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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 9 3251-3255
Copyright © 2000 by The Endocrine Society

Original Studies

Treatment of Hirsutism, Hyperandrogenism, Oligomenorrhea, Dyslipidemia, and Hyperinsulinism in Nonobese, Adolescent Girls: Effect of Flutamide1

Lourdes Ibáñez, Neus Potau, Maria Victoria Marcos and Francis de Zegher2

Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona (L.I.); Hormonal Laboratory, Hospital Vall d’Hebron, Autonomous University of Barcelona (N.P.); and Endocrinology Unit, Consorci Hospitalari de Terrassa (M.V.M.), Barcelona, Spain; and Department of Pediatrics, University of Leuven (F.d.Z.), Leuven, Belgium

Address all correspondence and requests for reprints to: Lourdes Ibáñez, M.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
 
Functional ovarian hyperandrogenism, a variant of polycystic ovary syndrome, is often associated with hyperinsulinism and dyslipidemia. The mechanisms interlinking this triad are poorly understood; both hyperandrogenism and hyperinsulinism have been proposed as factors involved in the pathogenesis of the dyslipidemia. Precocious pubarche (PP) in girls is a risk factor for subsequent anovulation, ovarian and adrenal hyperandrogenism, hyperinsulinism and dyslipidemia.

Flutamide, a nonsteroidal antiandrogen, is known to be effective in reducing hirsutism in patients with ovarian hyperandrogenism. However, the effects of flutamide on the endocrine-metabolic correlates of hyperandrogenism are uncertain. We assessed the effects of low dose flutamide treatment (250 mg daily for 18 months) on hormonal and metabolic variables in 18 nonobese adolescent girls (age, 16.8 ± 0.3 yr) with functional ovarian hyperandrogenism (diagnosis by GnRH agonist test) after PP.

Flutamide treatment was accompanied by a marked decrease in the hirsutism score, free androgen index, and testosterone, androstenedione, and dehydroepiandrosterone levels and by an increase in sex hormone-binding globulin concentrations. However, there were no substantial changes in the pattern of menstrual cycles, gonadotropin, estradiol, or dehydroepiandrosterone sulfate concentrations, and there was no detectable effect on the 17-hydroxyprogesterone response to GnRH agonist. Serum triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels decreased markedly during flutamide therapy, whereas high-density lipoprotein cholesterol, fasting glycemia/insulinemia, and the insulin response to a glucose load remained unchanged. Flutamide was well tolerated.

In conclusion, low dose flutamide treatment was found to be an effective and safe approach to reduce hirsutism and circulating androgen, low-density lipoprotein cholesterol, and triglyceride levels in girls with functional ovarian hyperandrogenism after PP. However, flutamide failed to increase high-density lipoprotein cholesterol levels or decrease hyperinsulinemia, i.e. to affect two major risk factors for subsequent cardiovascular disease.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
FUNCTIONAL OVARIAN hyperandrogenism is a variant of polycystic ovary syndrome, hallmarked by hirsutism, menstrual disturbances, hyperandrogenemia, and, specifically, an augmented 17-hydroxyprogesterone (17-OHP) response to GnRH agonist; the overactivity in thecal steroidogenesis has been mainly ascribed to dysregulation of the 17-hydroxylase and 17,20-lyase activities of cytochrome P450c17 (1, 2). Functional ovarian hyperandrogenism is often associated with hyperinsulinism and dyslipidemia in both lean and obese subjects; the mechanisms interlinking this triad are still poorly understood; both hyperandrogenism and hyperinsulinism have been proposed as factors that may be involved in the pathogenesis of the dyslipidemia (3, 4, 5, 6).

Flutamide is a nonsteroidal antiandrogen that conceivably exerts its major effects by blocking the nuclear binding of androgens to their receptors (7). Flutamide has proven effective in reducing hair growth in patients with idiopathic hirsutism or with ovarian hyperandrogenism when used in either standard or low doses (8, 9, 10, 11, 12). However, assessments of the endocrine-metabolic correlates of flutamide treatment in women with hyperandrogenism have yielded inconclusive results, possibly due to the heterogeneity of the populations studied. Some reports suggest that flutamide reduces both adrenal and ovarian androgen synthesis, restores ovulation, and ameliorates the metabolic profile of hyperandrogenic women (12, 13, 14, 15, 16), whereas others documented no substantial effects on circulating androgens, lipids, or insulin sensitivity (9, 10, 17, 18, 19).

Precocious pubarche (PP) in girls [defined as the appearance of pubic hair before the age of 8 yr (20)] is a risk factor for subsequent anovulation, ovarian and adrenal hyperandrogenism, hyperinsulinism, and dyslipidemia (21, 22, 23, 24, 25). PP and its endocrine-metabolic correlates in girls are known to often be preceded by reduced prenatal growth, a finding indicating that these constellations may have a common early origin whose genetic and/or environmental components remain to be identified (21, 26, 27).

We have now assessed the long-term effects of low dose flutamide treatment in nonobese adolescent girls with ovarian hyperandrogenism after PP to address the hypothesis that the hyperandrogenism itself has a significant impact on the other endocrine-metabolic abnormalities observed in these girls.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Eighteen girls (age range, 14–18 yr) with a history of PP were enrolled in the study. These girls were all at least 3 yr beyond menarche and had functional ovarian hyperandrogenism, i.e. they presented with oligomenorrhea (defined as menstrual cycles of >45-day duration) and/or hirsutism (score >=8 on the Ferriman-Gallwey scale) (28); elevated baseline serum androstenedione, total testosterone, and/or free androgen index [FAI; testosterone x 100/sex hormone-binding globulin (SHBG); an index of free testosterone (29)]; and a high 17-OHP response (>160 ng/dL) to leuprolide acetate, a GnRH agonist (Procrin, Abbott, Madrid, Spain; 500 µg, sc) (22, 29).

In all cases, PP had been attributed to pronounced adrenarche, as suggested by elevated androstenedione and/or dehydroepiandrosterone (DHEA) sulfate (DHEAS) levels at prepubertal diagnosis of PP (20, 30). At the time of study, body mass indexes were normal in all subjects (31); none had thyroid dysfunction, hyperprolactinemia, family or personal history of diabetes mellitus, or late-onset congenital adrenal hyperplasia (32, 33); and none was receiving oral contraceptive treatment or medication known to affect gonadal function, or carbohydrate/lipid metabolism.

Birth weight and gestational age data were obtained from hospital records and transformed into SD scores, as previously described (26).

Study protocol

All girls were considered to be in a steady state condition and received 250 mg flutamide (Eulexin, Schering-Plough Corp., Madrid, Spain), orally, once daily for 18 months. Before the start of flutamide treatment, all girls were screened for blood count, liver and renal function, and lipid profile; a standard 2-h oral glucose tolerance test (oGTT) was performed after 3 days on a high carbohydrate diet (300 g/day) and after an overnight fast. During the oGTT, the areas under the curves for mean serum glucose and mean serum insulin (MSI) were calculated according to the trapezoidal rule. A MSI value above 84 mU/L was defined as an insulin hyperresponse (23, 24).

After 18 months of flutamide treatment, the same examinations were repeated, together with a leuprolide acetate test in the early follicular phase (days 3–8) of the cycle. Liver function was also screened after 1, 3, 6, and 12 months as an additional safety variable. After 18 months of flutamide treatment, it was acceptable for 13 of the 18 girls to interrupt the treatment; after 3–4 months off flutamide, baseline endocrine status was assessed again.

Hormonal assays, statistics, and ethics

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 (CVs) were 4.7% and 7.2%, respectively. LH and FSH were measured using a microparticle enzyme immunoassay (IMX Systems, Abbott, Chicago, IL) with CVs of 3.0% and 5.4% for LH and 4.1% and 6.9% for FSH. Testosterone, 17-OHP, androstenedione, and estradiol were determined using commercially available RIA kits (29); serum SHBG and DHEAS levels were measured by enzymo-immunochemiluminiscence (34). DHEA was assayed using a tritiated kit (ICN Biomedicals, Inc., Carson, CA) with CVs of 7% and 14%. Serum samples were kept frozen at -20 C until assay.

Anthropometric data and hormonal results are expressed as the mean ± SEM unless stated otherwise. Independent variables were compared by Student’s t test. P < 0.05 was considered statistically significant.

The study was approved by the institutional review board of Barcelona Hospital. Informed consent was obtained from parents and/or girls, and assent was obtained from minors.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1Go summarizes the clinical characteristics, as well as the hormonal and metabolic status of the girls at start of flutamide treatment. Figure 1Go displays the main clinical, endocrine, and metabolic variables before and after 18 months of flutamide treatment. The hirsutism score decreased from 15.4 ± 0.8 to 8.3 ± 0.6 (P < 0.0001), whereas no changes were noted in body mass index or menstrual cyclicity. Flutamide treatment was accompanied by a decrease in FAI, androstenedione, and DHEA levels (Fig. 1Go, upper panels); the FAI decrease resulted from a combined drop in serum testosterone (from 62 ± 7.1 to 45.6 ± 4.0 ng/dL; P = 0.01) and an increment in serum SHBG (from 0.8 ± 0.2 to 1.1 ± 0.1 µg/dL; P = 0.0001). Serum LH, FSH, and estradiol remained unaltered, as did the ovarian 17-OHP response to leuprolide acetate (211 ± 14 ng/dL before and 200 ± 9 ng/dL after flutamide).


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  		Table 1. Clinical characteristics, serum hormone concentrations, and metabolic variables (mean ± SEM) before the start of flutamide treatment in 18 adolescent girls with functional ovarian hyperandrogenism after precocious pubarche (PP)

 


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  		Figure 1. Selected clinical, hormonal, and metabolic variables before and after 18 months of flutamide treatment in adolescent girls with functional ovarian hyperandrogenism after precocious pubarche. Upper panels, Changes in hirsutism score, FAI, and androstenedione ({Delta}4-A) and DHEA levels. Middle panels, Changes in the lipid profile (TG, triglycerides; TC, total cholesterol; LDL, LDL cholesterol; HDL, HDL cholesterol). Lower panels, Changes in fasting glucose and insulin, mean serum insulin (MSI) levels during oGTT, and DHEAS concentrations.

 
After 18 months of flutamide treatment, serum triglycerides, total cholesterol, and low-density lipoprotein (LDL) cholesterol levels had decreased markedly, whereas highdensity lipoprotein (HDL) cholesterol remained unaltered (Fig. 1Go, middle panels).

Glucose tolerance was normal in all girls (35). After 18 months of flutamide treatment, fasting glycemia and insulinemia, and MSI during oGTT remained unaltered, as did DHEAS, an androgen that is virtually exclusively of adrenal origin (Fig. 1Go, lower panels).

Two adolescents complained of dry skin, and one other girl had transient gastrointestinal discomfort during treatment. Indexes of liver function remained stable throughout flutamide treatment.

For 13 of the 18 treated girls, it was acceptable to withdraw flutamide treatment temporarily, and it was possible to reinvestigate their baseline endocrine status after 3–4 months off flutamide. In those 13 girls, a return toward pretreatment levels was observed for androstenedione (324.7 ± 34.8 off treatment vs. 219.0 ± 23.4 ng/dL at the end of the treatment phase; P = 0.01), testosterone (78.6 ± 7.3 vs. 45.6 ± 4.0 ng/dL; P = 0.0002), FAI (9.4 ± 1.4 vs. 4.3 ± 0.4; P = 0.0004), total cholesterol (190.3 ± 8.4 vs. 168.5 ± 4.2 mg/dL; P = 0.01), LDL (125.2 ± 6.7 vs. 105.6 ± 3.4 mg/dL; P = 0.007), triglycerides (95.1 ± 6.8 vs. 77.3 ± 4.4 mg/dL; P = 0.02), SHBG (1.0 ± 0.1 vs. 1.1 ± 0.1 µg/dL), and the hirsutism score (9.4 ± 1.4 vs. 4.3 ± 0.4; P = 0.0004). As expected, flutamide withdrawal was not followed by significant changes in baseline DHEAS, HDL cholesterol, glucose, insulin, LH, FSH, or estradiol.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present results indicate that low dose flutamide is an effective approach to treat hirsutism in adolescents with functional ovarian hyperandrogenism after PP. Flutamide therapy decreased signs of androgen action, levels of circulating androgens of predominantly ovarian origin, as well as levels of serum triglycerides and LDL cholesterol, but failed to augment HDL cholesterol levels or to affect indexes of insulin resistance.

The efficacy of low dose flutamide therapy on hirsutism was similar to the reported effects with higher daily doses (500–750 mg) used either alone or in combination with an oral contraceptive (8, 9, 10, 11, 12, 13). When long-term treatment is anticipated, the use of a low dose reduces both the cost of therapy and the likelihood of side-effects. Flutamide treatment can be complicated by skin dryness, gastrointestinal discomfort, breast tenderness, menstrual disturbances, and hepatotoxicity; the reported incidence of these side-effects increases with higher doses (8, 12, 36). Severe hepatotoxicity has hitherto not been described when the daily flutamide dose is below 500 mg (37, 38).

After flutamide treatment, a net decrease in testosterone, FAI, androstenedione, and DHEA and an increase in SHBG concentrations were documented, in agreement with some reports (8, 11, 13, 18) and in apparent disagreement with others (9, 10, 12, 17). Flutamide has been reported to inhibit ovarian 17,20-lyase activity of cytochrome P450c17 in vitro and to reduce adrenal steroidogenesis in vivo (16, 39). In the adolescents studied, flutamide treatment effectively lowered the concentrations of some androgens in the circulation, but had no detectable effect on fundamental variables such as baseline serum DHEAS concentrations and the 17-OHP response to GnRH agonist, suggesting that flutamide only partially or indirectly affects the enigmatic, more fundamental mechanism responsible for hyperandrogenism in these girls.

The constellation of hyperinsulinemia, low serum SHBG, and low insulin-like growth factor-binding protein-1 levels is thought to be part of the more fundamental mechanism generating adrenal and ovarian hyperandrogenism in girls and women (1, 2, 3, 4). This constellation is known to be present in the majority of prepubertal and pubertal girls with (a history of) PP, particularly in those with a low birth weight, and is usually accompanied by an abnormal lipid profile (23, 24, 26, 27), thus further supporting the idea that the cluster of atherogenic abnormalities encompassing the so-called syndrome X is already present in childhood (24, 40).

Flutamide treatment was found to reduce total cholesterol, LDL cholesterol, and triglyceride levels in the studied cohort, in agreement with other reports on the effects of flutamide in hyperandrogenic subjects (11, 14). However, flutamide failed to increase HDL cholesterol levels or reverse hyperinsulinemia, i.e. to affect two strong and independent risk factors for subsequent cardiovascular disease (41, 42, 43). As mentioned above, hyperinsulinemia is thought to be a key link between dyslipidemia and other components of syndrome X and to precede the development of type 2 diabetes in women both with and without ovarian hyperandrogenism (44, 45, 46).

The effects of flutamide on lipid metabolism are not ascribed to changes in insulin levels or variations in body weight, as these variables remained unaltered after flutamide treatment. Administration of androgens to obese, postmenopausal women has been reported to result in increased accumulation of visceral fat and decreased HDL cholesterol levels, without substantial changes in fasting glucose or insulin sensitivity (47). It is currently unknown whether androgens affect lipid metabolism or fat deposition, independently of insulin, in nonobese adolescent girls.

In summary, low-dose flutamide treatment was found to be an effective and safe approach to reduce hirsutism and serum androgen, LDL cholesterol, and triglycerides in girls with functional ovarian hyperandrogenism after PP. However, flutamide therapy failed to increase HDL cholesterol levels and to decrease hyperinsulinemia, i.e. to affect two major risk factors for subsequent cardiovascular disease. Accordingly, the next step is to explore the effects of insulin-sensitizing agents in girls with hyperandrogenism and metabolic correlates. If the effects of those agents are found to be different from those exerted by flutamide, then there is a potential for synergism and, hence, for the development of a combined treatment. Ultimately, a low-dose combination of flutamide and an insulin-sensitizing agent may become the dual treatment of choice.


   Acknowledgments
 
We thank Montserrat Gallart and Maria Jesus Gras for hormone measurements and Karin Vanweser, R.N., for editorial assistance.


   Footnotes
 
1 This work was supported by a scholarship from the European Society for Pediatric Endocrinology. Back

2 Clinical Research Investigator for the Fund for Scientific Research (Flanders, Belgium). Back

Received December 27, 1999.

Revised March 5, 2000.

Revised June 5, 2000.

Accepted June 14, 2000.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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R. V. Mehta, P. J. Malcom, and R. J. Chang
The Effect of Androgen Blockade on Granulosa Cell Estradiol Production after Follicle-Stimulating Hormone Stimulation in Women with Polycystic Ovary Syndrome
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R. Pasquali and A. Gambineri
Insulin-sensitizing agents in polycystic ovary syndrome.
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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.
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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.
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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.
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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.
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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. Vrbikova and D. Cibula
Combined oral contraceptives in the treatment of polycystic ovary syndrome
Hum. Reprod. Update, May 1, 2005; 11(3): 277 - 291.
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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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K. Unluhizarci, Y. Karababa, F. Bayram, and F. Kelestimur
The Investigation of Insulin Resistance in Patients with Idiopathic Hirsutism
J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2741 - 2744.
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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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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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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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Z. T. Bloomgarden
American Association of Clinical Endocrinologists (AACE) Consensus Conference on the Insulin Resistance Syndrome: 25-26 August 2002, Washington, DC
Diabetes Care, April 1, 2003; 26(4): 1297 - 1303.
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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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L. Ibanez, C. Valls, A. Ferrer, K. Ong, D. B. Dunger, and F. de Zegher
Additive Effects of Insulin-Sensitizing and Anti-Androgen Treatment in Young, Nonobese Women with Hyperinsulinism, Hyperandrogenism, Dyslipidemia, and Anovulation
J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2870 - 2874.
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