This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ibáñez, L. Articles by de Zegher, F. Search for Related Content PubMed PubMed Citation Articles by Ibáñez, L. Articles by de Zegher, F.

Flutamide-Metformin Therapy to Reduce Fat Mass in Hyperinsulinemic Ovarian Hyperandrogenism: Effects in Adolescents and in Women on Third-Generation Oral Contraception

Endocrinology Unit (L.I.), Hospital Sant Joan de Déu, University of Barcelona, 08950 Barcelona, Spain; and Department of Pediatrics (F.d.Z.), University of Leuven, 3000 Leuven, Belgium

Address all correspondence and requests for reprints to: Lourdes Ibáñez, M.D., Ph.D., 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.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Adolescents and young women with menstrual irregularities and hyperinsulinemic hyperandrogenism, so-called polycystic ovary syndrome, have abnormalities in body composition, even when nonobese. The combination of flutamide (125–250 mg/d) and metformin has additive benefits on endocrine- metabolic indices in women with polycystic ovary syndrome. However, it is unknown whether this combination also reverses the abnormalities in body composition in this population, especially if the flutamide dose is further reduced, the combination is given at a young age, and an oral contraceptive (OC) is added. Two randomized 3-month studies with flutamide-metformin were conducted in nonobese patients (n = 45) with hyperinsulinemic ovarian hyperandrogenism. In teenagers [n = 21; 15 yr; no use of OC (OC-)], we determined whether a minidose combination (flutamide 62.5 mg/d) improved body composition and endocrine-metabolic indices, and in young women (n = 24; 18 yr; OC+), we determined whether the addition of the minidose combination to a gestodene-containing OC exerted additive effects on the same variables. In OC- teenagers, flutamide-metformin improved fasting insulin/glucose ratio; serum IGF-binding protein-1, testosterone, SHBG, androstenedione, triglycerides, low- density lipoprotein and high-density lipoprotein cholesterol; lean mass, total fat, and abdominal fat (all P < 0.01). In OC+ women, the addition of flutamide-metformin was associated with gain of lean mass and loss of total fat (P < 0.01 vs. OC alone), but the addition failed to reduce abdominal fat. In conclusion, in nonobese adolescents with hyperinsulinemic ovarian hyperandrogenism, minidose flutamide-metformin reversed endocrine-metabolic anomalies and the excess of fat, including abdominal fat; in women, adding flutamide- metformin to a third-generation OC was also effective in improving body composition, but abdominal adiposity was not improved.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
IN ADOLESCENT GIRLS and young women, hyperinsulinemic ovarian hyperandrogenism is a common disorder that is known to confer risk for long-term complications, including cardiovascular disease. In some populations, this combination may be the forerunner of anovulatory polycystic ovary syndrome (PCOS). Insulin resistance and peripheral hyperinsulinemia contribute to the ovarian excess of androgen production (1, 2, 3).

Monotherapy with insulin-sensitizing or antiandrogen agents is partially effective in adolescents and young women with combinations of hyperinsulinism, hyperandrogenism, dyslipidemia, and anovulation (2, 3, 4, 5, 6, 7, 8, 9, 10). Each monotherapy acts through a separate pathway and, accordingly, has a different spectrum of endocrine-metabolic actions (11, 12, 13). The combination of flutamide (125–250 mg/d) and metformin (1275 mg/d) therapy has additive effects in these patients, particularly on hyperandrogenemia and dyslipidemia; thus, this combination may become part of a treatment of choice, with potential benefit for long-term prevention of cardiovascular disease (14, 15).

In women, centripetal fat distribution is related to excess androgen action (16, 17, 18). The body composition of young women with menstrual irregularity and hyperinsulinemic hyperandrogenism is hallmarked by a deficit of lean mass and an excess of central fat, which is a cardiovascular risk factor, even in the absence of obesity (19, 20, 21, 22).

Here we report on two pilot studies further exploring the potential of combined flutamide-metformin treatment. The first study determined whether a minidose combination, with flutamide at only 62.5 mg/d, is effective in correcting endocrine-metabolic indices and body composition in adolescent girls with hyperinsulinemic ovarian hyperandrogenism (age 15 yr). The second study was prompted by the observation that a rise in ovulation rate is an epiphenomenon of flutamide-metformin therapy in PCOS (14); because flutamide is contraindicated in pregnancy, this study determined whether the addition of the minidose combination to a third-generation oral contraceptive (OC) in young women with hyperinsulinemic ovarian hyperandrogenism (18 yr) has beneficial effects on their endocrine-metabolic state and body composition, in particular on abdominal fat mass.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

A total of 45 adolescents and young women participated. Adolescents who were not at risk of pregnancy (by history) were enrolled in one study (no OC given; OC-), whereas young women at possible risk were enrolled in the other (OC given; OC+). The OC- study population consisted of 21 teenagers (age 15 ± 0.3 yr; range 13–17 yr; postmenarche for 2–6 yr), and the OC+ study group consisted of 24 young women (18 ± 0.3 yr; 16–21 yr; postmenarche for 3–9 yr).

Inclusion criteria were hyperinsulinemia on a standard 2-h oral glucose tolerance testing, defined as peak serum insulin levels greater than 150 µU/ml and/or mean serum insulin (MSI) greater than 84 mU/liter (23, 24), and ovarian hyperandrogenism as defined by amenorrhea (absence of cycles for more than 3 months) or oligomenorrhea (cycle duration of > 45 d) and/or hirsutism (Ferriman and Gallwey score > 8) (25); elevated serum androstenedione and/or testosterone (26); and 17-hydroxyprogesterone hyperresponse (>160 ng/dl) to GnRH agonist (leuprolide acetate, Procrin, Abbott, Madrid, Spain, 500 µg sc) (26).

Exclusion criteria were body mass index >25 kg/m²; evidence for thyroid dysfunction, Cushing’s syndrome, hyperprolactinemia; glucose intolerance (27); family or personal history of diabetes mellitus; late-onset congenital adrenal hyperplasia (28, 29); taking of medication known to affect gonadal or adrenal function or carbohydrate-lipid metabolism; abnormal blood count or serum electrolytes; and abnormal results in screening tests for liver and kidney function.

The study was conducted in Barcelona, after approval by the Institutional Review Board of Hospital Sant Joan de Déu and after informed consent from parents and/or young women and assent from minors.

Study design

The OC- and OC+ studies were open labeled and had identical designs.

In the OC- study, the girls were randomized either to remain untreated [Flu-Met (-); n = 10] or receive the combination of two generics, flutamide in minidose (62.5 mg) and metformin (1275 mg), once daily at dinner time for 3 months [Flu-Met (+); n = 11].

In the OC+ study, all participants received a monophasic, low-dose estroprogestogen OC (Meliane, Schering; ethinyl-estradiol 20 µg + gestodene 75 µg, 21 d/month) and were randomized to receive OC alone [OC (+) Flu-Met (-); n = 13] or, in addition, the minidose combination of flutamide-metformin [OC (+) Flu-Met (+); n = 11].

Endocrine-metabolic assessment

Fasting glucose, insulin, lipid profile, SHBG, testosterone, androstenedione, and IGF-binding-protein 1 (IGFBP-1) were measured at baseline and after 3 months, together with indices of hepatic and renal function, as additional safety variables. Baseline hormonal assessments were performed in the follicular phase (d 3–7) or after 2 months of amenorrhea. Baseline values were compared with local references for postmenarcheal females of similar age (30, 31).

Body composition, hormone assays, and statistics

Body composition was assessed by dual-energy x-ray absorptiometry with a Lunar Prodigy coupled to Lunar software (version 3.4/3.5, Lunar Corp., Madison, WI) (32). Absolute (kilograms) whole-body fat and lean mass as well as fat content in the abdominal region, which was defined as the area encompassed between the dome of the diaphragm (cephalad limit) and the top of the great trochanter (caudal limit) were assessed (33). The total radiation dose for each examination was 0.1 mSievert. The coefficients of variation (CVs) for scanning precision, calculated from 30 consecutive scans of an external phantom (Hologic, Waltham, MA), were, respectively, 2.0% and 2.6% for fat and lean body mass (34); the intraindividual CV for abdominal fat mass was 0.7%. Body composition references were obtained from healthy volunteers matched for gender, age, height, body mass index, and ethnic background.

Serum glucose was measured by the glucose oxidase method. Immunoreactive insulin was assayed by IMX (Abbott, Santa Clara, CA); intra- and interassay CVs were 4.7% and 7.2%. Serum IGFBP-1 was measured by immunoradiometric assay (Diagnostic Systems Laboratories, Webster, TX); the lower limit of detection was 0.11 ng/ml; the intra- and interassay CVs were 4% and 5.3%. Serum testosterone, 17- hydroxyprogesterone, androstenedione, and SHBG levels were assayed as described (9). Samples were stored at -20 C until assay.

Anthropometric data and hormonal results are expressed as mean ± SEM. Two-sided t tests were used for statistical comparisons, with significance level at P < 0.01.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Tables 1 and 2 and Fig. 1 summarize the main findings. At start (0 months), there were no significant differences between the randomized subgroups. Each treatment was well tolerated; indices of hepatic and renal function remained stable.

View larger version (16K): [in this window] [in a new window]   FIG. 1. Changes (0–3 months) in lean body mass, body fat, and abdominal fat mass in two populations with hyperinsulinemic hyperandrogenism. Upper panels, Teenage girls (age, 15 yr), not receiving OC. Lower panels, Young women (age, 18 yr), starting all on OC at time 0. Each study population was randomized for treatment with flutamide-metformin (+) or not (-). Untreated girls with hyperinsulinemic ovarian hyperandrogenism present ongoing loss of lean mass and accumulation of fat excess. In young women on OCs, the deficit of lean mass is stable, as is the fat excess. The abnormalities in body composition were reversed by flutamide-metformin toward the norm, except for abdominal fat in young women on third-generation OC. Flutamide-metformin (-) vs. (+): **, P 0.01; ***, P 0.001.

In untreated girls, endocrine-metabolic indices remained unchanged over 3 months or diverged further away from the reference (Table 1; Fig. 1, upper panel). The menstrual pattern was also stable in these 10 girls, the distribution for normal/oligomenorrhea/amenorrhea being 5/4/1 at start and 4/6/0 after 3 months.

In girls receiving flutamide-metformin, all abnormal indices improved, including fasting insulin/glucose ratio; serum IGFBP-1, testosterone, SHBG, androstenedione, triglycerides, low-density lipoprotein and high-density lipoprotein cholesterol; total fat and abdominal fat mass, and lean mass (all P < 0.01 vs. untreated). At start, three of 11 girls had a regular menstrual pattern (cycles of 25–35 d) and eight of 11 girls were oligomenorrheic; in each of the latter, the menstrual pattern normalized within 3 months (intermenstrual interval 28–45 d; duration of menses 3–7 d).

Flutamide-metformin in young women with hyperinsulinemic ovarian hyperandrogenism on OC

In young women with PCOS receiving OC alone, body composition was unchanged over 3 months, despite beneficial endocrine-metabolic changes (testosterone; high- density lipoprotein cholesterol) and some pharmacological effects (rise in SHBG) (Table 2 and Fig. 1, lower panel).

In young women with PCOS who received flutamide-metformin in addition to OC, the additional endocrine-metabolic benefit was limited (low-density lipoprotein cholesterol); favorable effects on body composition were evidenced for lean body mass and total fat but not abdominal fat mass.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In nonobese adolescents and women with hyperinsulinemic ovarian hyperandrogenism, minidose flutamide in combination with metformin therapy, either given alone or added to a third-generation OC, increased lean body mass and reduced total fat mass. In adolescents, this reduction included abdominal fat.

The present data are additional evidence indicating that the excess fat in hyperinsulinemic ovarian hyperandrogenism is a consequence, rather than a cause, of the anomalies in the endocrine-metabolic equilibrium. It is known that central adiposity may in turn augment hyperinsulinemic hyperandrogenism, possibly by increasing circulating free fatty acids (35). Therefore, our findings are consistent with the existence of a positive feedback-loop, whereby the endocrine-metabolic changes and the central fat excess first aggravate and, subsequently, perpetuate each other. This concept suggests that early intervention may correct the adiposity of women with hyperinsulinemic ovarian hyperandrogenism.

The effects of flutamide-metformin on body composition were obtained without any instructions concerning diet, exercise, or lifestyle and also without changing body weight. These observations suggest that the body weight of nonobese women with hyperinsulinemic ovarian hyperandrogenism is less prone to modulation by insulin-androgen action than are their body composition, steroidogenesis, and carbohydrate-lipid metabolism.

Minidose flutamide and metformin treatment increased lean mass, and this increment matched the loss of fat mass. A similar effect, albeit less pronounced, has been observed with metformin therapy in anovulatory adolescents with mild hyperinsulinemic hyperandrogenism secondary to prenatal growth restraint (36), a condition that is hallmarked by reduced lean mass in early childhood (37) and central adiposity from late childhood onwards (38).

In the absence of oral contraception, the attenuations of endocrine-metabolic anomalies in teenage girls with hyperinsulinemic ovarian hyperandrogenism were of a magnitude similar to those in young women with PCOS using the same combination, but with flutamide at 125–250 mg/d (14, 15). A minidose of flutamide (1 mg/kg) now seems safe and effective to treat hyperinsulinemic hyperandrogenism, combined with metformin.

In the presence of an OC, the additional effects of flutamide-metformin were more readily detectable on body composition than on endocrine-metabolic variables, suggesting that an endocrine-metabolic assessment in the fasting state, as performed here, is less sensitive than dual-energy x-ray absorptiometry to detect the additional effects of flutamide-metformin. One of the explanations for this differential sensitivity may be that indices of body composition are more prone to cumulative effects than most endocrine- metabolic markers.

The capacity of flutamide-metformin to reduce abdominal fat mass (39) was not seen in the presence of a third-generation OC. This phenomenon may be attributable to the supraphysiological progestin actions of such OCs, which may have insulin-desensitizing effects (40).

In conclusion, in nonobese adolescents with hyperinsulinemic ovarian hyperandrogenism, minidose flutamide-metformin reversed endocrine-metabolic anomalies and the excess of fat, including abdominal fat; in women, adding flutamide-metformin to a third-generation OC was also effective in improving body composition, but abdominal adiposity was not improved.

	Acknowledgments

 
We thank Carme Valls, M.D., and Montserrat Gallart for hormone measurements.

	Footnotes

 
This work was supported by a Visiting Fellowship from the European Society for Pediatric Endocrinology. F.d.Z. is a Clinical Research Investigator of the Fund for Scientific Research, Flanders, Belgium.

Abbreviations: CV, Coefficient of variation; IGFBP-1, IGF-binding-protein 1; OC, oral contraceptive; OC-, no OC given; OC+, OC given; PCOS, polycystic ovary syndrome.

Received January 24, 2003.

Accepted July 15, 2003.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Dunaif A, Thomas A 2000 Current concepts in the polycystic ovary syndrome. Annu Rev Med 52:401–419[CrossRef]
2. Nestler JE, Jakubowicz DJ 1996 Decreases in ovarian cytochrome P450c17 activity and serum free testosterone after reduction in insulin secretion in polycystic ovary syndrome. N Engl J Med 335:617–623[Abstract/Free Full Text]
3. Nestler JE, Jakubowicz DJ 1997 Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 activity and serum androgens. J Clin Endocrinol Metab 82:4075–4079[Abstract/Free Full Text]
4. De Leo V, Lanzetta D, D’Antona D, la Marca A, Morgante G 1998 Hormonal effects of flutamide in young women with polycystic ovary syndrome. J Clin Endocrinol Metab 83:99–102[Abstract/Free Full Text]
5. Ibáñez L, Potau N, Marcos MV, de Zegher F 2000 Treatment of hirsutism, hyperandrogenism, oligomenorrhea, dyslipidemia and hyperinsulinism in non-obese, adolescent girls: effect of flutamide. J Clin Endocrinol Metab 85:3251–3255[Abstract/Free Full Text]
6. Moghetti P, Castello R, Negri C, Tosi F, Perrone F, Caputo M, Zanolin E, Muggeo M 2000 Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab 85:139–146[Abstract/Free Full Text]
7. Ibáñez L, Valls C, Potau N, Marcos MV, de Zegher F 2000 Sensitization to insulin in adolescent girls to normalize hirsutism, hyperandrogenism, oligomenorrhea, dyslipidemia, and hyperinsulinism after precocious pubarche. J Clin Endocrinol Metab 85:3526–3530[Abstract/Free Full Text]
8. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R 1998 Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med 338:1876–1880[Abstract/Free Full Text]
9. Ibáñez L, Valls C, Ferrer A, Marcos MV, Rodriguez-Hierro F, de Zegher F 2001 Sensitization to insulin induces ovulation in nonobese adolescents with anovulatory hyperandrogenism. J Clin Endocrinol Metab 86:3595–3598[Abstract/Free Full Text]
10. Azziz R, Ehrmann D, Legro RS, Whitcomb RW, Hanley R, Gmerek Fereshetian A, O’Keefe M, Ghazzi M, for the PCOS/Troglitazone Study Group 2001 Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial. J Clin Endocrinol Metab 86:1626–1632[Abstract/Free Full Text]
11. Simard J, Luthy I, Guay J, Berlanger A, Labrie F 1986 Characteristics of interaction of the antiandrogen flutamide with the androgen receptor in various target tissues. Mol Cell Endocrinol 44:261–270[CrossRef][Medline]
12. Bailey CJ, Path MRC, Turner RC 1996 Drug therapy. Metformin. N Engl J Med 334:574–579[Free Full Text]
13. Schoonjans K, Auwerx J 2000 Thiazolidinediones: an update. Lancet 355:1008–1010[CrossRef][Medline]
14. Ibáñez L, Valls C, Ferrer A, Ong K, Dunger D, de Zegher F 2002 Additive effects of insulin-sensitizing and antiandrogen treatment in young, nonobese women with hyperinsulinism, hyperandrogenism, dyslipidemia and anovulation. J Clin Endocrinol Metab 87:2870–2874[Abstract/Free Full Text]
15. Ibáñez L, de Zegher F 2003 Low-dose combination of flutamide, metformin and an oral contraceptive for non-obese, young women with polycystic ovary syndrome. Hum Reprod 18:57–60[Abstract/Free Full Text]
16. Lovejoy JC, Bray GA, Bourgeois MO, Macchiavelli Rood JC, Greeson C, Partington C 1996 Exogenous androgens influence body composition and regional body fat distribution in obese postmenopausal women—a clinical research center study. J Clin Endocrinol Metab 81:2198–2203[Abstract]
17. Elbers JM, Asscheman H, Seidell JC, Megens JA, Gooren LJ 1997 Long-term testosterone administration increases visceral fat in female to male transsexuals. J Clin Endocrinol Metab 82:2044–2047[Abstract/Free Full Text]
18. Nilsson C, Niklasson M, Eriksson E, Björntorp P, Hölmang A 1998 Imprinting of female offspring with testosterone results in insulin resistance and changes in body fat distribution at adult age in rats. J Clin Invest 101:74–78[Medline]
19. Kirchengast S, Huber J 2001 Body composition characteristics and body fat distribution in lean women with polycystic ovary syndrome. Hum Reprod 16:1255–1260[Abstract/Free Full Text]
20. Pech F, Bennet AP, Malet D, Tazi O, Perret B, Caron PJ, Louvet J, Functional adrenal and ovarian hyperandrogenism: body composition in patients with normal body mass index. Program of the 83rd Annual Meeting of The Endocrine Society, Denver, CO, 2001, p 381 (Abstract P2-411)
21. McFarlane SI, Banerji M, Sowers JR 2001 Insulin resistance and cardiovascular disease. J Clin Endocrinol Metab 86:713–718[Free Full Text]
22. Vanhala MJ, Pitkäjärvi TK, Kumpusalo EA, Takala JK 1998 Obesity type and clustering of insulin-resistance-associated cardiovascular risk factors in middle-aged men and women. Int J Obes 22:369–374[CrossRef]
23. Vidal-Puig A, Moller DE1997 Insulin resistance: Classification, prevalence, clinical manifestations, and diagnosis. In: Azziz R, Nestler JE, Dewailly D, eds. Androgen excess disorders in women. Philadelphia: Lippincott-Raven Publishers; 227–236
24. Ibáñez L, Potau N, Zampolli M, Riqué S, Saenger P, Carrascosa A 1997 Hyperinsulinemia and decreased insulin-like growth factor binding protein-1 are common features in prepubertal and pubertal girls with a history of premature pubarche. J Clin Endocrinol Metab 82:2283–2288[Abstract/Free Full Text]
25. Ferriman D, Gallwey JD 1961 Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 21:1440–1447
26. Ibáñez L, Potau N, Zampolli M, Prat N, Gussinyé M, Saenger P, Vicens-Calvet E, Carrascosa A 1994 Source localization of androgen excess in adolescent girls. J Clin Endocrinol Metab 79:1778–1784[Abstract]
27. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus 1997 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20:1183–1197.[Medline]
28. New MI, Lorenzen F, Lerner AJ, Kohn B, Oberfield SE, Pollack MS, Dupont B, Stoner E, Levy DJ, Pang S, Levine LS 1983 Genotyping steroid 21-hydroxylase deficiency: hormonal reference data. J Clin Endocrinol Metab 56:320–325[Abstract/Free Full Text]
29. Sakkal-Alkaddour H, Zhang L, Yang X, Chang YT, Kappy M, Slover RS 1996 Studies of 3ß-hydroxysteroid dehydrogenase genes in infants and children manifesting premature pubarche and increased adrenocorticotropin-stimulated 5-steroid levels. J Clin Endocrinol Metab 81:3961–3965[Abstract/Free Full Text]
30. Potau N, Ibáñez L, Sentis M, Carrascosa A 1999 Sexual dimorphism in the maturation of the pituitary-gonadal axis, assessed by GnRH agonist challenge. Eur J Endocrinol 141:27–34[Abstract]
31. Ibañez L, Potau N, Chacón P, Pascual C, Carrascosa A 1998 Hyperinsulinemia, dyslipidaemia and cardiovascular risk in girls with a history of premature pubarche. Diabetologia 41:1057–1063[CrossRef][Medline]
32. Ibáñez L, Potau N, Ong K, Dunger DB, de Zegher F 2000 Increased bone mineral density and serum leptin in non-obese girls with precocious pubarche: relation to low birth weight and hyperinsulinism. Horm Res 54:192–197[CrossRef][Medline]
33. Taylor RW, Keil D, Gold EJ, Williams SM, Goulding A 1998 Body mass index, waist girth, and waist-to-hip ratio as indexes of total and regional adiposity in women: evaluation using receiver operating characteristic curves. Am J Clin Nutr 67:44–49[Abstract]
34. Kiebzak GM, Leamy LJ, Pierson LM, Nord RH, Zhang ZY 2000 Measurement precision of body composition variables using the Lunar DPX-L densitometer. J Clin Densitom 3:35–41[CrossRef][Medline]
35. Hanley AJG, McKeown-Eyssen G, Harris SB, Hegele RA, Wolever TMS, Kwan J, Zinman B 2002 Cross-sectional and prospective associations between abdominal obesity and proinsulin concentration. J Clin Endocrinol Metab 87:77–83[Abstract/Free Full Text]
36. Ibañez L, Potau N, Ferrer A, Rodriguez-Hierro F, Marcos MV, de Zegher F 2002 Anovulation in adolescent girls born small for gestational age: insulin sensitization induces ovulation, increases lean body mass, and reduces abdominal fat excess, dyslipidemia and subclinical hyperandrogenism. J Clin Endocrinol Metab 87:5702–5705[Abstract/Free Full Text]
37. Hediger ML, Overpeck MD, Kuczmarski RJ, McGlynn A, Maurer KR, Davis WW 1998 Muscularity and fatness of infants and young children born small or large for gestational age. Pediatrics 102:e60
38. Garnett SP, Cowell CT, Baur LA, Fay RA, Lee J, Coakley J, Peat JK, Boulton TJ 2001 Abdominal fat and birth size in healthy prepubertal children. Int J Obes 25:1667–1673
39. Ibáñez L, Ong K, Ferrer A, Amin R, Dunger D, 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[Abstract/Free Full Text]
40. Picard F, Wanatabe M, Schoonjans K, Lydon J, O’Malley BW, Auwerx J 2002 Progesterone receptor knockout mice have an improved glucose homeostasis secondary to beta-cell proliferation. Proc Natl Acad Sci USA 99:15644–15648[Abstract/Free Full Text]

This article has been cited by other articles:

				K. K Ong, F. de Zegher, A. Lopez-Bermejo, D. B Dunger, and L. Ibanez Flutamide metformin for post-menarcheal girls with preclinical ovarian androgen excess: evidence for differential response by androgen receptor genotype Eur. J. Endocrinol., November 1, 2007; 157(5): 661 - 668. [Abstract] [Full Text] [PDF]

				L. Ibanez, A. Lopez-Bermejo, L. del Rio, G. Enriquez, C. Valls, and F. de Zegher Combined Low-Dose Pioglitazone, Flutamide, and Metformin for Women with Androgen Excess J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1710 - 1714. [Abstract] [Full Text] [PDF]

				S. Srinivasan, G. R. Ambler, L. A. Baur, S. P. Garnett, M. Tepsa, F. Yap, G. M. Ward, and C. T. Cowell Randomized, Controlled Trial of Metformin for Obesity and Insulin Resistance in Children and Adolescents: Improvement in Body Composition and Fasting Insulin J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2074 - 2080. [Abstract] [Full Text] [PDF]

				L. Ibanez and F. de Zegher Low-dose flutamide-metformin therapy for hyperinsulinemic hyperandrogenism in non-obese adolescents and women Hum. Reprod. Update, May 1, 2006; 12(3): 243 - 252. [Abstract] [Full Text] [PDF]

				J. C. Marshall Obesity in Adolescent Girls: Is Excess Androgen the Real Bad Actor? J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 393 - 395. [Full Text] [PDF]

				A. D. Coviello, R. S. Legro, and A. Dunaif Adolescent Girls with Polycystic Ovary Syndrome Have an Increased Risk of the Metabolic Syndrome Associated with Increasing Androgen Levels Independent of Obesity and Insulin Resistance J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 492 - 497. [Abstract] [Full Text] [PDF]

				L. Ibanez, C. Valls, and F. de Zegher Discontinuous low-dose flutamide-metformin plus an oral or a transdermal contraceptive in patients with hyperinsulinaemic hyperandrogenism: normalizing effects on CRP, TNF-{alpha} and the neutrophil/lymphocyte ratio Hum. Reprod., February 1, 2006; 21(2): 451 - 456. [Abstract] [Full Text] [PDF]

				M. Hero, O. A. Janne, K. Nanto-Salonen, L. Dunkel, and T. Raivio Circulating Antiandrogenic Activity in Children with Congenital Adrenal Hyperplasia during Peroral Flutamide Treatment J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5141 - 5145. [Abstract] [Full Text] [PDF]

				L. Ibanez, A. M. Jaramillo, A. Ferrer, and F. de Zegher High neutrophil count in girls and women with hyperinsulinaemic hyperandrogenism: normalization with metformin and flutamide overcomes the aggravation by oral contraception Hum. Reprod., September 1, 2005; 20(9): 2457 - 2462. [Abstract] [Full Text] [PDF]

				L. Ibanez, A. Jaramillo, A. Ferrer, and F. de Zegher Absence of hepatotoxicity after long-term, low-dose flutamide in hyperandrogenic girls and young women Hum. Reprod., July 1, 2005; 20(7): 1833 - 1836. [Abstract] [Full Text] [PDF]

				J. Vrbikova and D. Cibula Combined oral contraceptives in the treatment of polycystic ovary syndrome Hum. Reprod. Update, May 1, 2005; 11(3): 277 - 291. [Abstract] [Full Text] [PDF]

				L. Ibanez and F. d. Zegher Flutamide-Metformin plus Ethinylestradiol-Drospirenone for Lipolysis and Antiatherogenesis in Young Women with Ovarian Hyperandrogenism: The Key Role of Metformin at the Start and after More than One Year of Therapy J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 39 - 43. [Abstract] [Full Text] [PDF]

				L. Ibanez, C. Valls, S. Cabre, and F. de Zegher Flutamide-Metformin Plus Ethinylestradiol-Drospirenone for Lipolysis and Antiatherogenesis in Young Women with Ovarian Hyperandrogenism: The Key Role of Early, Low-Dose Flutamide J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4716 - 4720. [Abstract] [Full Text] [PDF]

				L. Ibanez and F. de Zegher Flutamide-metformin plus an oral contraceptive (OC) for young women with polycystic ovary syndrome: switch from third- to fourth-generation OC reduces body adiposity Hum. Reprod., August 1, 2004; 19(8): 1725 - 1727. [Abstract] [Full Text] [PDF]

				D. J. Salmi, H. C. Zisser, and L. Jovanovic Screening for and Treatment of Polycystic Ovary Syndrome in Teenagers Experimental Biology and Medicine, May 1, 2004; 229(5): 369 - 377. [Abstract] [Full Text] [PDF]

				L. Ibanez and F. de Zegher Ethinylestradiol-Drospirenone, Flutamide-Metformin, or Both for Adolescents and Women with Hyperinsulinemic Hyperandrogenism: Opposite Effects on Adipocytokines and Body Adiposity J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1592 - 1597. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ibáñez, L. Articles by de Zegher, F. Search for Related Content PubMed PubMed Citation Articles by Ibáñez, L. Articles by de Zegher, F.