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

Human Reproduction Update, Vol.12, No.3 pp. 243–252, 2006 Advance Access publication January 11, 2006 doi:10.1093/humupd/dmi054 Low-dose flutamide-metformin therapy for hyperinsulinemic hyperandrogenism in non-obese adolescents and women Lourdes Ibáñez1,3 and Francis de Zegher2 1 Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain and 2Department of Woman and Child, University of Leuven, Leuven, Belgium 3 To whom correspondence should be addressed at: Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona, Passeig de Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain. E-mail: Polycystic ovary syndrome (PCOS) is a variable disorder that is characterized in adolescents and young women by a broad spectrum of anomalies, including hyperandrogenemia, insulin resistance, dyslipidemia, body adiposity and low-grade inflammation. At present, there is no approved therapy for PCOS. Recent studies indicate that a low-dose combination of flutamide (Flu; a generic androgen-receptor blocker) and metformin (Met; a generic insulin-sensitizer) normalizes the adolescent PCOS spectrum more than an oral contraceptive (OC); in young women, the PCOS spectrum was found to be more normalized by OC plus Flu-Met than by OC alone. Within the pathophysiological cascade of PCOS, Flu-Met seems to counter upstream anomalies like hyperinsulinemia or hyperandrogenism, thereby preventing or reversing downstream effects. In contrast, an OC essentially masks downstream symptoms like hirsutism, acne or irregular menses, whereas the upstream aberrations remain unaltered or may even be worsened. The available experience with Flu-Met is limited but promising. We emphasize that Flu-Met may (as part of its efficacy) induce ovulation but is contra-indicated post-conception because of potential embryotoxicity; therefore, it seems wise to combine Flu-Met with an oral or a transdermal oestro-progestagen or with a non-endocrine method of contraception. May this update prompt further research into Flu-Met’s therapeutic potential in patients with PCOS. Until the abovementioned effects have been broadly confirmed, Flu-Met should not be regarded as a standard therapy for widespread clinical practice. Key words: drospirenone/flutamide/metformin/oral contraception/polycystic ovary syndrome Introduction It is now 70 years ago that the entity of ‘amenorrhea associated with bilateral polycystic ovaries’ was described (Stein and Leventhal, 1935). This condition was later broadened into polycystic ovary syndrome (PCOS), the main features of which are currently considered to be oligo- or an-ovulation, hyperandrogenism and a polycystic appearance of the ovaries (The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2004). The latter appearance may essentially be a late epiphenomenon of an early-onset disorder that includes endocrine, metabolic and inflammatory components. Indeed, PCOS is now recognized as the most prevalent endocrine-metabolic disorder of adolescents and young women; it is a condition that represents a major healthcare challenge, partly because of its co-morbidities including subfertility, dyslipidemia and cardiovascular disease (Asunción et al., 2000; Dunaif and Thomas, 2000; Azziz et al., 2004a, 2005; Buggs and Rosenfield, 2005). Acne and hirsutism are among the classic symptoms of PCOS; other features include a deficit of lean mass and an excess of fat, in particular of abdominal fat, even in the absence of obesity (Kirchengast and Huber, 2001; Ibáñez and de Zegher, 2003a; Ibáñez et al., 2003; Azziz et al., 2004a,b). Abdominal fat excess, endothelial dysfunction and impaired insulin sensitivity have each been related to the circulating levels of adiponectin and other adipocytokines, as well as to inflammatory markers such as interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), C-reactive protein (CRP) and the neutrophil count; hence, a prolonged state of low-grade inflammation and body adiposity is thought to contribute to the early appearance of cardiovascular disease in women with PCOS (Fernández-Real et al., 1998; Kelly et al., 2001; Morin-Papunen et al., 2003a; Rexrode et al., 2003; Boulman et al., 2004; Goldstein and Scalia, 2004; Ibáñez et al., 2004a, 2005c; Orio et al., 2004, 2005; Tarkun et al., 2004; Gonzalez et al., 2005; Ibáñez and de Zegher, 2005; Sjöholm and Nyström, 2005; Vural et al., 2005). At present, there is no approved therapy for PCOS in adolescents or women. 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 do not correct the low-grade inflammation, the adipose body composition and most other endocrine-metabolic anomalies (Baumann and Rosenfield, © The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: 243 L.Ibáñez and F.de Zegher 2002; Mastorakos et al., 2002; Diamanti-Kandarakis et al., 2003; Ibáñez and de Zegher, 2003a; Morin-Papunen et al., 2003b; Ibáñez et al., 2004a; Rautio et al., 2005; Vrbikova and Cibula, 2005). About 20 years ago, Dunaif recognized the importance of hyperinsulinemic insulin resistance in PCOS (Dunaif et al., 1985). This finding prompted the exploration of insulin-sensitization with metformin (Met) (Velazquez et al., 1994), an approach that is now broadly applied (reviewed by Lord et al., 2003; Cheang and Nestler, 2004; Kashyap et al., 2004; Checa et al., 2005; La Marca et al., 2005). In monotherapy, however, high doses of Met (∼2 g/day) may be needed (Nestler, 2001), and efficacy may still be suboptimal, even in non-obese adolescents (Ibáñez et al., 2000b). About 10 years ago, the therapeutic view on PCOS was further broadened by testing the potential of anti-androgens, flutamide (Flu) being a prime choice (Cusan et al., 1994; Diamanti-Kandarakis et al., 1995, 1998). Flu is a non-steroidal androgen-receptor blocker with pure anti-androgenic effects that are superior to those of spironolactone or cyproterone-acetate (Poyet and Labrie, 1985; Luthy et al., 1988; Cusan et al., 1994) and with a reassuring safety profile if given in a low dose (Diamanti-Kandarakis et al., 1998; Muderris et al., 2000; see in Low-dose Flu: hepatic safety section). In monotherapy, Flu has cosmetic benefits, attenuates the hyperandrogenemia and lowers serum low-density lipoprotein (LDL)-cholesterol, but it fails to improve insulin sensitivity or to raise high-density lipoprotein (HDL)-cholesterol (Diamanti-Kandarakis et al., 1995, 1998; Sahin et al., 2004), even in non-obese adolescents (Ibáñez et al., 2000a). Combination therapies are nowadays under accelerated investigation. For example, the addition of Met to an OC like ethinylestradiolcyproterone-acetate proved to result in a consistent benefit on insulin resistance and on androgen excess; however, the extrabenefit on dys (...truncated)