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Flutamide-Metformin Plus Ethinylestradiol-Drospirenone for Lipolysis and Antiatherogenesis in Young Women with Ovarian Hyperandrogenism: The Key Role of Early, Low-Dose Flutamide

Endocrinology Unit (L.I.), Hormonal Laboratory (C.V.), and Department of Gynecology (S.C.), Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain 08950; 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

Top Abstract Introduction Subjects and Methods Results Discussion References

 
A low-dose combination of flutamide-metformin and ethinylestradiol-drospirenone was recently found to reduce the excess of total and abdominal fat, to diminish the deficit in lean mass, and to attenuate the dysadipocytokinemia of young women with ovarian hyperandrogenism, a variant of polycystic ovary syndrome. We questioned the need to give flutamide, an androgen receptor blocker, together with an oral contraceptive that contains drospirenone, a progestin claimed to have antiandrogen properties.

The additive effects of low-dose flutamide (62.5 mg/d) were assessed over 3 months in young patients with hyperinsulinemic ovarian hyperandrogenism (n = 40; age, 17 yr; body mass index, 22 kg/m²); all participants started on metformin (850 mg/d) and a fourth-generation contraceptive (ethinylestradiol 30 µg plus drospirenone 3 mg, 21 d/month), and they were randomized to receive flutamide in addition (n = 20) or not (n = 20).

Fasting blood glucose, serum insulin, lipid profile, testosterone, adiponectin, and IL-6 were determined at baseline and after 3 months, together with body composition (by dual x-ray absorptiometry) and with Doppler assessment of ovarian arterial resistance. At start, the pulsatility and resistance indices of ovarian arteries were elevated.

By comparison of 3-month changes between randomized subgroups, the addition of low-dose flutamide was found to have consistently (more) normalizing effects on low-density lipoprotein cholesterol, IL-6, and adiponectin, lean body mass, total and abdominal fat mass, and arterial flow in the ovaries.

In conclusion, low-dose flutamide is herewith identified as a pivotal component within a first contraceptive combination therapy that has been shown to attenuate the hypoadiponectinemia, ovarian vascular hyperresistance, lean mass deficit, and central adiposity of young women with polycystic ovary syndrome. Finally, these data challenge any claim that drospirenone, as currently used in a contraceptive, is a clinically significant antiandrogen.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
POLYCYSTIC OVARY SYNDROME (PCOS), a variable constellation of anovulatory hyperandrogenism with hyperinsulinemia and/or dyslipidemia, is the most frequent endocrine disorder of young women (1, 2, 3). One of the physical stigmata of women with PCOS, even if nonobese, is an excess of fat and a deficit of lean mass, both of which seem to reflect the prolonged dysadipocytokinemia that accompanies hyperinsulinemic hyperandrogenism and is aggravated by monotherapy with an oral estro-progestagen contraceptive (OC), even with an OC of so-called fourth generation (4, 5, 6, 7, 8).

At present, there is no approved therapy for PCOS. A first contraceptive combination therapy was recently found capable of reducing the excesses of total and abdominal fat, diminishing the deficit in lean body mass, and attenuating the dysadipocytokinemia (as judged by IL-6 and adiponectin) of young women with PCOS (8). The development of this therapy, which consists of ethinylestradiol-drospirenone plus low-dose flutamide-metformin, departed from the evidence that flutamide and metformin exert additively beneficial effects on endocrine metabolic indices (9) and are together capable of correcting the dysadipocytokinemia and the adiposity of adolescents and young women with PCOS (5, 6, 8). However, although there is emerging consensus about the need for insulin-sensitizing treatment (for example, with metformin) in PCOS (10, 11, 12, 13), there is less agreement on the need for concomitant androgen receptor-blocking treatment (for example, with flutamide), in particular if the latter is to be given together with an OC containing drospirenone, a progestin that is claimed to have antiandrogen properties (14, 15, 16).

Androgen excess is thought to contribute to the increased vascular resistance in ovarian arteries that is often observed in women with PCOS and may serve as an early marker of more generalized cardiovascular disease (17, 18, 19).

In a randomized pilot study, we assessed the additive effects of flutamide in young PCOS patients starting on a combination of metformin and ethinylestradiol-drospirenone. Here, we report that low-dose flutamide proved pivotal to obtain the lipolytic and antiatherogenic properties characterizing the efficacy of ethinylestradiol-drospirenone plus flutamide-metformin in adolescents and young women with PCOS.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Study population and ethics

The study enrolled 40 teenage patients [mean ± SEM; age, 16.7 ± 0.4 yr; range, 13–19 yr; body mass index (BMI), 22.3 ± 0.4 kg/m²; range, 17.0–25.9 kg/m²; 2–8 yr post menarche).

Inclusion criteria were: 1) hyperinsulinemia on a standard 2-h oral glucose tolerance test, defined as peak serum insulin levels more than 150 U/ml and/or mean serum insulin more than 84 µU/ml (20, 21); and 2) ovarian hyperandrogenism as defined by amenorrhea (absence of menses for >3 months) or oligomenorrhea (duration of menstrual cycles > 45 d) and/or hirsutism (Ferriman and Gallwey score > 8) (22); elevated serum androstenedione, total testosterone, and/or free androgen index (testosterone x 100/SHBG); and a 17-hydroxyprogesterone hyperresponse (>160 ng/dl) to GnRH agonist (500 µg sc leuprolide acetate, Procrin, Abbott, Madrid, Spain) (23).

Exclusion criteria were: BMI at least 26 kg/m²; thyroid dysfunction, Cushing’s syndrome, or hyperprolactinemia; glucose intolerance (24); family or personal history of diabetes mellitus; late-onset congenital adrenal hyperplasia (25, 26); use of medication known to affect gonadal or adrenal function or carbohydrate or lipid metabolism; abnormal blood count or serum electrolytes; and abnormal results in screening tests for liver and kidney function.

The study was conducted after approval by the Institutional Review Board of Sant Joan de Déu University Hospital (Barcelona, Spain); informed consent was obtained from young women and/or from the parents, with assent from minors. None of the subjects or results in the present study have been reported previously.

Study design

In this open-labeled study, all participants started on metformin (850 mg/d) and a monophasic fourth-generation OC (Yasmin, Schering AG, Berlin, Germany; 30 µg ethinylestradiol plus 3 mg drospirenone, 21 d/month) at time zero. After stratification for age (16.0 and >16.0 yr), patients were randomized to receive flutamide in addition [62.5 mg, once daily at dinner time, for 3 months; Met and OC (+), Flu (+); n = 20] or not [Met and OC (+), Flu (–); n = 20].

Endocrine metabolic assessment

Fasting blood glucose, serum insulin, lipid profile, SHBG, testosterone, adiponectin, and IL-6 were determined at baseline and after 3 months, together with indices of hepatic and renal function, as safety variables.

Ultrasound and color Doppler measurements

At the start of the study and after 3 months, the ovarian volume morphology and the flow in ovarian vessels were assessed transabdominally, with a full bladder, between 0800 and 0100 h, either in the follicular phase (d 3–7) or after 2 months of amenorrhea.

Scans were obtained by a single observer with an Acuson XP/10 OB scanner (Acuson, Mountain View, CA) using a 5-MHz sector probe; throughout the study, the observer (S.C.) remained blinded for treatment randomization. Ovarian volume was calculated with the formula for a modified prolate ellipsoid (depth x breadth x length/2); ovarian morphology was assessed by standard criteria (27).

Doppler ultrasound had a frequency of 4 KHz in both color and spectral mode. The spatial peak temporal average intensity of ultrasound for B-mode and for Doppler examinations was less than 100 mW/cm². Color signals were sought in the ovarian stroma at maximal distance from the ovarian surface; when more than one artery was detected, the artery with lowest downstream impedance was selected for Doppler measurements. In each session, three consecutive waveforms were averaged, and the following indexes were calculated: pulsatility index, defined as the difference between peak systolic and end diastolic flow divided by the mean maximum blood velocity; and the resistance index, defined as the difference between peak systolic and end diastolic blood flow divided by the peak systolic velocity (17, 18, 19). There was not a significant difference between the right and the left ovary (two-sided, paired Student’s t test) for any of the assessed indices. For logistic reasons, only the 21 last-enrolled study participants underwent Doppler studies (n = 11 receiving additional flutamide and n = 10 not); there were no significant differences between Doppler-assessed (n = 21) and nonassessed (n = 19) subgroups for any of the other study variables (two-sided, unpaired Student’s t test).

Body composition, assays, and statistics

Body composition was assessed by dual-energy x-ray absorptiometry at study start and after 3 months, with a Lunar Prodigy coupled to Lunar software (version 3.4/3.5, Lunar Corporation, Madison, WI) (28). Absolute (kilograms) whole-body fat and lean mass were assessed, as well as fat content in the abdominal region, which was defined as the area between the dome of the diaphragm (cephalad limit) and the top of the great trochanter (caudal limit) (29). Total irradiation dose per assessment was 0.1 mSievert. Coefficients of variation (CV) for scanning precision were 2.0 and 2.6% for fat and lean body mass (30); intraindividual CV for abdominal fat mass was 0.7%.

Serum glucose was measured by the glucose oxidase method. Immunoreactive insulin was assayed by IMX (Abbott, Santa Clara, CA); intra- and interassay CV were 4.7 and 7.2%, respectively. Serum testosterone, 17-hydroxyprogesterone, and SHBG were assayed as described (5, 7). IL-6 was measured by immunochemiluminescence (Immulite 2000, Diagnostic Products, Los Angeles, CA), with a lower detection limit of 100 fg/ml; intra- and interassay CV were 3.5 and 5.1%, respectively. Adiponectin was measured by RIA (Linco Research, St. Charles, MO); intra- and interassay CV were 6.2 and 6.9%, respectively. Samples were stored at –20 C until assay.

For uniformity, results are expressed as mean ± SEM. Two-sided Student’s t tests (paired or unpaired, as appropriate) were used for statistical comparisons between subgroups; per variable, only one comparison was performed; significance level was set at P < 0.05.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Table 1 and Fig. 1 summarize the main findings. At the start, the study population was characterized by hyperandrogenism, dyslipidemia, dysadipocytokinemia, adiposity, and by elevated pulsatility and resistance indices of ovarian arteries. All study variables were comparable between randomized subgroups. Each treatment was well tolerated; indices of hepatic and renal function remained unchanged.

View larger version (14K): [in this window] [in a new window]   FIG. 1. Changes over 3 months in lean body mass, body fat mass, and abdominal fat mass in 40 adolescents and young women with ovarian hyperandrogenism (age, 17 yr). All study participants started on metformin and on an oral contraceptive [ethinylestradiol (EE) + drospirenone], and they were randomized to receive flutamide (62.5 mg/d) in addition (flutamide +; n = 20; •) or not (flutamide +; n = 20; ). Addition of low-dose flutamide was found to increase lean mass and reduce total and abdominal fat excess, without changing total body weight (see Table 1 for statistics).

In girls receiving flutamide in addition to metformin plus OC, the changes in most endocrine metabolic variables were similar to those in girls on metformin plus OC alone; however, low-density lipoprotein (LDL) cholesterol dropped to nearly normal levels. In addition, adiponectinemia, body composition, and Doppler indices of ovarian flow all changed detectably toward the norm in the copresence of flutamide.

By comparison of 3-month changes between subgroups, the addition of flutamide was found to have consistently beneficial effects on LDL cholesterol, IL-6, adiponectin, body composition, and arterial flow in the ovaries.

Body weight remained virtually unchanged in each subgroup. At the start, 13 of 40 patients had regular menses (cycles of 25–35 d), and 27 were oligo- or amenorrheic; after 3 months, menses were regular in all. None of these patients had enlarged or polycystic ovaries on ultrasound. One adolescent experienced spotting without breakthrough bleeding at the beginning of the second cycle on OC.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
To our knowledge, this is the first manuscript comparing the efficacy of metformin and ethinylestradiol drospirenone with that of the same duo plus low-dose flutamide in teenagers with PCOS. Efficacy was judged not only by classic markers such as BMI, fasting glucose/insulin and lipids, testosterone, and SHBG, but also by newly recognized indices as IL-6, adiponectin, body composition, and ovarian vascular resistance. The compared treatments were found to yield mostly similar results for the classic markers but strikingly different or even opposite outcomes for the newer indices. The differential results concerned LDL cholesterol, IL-6, adiponectin, ovarian artery flow, total and abdominal fat, and lean body mass; each of these was to the advantage of adding flutamide. Together, these differences indicate that the addition of low-dose flutamide confers lipolytic and antiatherogenic benefits and that, hence, it holds potential as an adjuvant therapy in the long-term prevention of cardiovascular and metabolic disorders that are known to be linked to PCOS (31, 32, 33, 34).

When given in monotherapy to women with PCOS, flutamide lowers the high serum LDL cholesterol levels (35) and the heightened pulsatility index of the uterine artery (19). These antiatherogenic benefits of flutamide in monotherapy now proved to be still readily detectable in the copresence of metformin and a fourth-generation OC. It remains to be studied whether the latter cotherapies amplify or attenuate flutamide’s capacity to improve the hyperandrogenic, insulin-resistant, hypersomatotropic, dyslipidemic, adipose, and/or proinflammatory state of adolescents and young women with PCOS (5, 6, 8, 9, 36, 37, 38).

The pathways through which low-dose flutamide exerts its lipolytic and antiatherogenic effects in hyperandrogenic women are likely to be complex. IL-6 and adiponectin are plausible mediators of excessive androgen action and of the therapeutic benefits through androgen receptor blockade because these adipocytokines have both been implicated into androgen expression and action and also into insulin sensitivity, lipid metabolism, and cardiovascular risk (39, 40, 41, 42, 43). Serum IL-6 levels are up-regulated in states of insulin resistance and are thought to contribute to the accompanying lipid abnormalities, including to the hypertriglyceridemia and increase in circulating free fatty acids (42). In addition, IL-6 differentially regulates androgen receptor transactivation via three distinct signaling transduction pathways, the overall effect depending on the balance among these pathways and the androgen concentrations. For example, at androgen concentrations above normal female range and below normal male range, IL-6 and androgens could act synergistically on the androgen receptor (40, 44), hereby amplifying androgen action. Adiponectin, in contrast to IL-6, exerts insulin-sensitizing effects by increasing insulin action in muscle and liver (45). Serum adiponectin is reversibly down-regulated by androgens and IL-6 but not by estrogens (39, 41); hypoadiponectinemia has been linked to insulin resistance and dyslipidemia, independently of total or central adiposity (43). Collectively, these data suggest that the efficacy of low-dose flutamide in reducing not only LDL cholesterol but also fat excess and ovarian vascular resistance might be partly based on restoration of the androgen receptor transactivation balance and counteraction of the androgen- and IL-6-induced down-regulation of adiponectinemia.

There is a gap between normal ranges of serum testosterone in men and women. Intermediate states, such as in hypogonadal males and in hyperandrogenic females, are associated with an adipose body composition, including in the abdominal region (4, 46, 47). In hypogonadal men, restoration of testosterone levels into the upper male range is known to reduce total and abdominal fat (46, 47, 48). Here, we showed in hyperandrogenic teenagers that androgen receptor blockade, when added to metformin and a fourth-generation OC, also reduces body and abdominal adiposity. This apparent paradox can be partly clarified by the dose dependency of the direct effects that androgens exert in human adipose tissue and, in particular, in abdominal adipocytes (49). The androgen effects on the expression of two key enzymes in lipolysis and lipogenesis, hormone-sensitive lipase and lipoprotein lipase, respectively, are dose dependent but in opposite directions (49). The most lipogenic combination occurs when androgen exposure is intermediate: the expression of hormone-sensitive lipase is down-regulated, and the expression of lipoprotein lipase is up-regulated (49). Such androgen-induced up-regulation of lipoprotein lipase in abdominal fat can be blocked by flutamide, possibly through a mechanism that does not only involve the androgen receptor but also the MAPK pathway (49), which can be modulated by metformin and adiponectin too.

In conclusion, low-dose flutamide is herewith identified as a pivotal component within the first contraceptive combination therapy that has been shown to attenuate the hypoadiponectinemia, ovarian vascular hyper-resistance, lean mass deficit, and central adiposity of young women with PCOS. Finally, these data challenge any claim that drospirenone, as currently used in a contraceptive, is a clinically significant antiandrogen.

	Acknowledgments

 
We thank Montserrat Gallart for hormone measurements.

	Footnotes

 
This work was supported by the Social Security Research Fund, Health Institute Carlos III, Spain (PI/021013). F.d.Z. is a Clinical Research Investigator of the Fund for Scientific Research (Flanders, Belgium).

Abbreviations: BMI, Body mass index; CV, coefficient(s) of variation; HDL, high-density lipoprotein; LDL, low-density lipoprotein; OC, oral estro-progestagen contraceptive; PCOS, polycystic ovary syndrome.

Received January 12, 2004.

Accepted May 18, 2004.

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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. [Abstract] [Full Text] [PDF]

				H. S. Willenberg, M. Bahlo, W. A. Scherbaum, F. de Zegher, D. B. Dunger, L. Ibanez, and R. L. Rosenfield Hirsutism. N. Engl. J. Med., April 6, 2006; 354(14): 1533 - 1535. [Full Text] [PDF]

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