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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 6 2870-2874
Copyright © 2002 by The Endocrine Society

Other Original Articles

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

Lourdes Ibáñez, Carme Valls, Angela Ferrer, Ken Ong, David B. Dunger and Francis de Zegher

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 1Go).


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  		Table 1. No significant differences in baseline clinical and fasting biochemical characteristics between randomized treatment groups

 
However, after 9 months of treatment, significant differences were apparent between the treatment groups (Table 2Go). The women who received combined flutamide-metformin therapy tended to have less hirsutism, lower levels of testosterone, androstenedione, DHEAS, and LDL cholesterol, and higher SHBG levels and insulin sensitivity than other groups. Women who received metformin alone, or in combination with flutamide, tended to have higher HDL cholesterol and lower triglyceride levels than women who received flutamide only. Comparisons of percentage change from baseline showed that compared with flutamide alone, combined flutamide-metformin therapy resulted in significantly greater improvements in insulin sensitivity, LDL/HDL cholesterol ratio and triglyceride, testosterone, androstenedione and DHEAS levels (Fig. 1Go); compared with metformin alone, combined flutamide-metformin therapy resulted in significantly greater improvements in LDL/HDL cholesterol ratio and triglyceride, androstenedione, and DHEAS levels (Fig. 1Go). No treatment produced any change in BMI (post-treatment vs. pretreatment, P > 0.8 for all treatment groups; Tables 1Go and 2Go).


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  		Table 2. Clinical and biochemical differences between randomized treatment groups after 9 months of treatment

 


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  		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.

 
The monthly fraction of ovulatory cycles, as monitored by weekly serum progesterone measurements, increased with metformin alone (baseline vs. after 9 months, 5 vs. 75%; P < 0.01) and also with combined therapy (8 vs. 92%; P < 0.0001), but were unimproved with flutamide alone (15 vs.20%; P = NS) (Table 3Go).


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  		Table 3. Fractions (%) of ovulatory cycles in young (5–10 yr after menarche), nonobese women with hyperinsulinemic hyperandrogenism

 
Each treatment regimen was well tolerated; indices of hepatic and renal function were stable throughout the study. One woman receiving flutamide (1 of 10) complained of dry skin; three women receiving metformin or flutamide- metformin (3 of 21) reported transient abdominal discomfort.

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. 1Go), 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.

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Hum. Reprod., September 1, 2005; 20(9): 2457 - 2462.
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 Hum ReprodHome page
S. A.R. Doi, M. Al-Zaid, P. A. Towers, C. J. Scott, and K. A.S. Al-Shoumer
Irregular cycles and steroid hormones in polycystic ovary syndrome
Hum. Reprod., September 1, 2005; 20(9): 2402 - 2408.
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 Hum Reprod UpdateHome page
M.A. Checa, A. Requena, C. Salvador, R. Tur, J. Callejo, J.J. Espinos, F. Fabregues, J. Herrero, and (Reproductive Endocrinology Interest Group of the
Insulin-sensitizing agents: use in pregnancy and as therapy in polycystic ovary syndrome
Hum. Reprod. Update, July 1, 2005; 11(4): 375 - 390.
[Abstract] [Full Text] [PDF]

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 Hum ReprodHome page
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.
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 J. Clin. Endocrinol. Metab.Home page
C. Ortega-Gonzalez, S. Luna, L. Hernandez, G. Crespo, P. Aguayo, G. Arteaga-Troncoso, and A. Parra
Responses of Serum Androgen and Insulin Resistance to Metformin and Pioglitazone in Obese, Insulin-Resistant Women with Polycystic Ovary Syndrome
J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1360 - 1365.
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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.
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 J. Clin. Endocrinol. Metab.Home page
L. Ibanez, C. Valls, M. V. Marcos, K. Ong, D. B. Dunger, and F. de Zegher
Insulin Sensitization for Girls with Precocious Pubarche and with Risk for Polycystic Ovary Syndrome: Effects of Prepubertal Initiation and Postpubertal Discontinuation of Metformin Treatment
J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4331 - 4337.
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 J. Clin. Endocrinol. Metab.Home page
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.
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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.
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S. R. Rose
Drug Therapy in Polycystic Ovarian Syndrome
AAP Grand Rounds, November 1, 2003; 10(5): 65 - 66.
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 J. Clin. Endocrinol. Metab.Home page
L. Ibanez and F. de Zegher
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., October 1, 2003; 88(10): 4720 - 4724.
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 J. Clin. Endocrinol. Metab.Home page
L. Ibanez, K. K. Ong, N. Mongan, J. Jaaskelainen, M. V. Marcos, I. A. Hughes, F. de Zegher, and D. B. Dunger
Androgen Receptor Gene CAG Repeat Polymorphism in the Development of Ovarian Hyperandrogenism
J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3333 - 3338.
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L. Ibanez, K. Ong, A. Ferrer, R. Amin, D. Dunger, and F. de Zegher
Low-Dose Flutamide-Metformin Therapy Reverses Insulin Resistance and Reduces Fat Mass in Nonobese Adolescents with Ovarian Hyperandrogenism
J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2600 - 2606.
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L. Morin-Papunen, I. Vauhkonen, R. Koivunen, A. Ruokonen, H. Martikainen, and J. S. Tapanainen
Metformin Versus Ethinyl Estradiol-Cyproterone Acetate in the Treatment of Nonobese Women with Polycystic Ovary Syndrome: A Randomized Study
J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 148 - 156.
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 Hum ReprodHome page
L. Ibanez and F. de Zegher
Low-dose combination of flutamide, metformin and an oral contraceptive for non-obese, young women with polycystic ovary syndrome
Hum. Reprod., January 1, 2003; 18(1): 57 - 60.
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 J. Clin. Endocrinol. Metab.Home page
L. Ibanez, N. Potau, A. Ferrer, F. Rodriguez-Hierro, M. V. Marcos, and F. de Zegher
Reduced Ovulation Rate in Adolescent Girls Born Small for Gestational Age
J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3391 - 3393.
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