive protein. Ibáñez and de Zegher. Flutamide-metformin for PCOS. Fertil Steril 2006. In summary, within the pathophysiologic cascade of PCOS, Flu-Met seems to counter upstream anomalies such as hyperinsulinemia or hyperandrogenism, thereby preventing or reversing downstream effects. In contrast, OC essentially masks downstream symptoms such as hirsutism, acne, and irregular menses, but the upstream aberrations remain unaltered or may even be worsened. So far, the experience with Flu-Met is limited but promising. We emphasize that Flu-Met may induce ovulation but is contraindicated postconception because of potential embryotoxicity; therefore, it seems wise to combine Flu-Met with an oral or transdermal estroprogestagen (9Ibáñez L. Valls C. de Zegher F. Discontinuous flutamide-metformin plus an oral or a transdermal contraceptive in patients with hyperinsulinemic hyperandrogenism normalizing effects on C-reactive protein, tumor necrosis factor-α and the neutrophil/lymphocyte ratio.Hum Reprod. 2006; 21: 451-456Crossref PubMed Scopus (24) Google Scholar) or a nonendocrine method of contraception. Until the abovementioned effects have been broadly confirmed, Flu-Met should not yet be regarded as a standard therapy for widespread clinical practice.