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Additive Effects of Insulin-Sensitizing and Anti-Androgen Treatment in Young, Nonobese Women with Hyperinsulinism, Hyperandrogenism, Dyslipidemia, and Anovulation

Endocrinology Unit (L.I., A.F.) and Hormonal Laboratory (C.V.), Hospital Sant Joan de Déu, University of Barcelona, 08950 Barcelona, Spain; Department of Pediatrics (K.O., D.B.D.), University of Cambridge, Cambridge CB2 2QQ, United Kingdom; and Department of Pediatrics (F.d.Z.), University of Leuven, B-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

The endocrine-metabolic hallmarks of polycystic ovary syndrome are hyperinsulinism, hyperandrogenism, dyslipidemia, and anovulation. We hypothesized that dyslipidemia and anovulation in nonobese women with polycystic ovary syndrome are essentially secondary to the concerted effects of hyperandrogenism and insulin resistance.

We tested this hypothesis by comparing the efficacy of anti-androgen (flutamide) or insulin-sensitizing (metformin) monotherapy to that of combined therapy in normalizing the endocrine-metabolic and anovulatory status of nonobese, young women with hyperinsulinemic hyperandrogenism.

Thirty-one young women (mean age, 18.7 yr; body mass index, 21.9 kg/m²; hirsutism score, 16; monthly ovulation rate monitored by weekly serum progesterone, 10%) were randomly assigned to receive once daily flutamide (250 mg; n = 10), metformin (1275 mg; n = 8), or combined flutamide- metformin therapy (n = 13) for 9 months. At baseline, there were no endocrine-metabolic differences among treatment groups. Compared with monotherapy, combined flutamide-metformin therapy resulted in greater improvements in insulin sensitivity, in testosterone, androstenedione, dehydroepiandrosterone sulfate, and triglyceride levels, and in low-density lipoprotein/high-density lipoprotein-cholesterol ratio (all P < 0.005). Monthly ovulation rates increased after 9 months to 75 and 92%, respectively, with metformin alone or with combined therapy, but were unimproved with flutamide alone. All treatments were well tolerated.

In conclusion, combined anti-androgen and insulin-sensitizing treatment in young, nonobese women with hyperinsulinemic hyperandrogenism had additive benefits on insulin sensitivity, hyperandrogenemia, and dyslipidemia. The data from this small study suggest that dyslipidemia is secondary to excess androgen action in concert with the hyperinsulinemia associated with insulin resistance. In contrast, anovulation seems to be mainly attributable to insulin resistance and hyperinsulinemia.

THE ENDOCRINE-METABOLIC HALLMARKS of polycystic ovary syndrome in nonobese women are hyperinsulinism, hyperandrogenism, dyslipidemia, and anovulation (1, 2, 3, 4).

Insulin-sensitizing and anti-androgen monotherapies are partially effective treatments that act through different pathways and, accordingly, have a different spectrum of endocrine-metabolic actions (5, 6, 7). Treatment with flutamide, a nonsteroidal anti-androgen, reduces hirsutism and circulating levels of androgens, triglycerides, and low-density lipoprotein (LDL) cholesterol in adolescents and women with hyperinsulinemic hyperandrogenism, but it does not restore menstrual cyclicity. Furthermore, it fails to increase high-density lipoprotein (HDL) cholesterol or to decrease hyperinsulinemia, i.e. to affect two major risk factors for subsequent cardiovascular disease (8, 9, 10, 11, 12). Insulin-sensitizing treatment with metformin is known to reduce hyperinsulinism, hyperandrogenism, and the atherogenicity of the lipid profile, and to restore eumenorrhea and ovulatory function, but it may be less effective in decreasing hirsutism (13, 14, 15, 16, 17, 18, 19, 20).

We hypothesized that, in the absence of obesity, dyslipidemia and anovulation are essentially secondary to the concerted, rather than separate, effects of hyperandrogenism and hyperinsulinemia resulting from insulin resistance. We tested this hypothesis by comparing the efficacy of anti-androgen (flutamide) or insulin-sensitizing (metformin) monotherapy to that of combined treatment in normalizing the endocrine-metabolic and/or anovulatory status of nonobese, young women with hyperinsulinemic hyperandrogenism.

Subjects and Methods

Study population

The study population consisted of 31 nonobese, young women (age, 18.7 ± 0.3 yr; range, 18–22 yr) who were 5–10 yr beyond menarche and who were either not at risk of pregnancy or using a nonhormonal contraceptive method.

Inclusion criteria were: 1) hyperinsulinemia on standard 2-h oral glucose tolerance testing, defined as peak serum insulin concentration greater than 150 µU/ml (21) and/or mean serum insulin greater than 84 mU/liter (22, 23); 2) normal oral glucose tolerance (24); 3) ovarian hyperandrogenism as defined by hirsutism (score 8 on Ferriman-Gallwey scale) (25), plus elevated serum androstenedione, total testosterone, and/or free androgen index [testosterone x 100/SHBG, an index of free testosterone (26)], and 17-hydroxyprogesterone (17-OHP) hyper- response (>160 ng/dl) to leuprolide acetate, a GnRH agonist (Procrin, Abbott, Madrid, Spain) (26, 27).

None of the women had a body mass index (BMI) greater than 25 kg/m² ; none had thyroid dysfunction, hyperprolactinemia, a family or personal history of diabetes mellitus, or late-onset congenital adrenal hyperplasia (28, 29); and none was receiving a medication known to affect gonadal or adrenal function, or carbohydrate or lipid metabolism. All of the women were screened for blood count, serum electrolytes, and liver and kidney function.

Study design

At the start of this open-labeled study, women were considered to be in a steady-state condition and were randomized to receive once daily flutamide (250 mg; Eulexin, Schering-Plough Corp., Madrid, Spain; n = 10), metformin (1275 mg; Dianben, Andreu-Roche, Barcelona, Spain; n = 8), or flutamide-metformin (Eulexin, 250 mg; Dianben, 1275 mg; n = 13) for 9 months.

At baseline and after 9 months on either monotherapy or combined treatment, fasting glucose and insulin were assessed together with serum LH, FSH, estradiol, testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS), SHBG, and lipid profile. Insulin sensitivity was calculated from fasting glucose and insulin data using the homeostasis model assessment (HOMA) (30, 31). Blood count and liver and kidney function were also screened after 1, 3, 6, and 9 months, as additional safety variables.

Ovulation assessment

Before the start of treatment, ovulatory function was documented twice by measuring serum progesterone concentrations in four consecutive weekly samples; results of 3 months and 1 month before the start of treatment were averaged. Ovulation rate was assessed similarly after 3 months (average of 2 and 4 months), 6, and 9 months of treatment; ovulation was post-factum considered to have occurred if a serum progesterone level greater than 8 ng/ml was found in a sample obtained 5–8 d before menses (18).

Hormonal assays

Serum glucose was measured by the glucose oxidase method. Immunoreactive insulin was assayed by IMX (Abbott Diagnostics, Santa Clara, CA). The mean intra- and interassay coefficients of variation were 4.7 and 7.2%, respectively. LH, FSH, and progesterone were measured by immuno-chemiluminescence (IMMULITE 2000, Diagnostic Products Corp., Los Angeles, CA), with coefficients of variation 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 (17). Serum samples were kept frozen at -20 C until assay.

Statistics and ethics

Anthropometric data and hormonal results are expressed as mean ± SEM, unless stated otherwise. Comparisons between the three study groups were compared at baseline and after 9 months using ANOVA. Where significant between-group differences were observed post treatment, we tested the a priori hypothesis that combined therapy was better than either monotherapy by comparing percentage changes from baseline between the combined therapy group and each monotherapy treatment group using unpaired two-sided t tests. P values less than 0.05 were considered statistically significant.

Informed consent was obtained from each woman. The study was conducted in Barcelona after approval by the Institutional Review Board of Barcelona Hospital; in view of the available evidence with monotherapy (10, 17), inclusion of a randomized, untreated control group was judged ethically unacceptable.

Results

At baseline, there were no significant differences between the randomized treatment groups for any clinical, biochemical, or endocrine-metabolic variable (Table 1).

View larger version (19K): [in this window] [in a new window]   Figure 1. Comparison of percentage change between 0 and 9 months in insulin sensitivity, LDL/HDL ratio, triglyceride, testosterone, androstenedione, and DHEAS levels by treatment group. *, P < 0.01; **, P < 0.001 for flutamide alone or metformin alone compared with the combined flutamide-metformin (Flu + Met) group.

Discussion

To gain more insight into the sequence of pathophysiological events underpinning hyperinsulinemic hyperandrogenism and to explore novel therapeutic avenues for this frequent condition, we conducted a small intervention study comparing (in the absence of obesity) the effects of an anti-androgen (flutamide) and an insulin-sensitizing (metformin) monotherapy to their combination. Flutamide and metformin act through different pathways and, when given in monotherapy, exert different effects in nonobese, young women with combinations of hyperandrogenism, hyperinsulinism, dyslipidemia, and their clinical correlates, including hirsutism, anovulation, and oligomenorrhea (10, 17, 32). In this randomized open-label study, combined anti-androgen and insulin-sensitizing treatment was found to have additively normalizing effects, in particular on dyslipidemia and hyperandrogenemia (Fig. 1), suggesting that these abnormalities are secondary to the concerted actions of hyperandrogenism and insulin resistance/hyperinsulinism (33, 34). These observations corroborate the concept that the interplay between hyperinsulinism and androgen excess contributes to the high prevalence of cardiovascular disease in women with hyperinsulinemic hyperandrogenism (11, 35), because this interplay appears to induce a male-type lipid profile as soon as serum androgens increase above the normal female range and well before they reach the lower limit of the normal male range (36, 37).

Monotherapy with an insulin-sensitizer has recently proven to be an efficient approach to induce ovulation in obese and nonobese women with hyperinsulinemic hyperandrogenism accompanied by anovulation (18, 19, 20, 32). The present findings indicate that the key factor responsible for anovulation in these women is insulin resistance/hyperinsulinemia, rather than the hyperandrogenism. If androgen receptor-mediated effects of ovarian and/or adrenal androgens play any role in the characteristic anovulation of hyperinsulinemic hyperandrogenism, then in the majority of cases these effects appear to be swiftly overcome by insulin-sensitizing monotherapy, but not by flutamide alone.

Of the two monotherapies studied in this cohort of nonobese women with hyperinsulinemic hyperandrogenism, metformin seems to be more effective than flutamide, as judged by safe near-normalization of the ovulation rate and by correction of insulin sensitivity, dyslipidemia, and hyperandrogenemia. Sensitization to insulin is the monotherapy of choice, in particular if ovulation induction and pregnancy are among the aims of intervention (38, 39).

Although the monthly ovulation rate failed to increase during flutamide monotherapy, it did increase within 9 months, from below 10% to above 90% in women receiving combined flutamide-metformin treatment. From a pathophysiological point of view, these observations indicate that the addition of an anti-androgen to an insulin-sensitizing treatment does not seem to reduce, but rather seems to augment the capacity of the latter to induce ovulation. Paradoxically, for daily practice, this high ovulation rate is a side effect rather than a benefit of combined treatment, because flutamide is contraindicated during early pregnancy. Hence, it is only for a small subgroup of women with hyperinsulinemic hyperandrogenism that combined anti-androgen and insulin-sensitizing treatment seems appropriate, namely those who are not at risk of pregnancy and for whom long-term correction of dyslipidemia and hyperandrogenemia is a priority. It is anticipated, however, that the therapeutic applications of this novel combination will be amplified, once its endocrine-metabolic advantages prove to be maintained or further increased by the coadministration of a hormonal contraceptive.

Acknowledgments

We thank Montserrat Gallart for hormone measurements and Inge Laleeuwe for editorial assistance.

Footnotes

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

Abbreviations: BMI, Body mass index; DHEAS, dehydroepiandrosterone sulfate; HDL, high-density lipoprotein; HOMA, homeostasis model assessment; LDL, low-density lipoprotein; 17-OHP, 17-hydro-xyprogesterone.

Received June 12, 2001.

Accepted March 6, 2002.

References

1. Taylor AE 1998 Polycystic ovary syndrome. Endocrinol Metab Clin North Am 27:877–902[CrossRef][Medline]
2. Rosenfield RL 1997 Current concepts of polycystic ovary syndrome. Baillière’s Clin Obstet Gynaecol 11:307–333[CrossRef][Medline]
3. Dunaif A 1997 Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 18:774–800[Abstract/Free Full Text]
4. Robinson S, Henderson AD, Gelding SV, Kiddy D, Niththyananthan R, Bush A, Richmond W, Johnston DG, Franks S 1996 Dyslipidemia is associated with insulin resistance in women with polycystic ovaries. Clin Endocrinol (Oxf) 44:277–284[CrossRef][Medline]
5. 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]
6. Bailey CJ, Path MRC, Turner RC 1996 Drug therapy. Metformin. N Engl J Med 334:574–579[Free Full Text]
7. Schoonjans K, Auwerx J 2000 Thiazolidinediones: an update. Lancet 355:1008–1010[CrossRef][Medline]
8. Diamanti-Kandarakis E, Mitrakou A, Raptis S, Tolis G, Duleba AJ 1998 The effect of a pure antiandrogen receptor blocker, flutamide, on the lipid profile in the polycystic ovary syndrome. J Clin Endocrinol Metab 83:2699–2705[Abstract/Free Full Text]
9. 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]
10. Ibáñez L, Potau N, Marcos MV, de Zegher F 2000 Treatment of hirsutism, hyperandrogenism, oligomenorrhea, dyslipidemia and hyperinsulinism in nonobese, adolescent girls: effect of flutamide. J Clin Endocrinol Metab 85:3251–3255[Abstract/Free Full Text]
11. Mather KJ, Kwan F, Corenblum B 2000 Hyperinsulinemia in polycystic ovary syndrome correlates with increased cardiovascular risk independent of obesity. Fertil Steril 73:150–156[CrossRef][Medline]
12. Goldbourt U, Yaari S, Medalie JH 1997 Isolated low HDL cholesterol as a risk factor for coronary heart disease mortality: a 21-year follow-up of 8000 men. Arterioscler Thromb Vasc Biol 17:107–113[Abstract/Free Full Text]
13. Velázquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ 1994 Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 43:647–654[CrossRef][Medline]
14. Nestler JE, Jakubowicz DJ 1996 Decreases in ovarian cytochrome P450c17a 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]
15. Nestler JE, Jakubowicz DJ 1997 Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17a activity and serum androgens. J Clin Endocrinol Metab 82:4075–4079[Abstract/Free Full Text]
16. 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]
17. 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]
18. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R 1998 Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Eng J Med 338:1876–1880[Abstract/Free Full Text]
19. DeLeo V, la Marca A, Ditto A, Morgante G, Cianci A 1999 Effects of metformin on gonadotropin-induced ovulation in women with polycystic ovary syndrome. Fertil Steril 72:282–285[CrossRef][Medline]
20. Hasegawa I, Murakawa H, Suzuki M, Yamamoto Y, Kurabayashi T, Tanaka K 1999 Effect of troglitazone on endocrine and ovulatory performance in women with insulin resistance-related polycystic ovary syndrome. Fertil Steril 71:323–327[CrossRef][Medline]
21. Vidal-Puig A, Moller DE 1997 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
22. 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]
23. Ibáñez L, de Zegher F, Potau N 1999 Anovulation after precocious pubarche: early markers and time course in adolescence. J Clin Endocrinol Metab 84:2691–2695[Abstract/Free Full Text]
24. 1997 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20:1183–1181
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, Gussinye 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. Ibáñez L, Potau N, Virdis R, Zampolli M, Terzi C, Gussinye M, Carrascosa A, Vicens-Calvet E 1993 Postpubertal outcome in girls diagnosed of premature pubarche during childhood: increased frequency of functional ovarian hyperandrogenism. J Clin Endocrinol Metab 76:1599–1603[Abstract]
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 57:320–326[Abstract]
29. Sakkal-Alkaddour H, Zhang L, Yang X, Chang YT, Kappy M, Slover RS, Jorgensen V, Pang S 1996 Studies of 3ß-hydroxysteroid dehydrogenase genes in infants and children manifesting premature pubarche and increased adrenocorticotropin-stimulated D5-steroid levels. J Clin Endocrinol Metab 81:3961–3965[Abstract/Free Full Text]
30. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC 1985 Homeostasis model assessment: insulin resistance and ß-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419[CrossRef][Medline]
31. Phillips DI, Clark PM, Hales CN, Osmond C 1994 Understanding oral glucose tolerance: comparison of glucose or insulin measurements during the oral glucose tolerance test with specific measurements of insulin resistance and insulin secretion. Diabet Med 11:286–292[Medline]
32. Ibáñez L, Valls C, Ferrer A, Marcos MV, Rodriguez-Hierro F, de Zegher F 2001 Sensitization to insulin induces ovulation in non-obese adolescents with anovulatory hyperandrogenism. J Clin Endocrinol Metab 86:3595–3598[Abstract/Free Full Text]
33. Sozen I, Arici A 2000 Hyperinsulinism and its interaction with hyperandrogenism in polycystic ovary syndrome. Obstet Gynecol Surv 55:321–328[CrossRef][Medline]
34. Porettsky L, Cataldo NA, Rosenwaks Z, Giudice LC 1999 The insulin-related ovarian regulatory system in health and disease. Endocr Rev 20:535–582[Abstract/Free Full Text]
35. Elting MW, Korsen TJM, Bezemer PD, Schoemaker J 2001 Prevalence of diabetes mellitus, hypertension and cardiac complaints in a follow-up study of a Dutch PCOS population. Hum Reprod 16:556–560[Abstract/Free Full Text]
36. Bagatell CJ, Knopp RH, Vale WW, Rivier JE, Bremner WJ 1992 Physiologic testosterone levels in normal men suppress high-density lipoprotein cholesterol levels. Ann Intern Med 116:967–973
37. Jockenhövel F, Bullmann C, Schubert M, Vogel E, Reinhardt W, Reinwein D, Muller-Wieland D, Krone W 1999 Influence of various modes of androgen substitution on serum lipids and lipoproteins in hypogonadal men. Metabolism 48:590–596[CrossRef][Medline]
38. Glueck CJ, Phillips H, Cameron D, Sieve-Smith L, Wang P 2001 Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study. Fertil Steril 75:46–52[CrossRef][Medline]
39. Jakubowicz DJ, Seppälä M, Jakubowicz S, Rodriguez-Armas O, Rivas- Santiago A, Koistinen H, Koistinen R, Nestler JE 2001 Insulin reduction with metformin increases luteal phase serum glycodelin and insulin-like growth factor-binding protein 1 concentrations and enhances uterine vascularity and blood flow in the polycystic ovary syndrome. J Clin Endocrinol Metab 86:1126–1133[Abstract/Free Full Text]

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