Hum. Reprod. Advance Access originally published online on June 30, 2004
Human Reproduction 2004 19(8):1725-1727; doi:10.1093/humrep/deh329
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Flutamide–metformin plus an oral contraceptive (OC) for young women with polycystic ovary syndrome: switch from third- to fourth-generation OC reduces body adiposity
1 Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona, Spain and 2 Department of Pediatrics, University of 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. Email: libanez{at}hsjdbcn.org
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Abstract |
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 Top Abstract IntroductionStudy population and methodsResultsDiscussionAcknowledgementsReferences |
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BACKGROUND: Low-dose flutamide–metformin has been developed as a background therapy for non-obese adolescents and young women with hyperinsulinaemic hyperandrogenism, a variant of polycystic ovary syndrome (PCOS). We verified whether the lipolytic efficacy of flutamide–metformin in women with PCOS is enhanced by giving an oral contraceptive (OC) co-therapy that contains drospirenone, instead of gestodene, as progestin. METHODS: An open-labelled study was carried out in which non-obese women with PCOS (n=29; age
20 years), who had been on a combination of flutamide (62.5 mg/day), metformin (850 mg/day) and ethinylestradiol–gestodene for 8–15 months, were randomized for replacement of the gestodene OC by a drospirenone OC. Assessments of endocrine–metabolic state and body composition (by dual-energy X-ray absorptiometry) were performed at randomization and after 6 months. RESULTS: The switch to drospirenone OC was accompanied by a reduction of total and abdominal fat (mean –0.8 and –0.5 kg) and by an increment of lean body mass (+0.6 kg; all P<0.01), so that body adiposity was strikingly reduced without changing body weight. CONCLUSION: In non-obese women with PCOS, low-dose flutamide–metformin reduces total and abdominal fat excess more effectively if contraceptive co-therapy contains drospirenone, instead of gestodene, as progestin.
Key words: abdominal fat mass/drospirenone/flutamide/metformin/PCOS
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Introduction |
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TopAbstractIntroductionStudy population and methodsResultsDiscussionAcknowledgementsReferences |
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Low-dose flutamide–metformin has been developed as a background therapy for non-obese adolescents and young women with hyperinsulinaemic hyperandrogenism, a variant of polycystic ovary syndrome (PCOS); low-dose flutamide–metformin improves a broad spectrum of PCOS anomalies, including hyperinsulinaemia, hyperandrogenaemia, hypersomatotropism, anovulation, dyslipidaemia, dysadipocytokinaemia, ovarian artery hyper-resistance, lean mass deficit, and excess of total and abdominal fat mass (Ibáñez and de Zegher, 2003a
, 2004a; Ibáñez et al., 2003). Flutamide is an androgen receptor blocker that is contra-indicated in pregnancy; therefore, an oral contraceptive (OC) is often added as a safety measure, that also happens to augment circulating sex hormone-binding globulin (SHBG) (Ibáñez and de Zegher, 2003b).
Independent study cohorts have disclosed that the efficacy of flutamide–metformin in reducing the body adiposity of PCOS is counteracted by the co-presence of a third-generation OC with gestodene (Ibáñez and de Zegher, 2003a), and less so by the co-presence of a fourth-generation OC with drospirenone (Ibáñez and de Zegher, 2004a). We have now performed a follow-up study in which young PCOS women on the combination of flutamide–metformin plus ethinylestradiol–gestodene were randomized for replacement of the gestodene OC by a drospirenone OC.
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Study population and methods |
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TopAbstractIntroductionStudy population and methodsResultsDiscussionAcknowledgementsReferences |
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The study population consisted of 29 non-obese, young women [age 19.7±0.3 years; range 15–23; body mass index (BMI) <26 kg/m2; 4–11 years post-menarche; Table I) who had participated in earlier studies (Ibáñez and de Zegher, 2003a
,b; Ibáñez et al., 2003), in which the two criteria for their PCOS diagnosis were described: (i) hyperinsulinaemia during a 2 h oral glucose tolerance test, defined as peak serum insulin >150 mU/ml (Vidal-Puig and Moller, 1997) and/or mean insulin >84 mU/ml (Ibáñez et al., 2003); and (ii) ovarian hyperandrogenism as defined by mild oligomenorrhoea (<10 cycles per year), severe oligomenorrhoea (<6 cycles per year), amenorrhoea (no menses for >6 months) and/or hirsutism (Ferriman and Gallwey score >8) (Ferriman and Gallwey, 1961); elevated serum androstenedione, total testosterone and/or free androgen index (testosterone x100/SHBG); and a 17-hydroxyprogesterone hyper-response (>160 ng/dl) to GnRH agonist (Ibáñez et al., 1994).
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Prior to this open-labelled study, the participating PCOS women had been treated for a mean duration of 11 months (range 8–15 months) with flutamide (62.5 mg/day), metformin (850 mg/day) and a third-generation OC (Meliane; Schering; 21 days/month; 20 µg of ethinylestradiol and 75 µg of gestodene). The women were randomized to continue on the same combination (Flu–Met and gestodene OC) or to switch to a fourth-generation OC [Yasmin; Schering; 21 days/month; 30 µg of ethinylestradiol and 3 mg of drospirenone (Flu–Met and drospirenone OC)] for 6 months. Patients were randomly (1:1 ratio) allocated according to a list generated by the Gran Mos computer program, prior to study start. Patients meeting the study criteria were included consecutively (continue OC versus switch OC), according to their position within this list.
Fasting blood glucose, serum insulin, lipid profile, SHBG and testosterone were measured, and body composition was assessed by dual-energy X-ray absorptiometry (with a Lunar Prodigy) at 0 and 6 months, together with safety indices of hepatic and renal function, as described (Ibáñez and de Zegher, 2003a,b, 2004a; Ibáñez et al., 2003). Comparisons were performed by t-test, with significance level at P<0.05. For uniformity, results are expressed as mean±SEM.
The study was conducted in Barcelona, after approval by the Institutional Review Board of the Sant Joan de Déu University Hospital; informed consent was obtained from young women and/or from their parents, with assent from minors.
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Results |
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TopAbstractIntroductionStudy population and methodsResultsDiscussionAcknowledgementsReferences |
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The switch from gestodene OC to drospirenone OC had no readily detectable impact on the endocrine–metabolic indices, but was accompanied by a substantial reduction of total and abdominal fat, and by an equivalent increment of lean body mass (Table I), so that body adiposity was reduced without changing body weight. Within 6 months, abdominal fat excess increased further in most non-switching women (13 out of 14), while it decreased in all (15 out of 15) women who had switched to drospirenone OC (Figure 1). Each treatment was well tolerated; indices of hepatic and renal function remained stable.
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; n=14) or to switch from a gestodene OC to a drospirenone OC (•; n=15), while background therapy with low-dose flutamide–metformin remained unaltered in both subgroups. The switch from gestodene OC to drospirenone OC was accompanied by a loss of abdominal fat excess, as judged by dual-energy X-ray absorptiometry. See |
Discussion |
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TopAbstractIntroductionStudy population and methodsResultsDiscussionAcknowledgementsReferences |
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In women with hyperinsulinaemic hyperandrogenism, the capacity of flutamide–metformin to reduce body and abdominal fat excess was found recently to depend on whether a gestodene OC or a drospirenone OC was added as contraceptive safety measure (Ibáñez and de Zegher, 2003a
, 2004b). Those findings from independent cohorts have now been corroborated by a randomized study within a single cohort.
In adolescents and women with non-obese PCOS, monotherapy with drospirenone OC does not result in a reduction of abdominal fat excess; however, a striking loss of abdominal fat is observed when drospirenone OC is combined with flutamide–metformin (Ibáñez and de Zegher, 2004a); such a loss is less obvious when only flutamide or metformin is added (Ibáñez and de Zegher, 2004a 2004b; and unpublished observations). The loss of fat mass and the gain of lean mass on flutamide–metformin plus drospirenone OC are known to be linked to improved dysadipocytokinaemia (as judged by circulating interleukin-6 and adiponectin) rather than to changes in classic markers such as high-density lipoprotein (HDL)-cholesterol or triglycerides (Ibáñez and de Zegher, 2004a). Hence, it is consistent with previous evidence that OCs with comparable effects on circulating lipids may have quite divergent effects on the abdominal fat excess that characterizes the body composition of young women with PCOS.
The differential effects of gestodene OC versus drospirenone OC on the total and abdominal adiposity of PCOS women on flutamide–metformin remain to be fully elucidated. There is no evidence to speculate that these differential effects are attributable to the difference in ethinylestradiol dose within the compared OCs. The differential effects are more likely to reflect divergence in the pharmacological properties of the studied progestins: gestodene is more androgen- and glucocorticoid-like, whereas drospirenone is claimed to be more anti-androgenic (Krattenmacher, 2000; Schindler et al., 2003). Hence, it is plausible that gestodene and drospirenone modulate the anti-androgenic activity of flutamide in opposite directions and, in PCOS women, flutamide (not drospirenone) action is known to be pivotal in order to achieve lipolysis, to reduce lean mass deficit and to restore adipocytokine balance with low-dose flutamide–metformin plus drospirenone OC (Ibáñez et al., 2004b). In other words, although drospirenone itself (as used in fourth-generation OCs) may not be a clinically relevant anti-androgen (Ibáñez et al., 2004b), it seems to be a progestin that, in contrast to gestodene, allows flutamide to exert its anti-androgen actions.
In conclusion, flutamide–metformin reduces total and abdominal fat excess more effectively in women with PCOS if contraceptive co-therapy contains drospirenone rather than gestodene.
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Acknowledgements |
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TopAbstractIntroductionStudy population and methodsResultsDiscussionAcknowledgementsReferences |
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We thank Carme Valls, MD and Montserrat Gallart for hormone measurements. Supported by the Social Security Research Fund, Health Institute Carlos III, Spain (PI/021010). F.d.Z. is a Clinical Research Investigator of the Fund for Scientific Research, Flanders, Belgium.
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References |
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TopAbstractIntroductionStudy population and methodsResultsDiscussionAcknowledgementsReferences |
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Ferriman D and Gallwey JD (1961) Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 21, 1440–1447.[ISI][Medline]
Ibáñez L and de Zegher F (2003a) Flutamide-metformin therapy to reduce fat mass in hyperinsulinemic ovarian hyperandrogenism: effects in adolescents and in women on third-generation oral contraception. J Clin Endocrinol Metab 88, 4720–4724.
Ibáñez L and de Zegher F (2003b) Low-dose combination of flutamide, metformin and an oral contraceptive for non-obese, young women with polycystic ovary syndrome. Hum Reprod 18, 57–60.
Ibáñez L and de Zegher F (2004a) Ethinylestradiol-drospirenone, flutamide-metformin, or both for adolescents and women with hyperinsulinemic hyperandrogenism: opposite effects on adipocytokines and body adiposity. J Clin Endocrinol Metab 89, 1592–1597.
Ibáñez L, Potau N, Zampolli M, Prat N, Gussinyé M, Saenger P, Vicens-Calvet E and Carrascosa A (1994) Source localization of androgen excess in adolescent girls. J Clin Endocrinol Metab 79, 1778–1784.[Abstract]
Ibáñez L, Ong K, Ferrer A, Amin R, Dunger D and de Zegher F (2003) Low-dose flutamide-metformin therapy reverses insulin resistance and reduces fat mass in non-obese adolescents and young women with ovarian hyperandrogenism. J Clin Endocrinol Metab 88, 2600–2606.
Ibáñez L, Valls C, Cabré S and de Zegher F (2004b) Flutamide-metformin plus ethinylestradiol-drospirenone for lipolysis and anti-atherogenesis in young women with ovarian hyperandrogenism: the key role of early, low-dose flutamide. J Clin Endocrinol Metab, in press.
Krattenmacher R (2000) Drospirenone: pharmacology and pharmacokinetics of a unique progestogen. Contraception 62, 29–38.[CrossRef][ISI][Medline]
Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW et al. (2003) Classification and pharmacology of progestins. Maturitas 46S1, S7–S16.[CrossRef]
Vidal-Puig A and Moller DE (1997) Insulin resistance: classification, prevalence, clinical manifestations, and diagnosis. In Azziz R, Nestler JE and Dewailly D (eds) Androgen Excess Disorders in Women. Lippincott-Raven, Philadelphia, pp. 227–236.
Submitted on March 8, 2004; accepted on April 30, 2004.
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