1 Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona, 08950 Esplugues, Barcelona, Spain and 2 Department of Pediatrics, University of Leuven, 3000 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: libanez{at}hsjdbcn.org
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Abstract |
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Key words: dyslipidaemia/flutamide/hyperinsulinism/metformin/oral contraception
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Introduction |
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The endocrine-metabolic status of 31 non-obese, young women with PCOS was recently found to be normalized more effectively by combined treatment with flutamide (250 mg/day) and metformin (1275 mg/day) than by either of these drugs in monotherapy, over 9 months; flutamide-metformin proved particularly effective in correcting dyslipidaemia and hyperandrogenaemia (Ibáñez et al., 2002).
An epi-phenomenon of flutamide-metformin therapy was a striking increment in the ovulation rate, thus pointing to the possible need for concomitant contraception (since flutamide is contra-indicated in pregnancy) and raising the question whether the benefits of the combined flutamide-metformin treatment would be maintained, if an oral contraceptive (OC) were added (Ibáñez et al., 2002).
To answer this question, we report here on the course of the original study cohort (Ibáñez et al., 2002) during the 9 months following a period of 9 months on flutamide and/or metformin treatment, for a total follow-up of 18 months.
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Materials and methods |
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All women had: (i) hyperinsulinaemia on standard 2 h oral glucose tolerance testing (oGTT), defined as peak serum insulin concentration >150 µU/ml (Vidal-Puig and Moller, 1997) and/or mean serum insulin (MSI) >84 mU/l (Ibáñez et al., 1997
); (ii) ovarian hyperandrogenism, as defined by hirsutism (score
8 on Ferriman-Gallwey scale) (Ferriman and Gallwey, 1961
), plus elevated serum androstenedione, total testosterone and/or free androgen index [testosterone x 100/sex hormone-binding globulin (SHBG)], an index of free testosterone (Ibáñez et al., 1994
); and 17-hydroxyprogesterone (17-OHP) hyperresponse (>160 ng/dl) to leuprolide acetate, a GnRH agonist (Procrin, Abbott, Madrid, Spain) (Ibáñez et al., 1994
).
None of the women had a body mass index (BMI) >25 kg/m2; thyroid dysfunction; hyperprolactinaemia; abnormal glucose tolerance (The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 1997); a family or personal history of diabetes mellitus; late-onset congenital adrenal hyperplasia (New et al., 1983
; Sakkal-Alkadour et al., 1996
); evidence of thromboembolic or hepatic disease, or was receiving a medication known to affect gonadal or adrenal function, or carbohydrate- or lipid-metabolism.
Study design
The study protocol is summarized in Figure 1. At the start of the study, women were randomized to receive, once daily, flutamide (Eulexin, Schering-Plough, Spain, 250 mg), metformin (Dianben, Andreu-Roche, Spain, 1275 mg) or flutamide-metformin (250 mg and 1275 mg) for 9 months (Ibáñez et al., 2002). Between months 912, all women received flutamide-metformin (Flu-Met), but with a lower flutamide dose (125 mg/day). Between months 1218, a monophasic, low-dose estro-progestogen OC (ethinyl estradiol 20 µg + gestodene 75 µg; Meliane, Schering) was also taken to avoid pregnancy risk. A total of 12 young women elected to take an OC (OC+), and this subgroup was then matched to a subgroup of 12 women who continued on Flu-Met alone (OC); clinical and endocrine-metabolic variables were matched, not only at 0 months, but also at 12 months, by which time a considerable normalization of the endocrine-metabolic state had occurred (Tables I and II).
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Hormonal assays
Serum glucose was measured by the glucose oxidase method. Immunoreactive insulin was assayed by IMx (Abbott Diagnostics, Santa Clara, CA, USA). The mean intra- and inter-assay coefficients of variation (CVs) were 4.7 and 7.2% respectively. LH, FSH and progesterone were measured by immuno-chemiluminescence (IMMULITE 2000; Diagnostic Products Corp, Los Angeles, CA, USA), with CVs of 3.5 and 5.0% for LH, 4.6 and 6.3% for FSH, and 7.8 and 8.5% for progesterone. Serum testosterone, 17-OHP, androstenedione, estradiol, SHBG and DHEAS levels were assayed as previously described (Ibáñez et al., 2002). Serum samples were kept frozen at 20°C until assay.
Statistics and ethics
Results are expressed as mean ± SEM. Two-sided t-test was used for statistical comparisons, unless mentioned otherwise; significance level was set at P < 0.01.
The study protocol was approved by the Institutional Review Board of Sant Joan de Déu, Barcelona University Hospital. Informed consent was obtained from each woman.
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Results |
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Within the OC subgroup, 12 versus 18 months comparisons indicate that the newly induced equilibrium remains stable over those 6 months with no significant changes in the clinical or endocrine-metabolic parameters. Such novel equilibrium is also maintained in the OC+ subgroup, except for an additional (and expected) increment in SHBG, and thus a further drop in the free androgen index.
Each treatment regimen was well tolerated; indices of hepatic and renal function were stable throughout the study.
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Discussion |
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Monotherapy with OCs has long been considered the first therapeutic approach in PCOS women who wish to get pregnant. These drugs increase circulating SHBG and suppress adrenal and ovarian androgen production, and thus reduce the clinical markers of androgen excess (Coenen et al., 1996; Venturoli et al., 1999
); in addition, their use does not seem to be associated with an increased risk of breast cancer, even when started at a young age (Marchbanks et al., 2002
). However, the effects of OCs on PCOS-associated dyslipidaemia and hyperinsulinism are still controversial (Crook et al., 1993
; Pedersen et al., 2000
; Cibula et al., 2002
). For example, a combination of ethinyl estradiol and cyproterone-acetate (2 mg/day), one of the most commonly prescribed regimens for PCOS, is effective in reducing hirsutism (Venturoli et al., 1999
), but may facilitate weight gain and decrease both insulin sensitivity and circulating high-density lipoprotein (HDL)-cholesterol (Venturoli et al., 1999
; Morin-Papunen et al., 2000
; Carmina., 2002
); in turn, these adverse effects may be reduced by the addition of metformin (Elter et al., 2002
), but the long-term efficacy and safety of such a combination remain to be established.
Combined flutamide-metformin therapy was well-tolerated in both the OC+ and OC subgroups. The safety and efficacy of metformin in PCOS has been addressed in many populations, including in adolescents and pregnant women (Nestler and Jakubowicz, 1997; Nestler et al., 1998
; Ibáñez et al., 2000b
, 2001; Moghetti et al., 2000
; Glueck et al., 2002
, Jakubowicz et al., 2002
). The side-effects of flutamide are essentially dose-dependent (Muderris et al., 1997
); hepatotoxicity is a potential complication with daily doses >500 mg (Wysowski et al., 1993
), this cut-off dose being 4-fold higher than the flutamide dose used in the present study.
In conclusion, when a low-dose OC is added to low-dose flutamide-metformin in women with PCOS, then the beneficial effects are maintained on hyperinsulinaemia and dyslipidaemia, which are the key determinants of the long-term complications of PCOS. Hence, in daily practice, such a low-dose quatuor may become a therapeutic option of first choice for women with PCOS.
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Acknowledgements |
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References |
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Submitted on July 10, 2002; resubmitted on August 29, 2002. accepted on October 15, 2002