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The Effect of a Pure Antiandrogen Receptor Blocker, Flutamide, on the Lipid Profile in the Polycystic Ovary Syndrome

Laiko Hospital, First Department of Internal Medicine, University of Athens (E.D.-K., G.T.), and Evangelismos Hospital, Second Department of Internal Medicine, University of Athens (A.M., S.R.), Athens, Greece; and the Department of Obstetrics and Gynecology, Yale University School of Medicine (A.J.D.), New Haven, Connecticut 06520

Address all correspondence and requests for reprints to: Dr. Evanthia Diamanti-Kandarakis, First Department of Internal Medicine, Endocrinology Section, University of Athens Medical School, 17 Ag. Thomas Street, Athens 115–27, Greece.

	Abstract

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Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting women of reproductive age; it is associated with hyperandrogenism, hyperinsulinemia, and dyslipidemia. This study was designed to assess the long term effects of a pure androgen receptor blocker, flutamide, on the lipid profile in women with PCOS and to examine the possible mechanisms by which androgens may exert their influence. Seventeen women with PCOS (10 obese and 7 lean) were studied. All subjects received a 12-week course of oral flutamide (500 mg/day). The baseline and posttreatment evaluations included lipid profile, androgen levels, insulin sensitivity, and serum catecholamine determinations. The primary outcome was the change in the ratio of low density lipoproteins (LDL) to high density lipoproteins (HDL). Treatment with flutamide was associated with a significant decrease in the LDL/HDL ratio by 23% (P = 0.005), in total cholesterol by 18% (P < 0.0001), in LDL by 13% (P = 0.002), and in triglycerides by 23% (P = 0.002). Flutamide treatment was also associated with a trend toward an increase in HDL (by 14%; P = 0.14). The effects on lipid profile were found regardless of obesity and were not associated with a change in weight. Furthermore, actions of flutamide on lipid metabolism were not associated with significant changes in circulating adrenaline or noradrenaline, glucose metabolism, or insulin sensitivity. This report has demonstrated for the first time that treatment with the pure antiandrogen, flutamide, may improve the lipid profile and that this effect may be due to direct inhibition of androgenic actions.

	Introduction

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POLYCYSTIC ovary syndrome (PCOS) is one of the most common endocrinopathies, affecting 5–10% of premenopausal women (1). Hyperandrogenism in women with PCOS is associated with metabolic aberrations of much greater importance than cosmetic problems such as hirsutism or acne. These aberrations include insulin resistance with accompanying hyperinsulinemia and dyslipidemia (2, 3, 4, 5, 6, 7, 8). To our knowledge, there is no definitive prospective study demonstrating that PCOS represents an independent of obesity risk factor for development of cardiovascular disease. However, several retrospective and case-control studies indicated that, in the long term, women with a history of PCOS may be at increased risk for developing hypertension, noninsulin-dependent diabetes mellitus, atherosclerosis, coronary artery disease, and myocardial infarction (6, 9, 10, 11).

Most reports suggest that the lipid profile of women with PCOS is characterized by elevated serum levels of cholesterol, low density lipoproteins (LDL), very low density lipoproteins (VLDL), and triglycerides, with concomitantly reduced concentration of high density lipoproteins (HDL) (5, 6, 8, 12, 13, 14, 15). These abnormalities in lipid levels have serious atherogenic consequences; in particular, as observed in the Framingham study, high LDL and low HDL predict the development of coronary artery disease (16, 17).

Dyslipidemia typically occurs within a cluster of several interrelated cardiovascular risk factors, including obesity, high waist to hip ratio (WHR), hyperinsulinemia, and hyperandrogenism. The elucidation of cause and effect relationships among these factors and hence the identification of independent risk factors are exceedingly difficult. In light of recent studies, it appears that although obesity is a major contributor to dyslipidemia in women with PCOS, some abnormalities of lipid profile are independent of obesity. Graf et al. observed that obesity was associated with a decrease in HDL levels in both PCOS and control subjects (18). Subsequently, Robinson et al. observed that low HDL in women with PCOS cannot be explained solely by obesity, indicating, therefore, that other inherent features of PCOS predispose to dyslipidemia (19).

Potential mechanisms of dyslipidemia in women with PCOS include hyperinsulinemia and hyperandrogenism. Alternatively, genetic variation in each of these mechanisms modified by environment may be occurring. The roles of insulin and sex hormones in the regulation of lipid metabolism have been well recognized. In particular, levels of HDL₂ are regulated by lipoprotein lipase and hepatic lipase; these activities are responsive to insulin and sex steroids, respectively (20, 21). Ek et al. observed that women with PCOS had an impairment of catecholamine-induced adipocyte lipolysis due to defects such as a decreased number of ß₂-adrenoreceptors as well as postreceptor dysfunction of the protein kinase A or hormone-sensitive lipase (22). These defects in the adrenergic regulation of lipolysis may be attributable to insulin resistance and hyperinsulinemia.

Elevation of androgens offers another plausible explanation of metabolic disturbances in insulin resistance syndromes such as PCOS (23, 24). Hyperandrogenism is associated with upper body obesity (expressed as WHR) independently of weight (25, 26, 27). Furthermore, administration of exogenous androgen to women leads to increased visceral fat accumulation and decreased serum HDL (28). However, the mechanisms of androgen actions on lipid metabolism are still poorly understood. There is growing evidence that androgens may influence the predominant site of body fat deposition and muscle morphology, possibly in relation to alterations in splanchnic insulin metabolism and insulin sensitivity (29, 30, 31, 32). It appears that androgens may also adversely affect lipid metabolism by direct modulation of lipoprotein lipase and lipolysis (33). The effects of androgens on lipid profile may be sex dependent; studies in hypogonadal men are inconsistent and indicate that androgen replacement may have either an adverse or a beneficial effect (34, 35).

The present study was undertaken to assess the long term effects of a pure androgen receptor blocker, flutamide, on the lipid profile of women with PCOS and to examine the possible mechanisms by which androgens may exert their influence. To our knowledge, this is the first report demonstrating that flutamide exerts a beneficial effect on serum lipids.

	Subjects and Methods

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Subjects

Seventeen women with PCOS (10 obese and 7 lean) were studied (Table 1). The diagnosis of PCOS was made in the presence of chronic anovulation, and hyperandrogenism was confirmed by an elevation of at least 2 of the following plasma androgens: total testosterone, free testosterone, androstenedione, and 3-androstanediol glucuronide. Hirsutism and acne were present in 9 subjects, 6 subjects had only hirsutism, and 2 subjects had only acne. The diagnosis of PCOS was further substantiated by the finding of thickened stroma and multiple subcapsular cysts on ovarian ultrasonographic examination.

Body mass index (BMI) was calculated as weight (kilograms)/height (meters)². Patients were considered lean when their BMI was below 25 kg/m² and obese when their BMI was at least 25 kg/m². Body fat distribution was assessed by measuring the WHR as described by others (36).

After the completion of the baseline studies (see below), all subjects received a 12-week course of oral flutamide (Flucinom, Schering-Plough, Kenilworth, NJ) at a dose of 500 mg/day. Flutamide treatment was initiated on the first day of the menstrual cycle. The patients were advised not to change their eating habits or their activities throughout the study period. All participants were nonsmokers and nondrinkers; they received regular meals with a weight-maintaining diet. The study was approved by the local ethics board. Informed consent was obtained from all patients. Throughout the study, the subjects were using barrier contraception.

Study protocol

All evaluations were conducted within 10 days from the onset of menstrual flow. In the absence of spontaneous menstruation, periods were induced by medroxyprogesterone acetate withdrawal. The baseline evaluations were performed as follows: blood samples were collected at 0800 h after an overnight fast to determine serum levels of steroids (testosterone, free testosterone, androstenedione, and 3-androstanediol glucuronide), sex hormone-binding globulin (SHBG), and lipids (total cholesterol, triglycerides, HDL, and LDL). Glucose metabolism and insulin sensitivity were evaluated using an oral glucose tolerance test (OGTT) and hyperinsulinemic-euglycemic clamp procedure. OGTT was performed by collection of baseline blood samples followed by ingestion of a 75-g glucose load and subsequent blood sampling at 30-min intervals for 2 h to determine serum levels of insulin and glucose; the test was used to determine the area under the curve (AUC) for glucose and insulin. Insulin sensitivity was determined (5–7 days after OGTT) by measuring glucose uptake during the hyperinsulinemic euglycemic clamp procedure, as described previously (23). Briefly, after an overnight fast, catheters were inserted into a dorsal hand vein and an antecubital vein. Crystalline human insulin (Actrapid, Novo-Nordisk, Athens, Greece) was infused via a Harvard pump (Harvard Apparatus, Millis, MA) at a rate of 287 pmol (40 mU)/m²·min for 180 min to increase the plasma insulin level to approximately 500 pmol/L (75 µU/mL). Serum glucose was kept constant at the fasting level with the aid of bedside serum glucose determinations every 5 min and appropriate adjustment of a variable infusion of 20% glucose. Serum adrenaline and noradrenaline were assessed at a baseline (from three pooled samples collected every 5 min) and at the end of the hyperinsulinemic-euglycemic clamp study (from pooled samples collected at 170, 175, and 180 min). All of the above studies were repeated at the end of the 12-week course of flutamide.

Analytical procedures

Plasma glucose was determined with a Beckman glucose analyzer (Palo Alto, CA), using a glucose oxidase method. A solid phase ¹²⁵I RIA was used for quantitative measurement of serum insulin levels as described by others (29). Serum samples were analyzed using commercial RIA kits to determine levels of total testosterone (Byk-Sangtec Diagnostica, Dietzenbach, Germany) and free testosterone (Diagnostic Products Corp., Los Angeles, CA). Androstenedione, dehydroepiandrosterone sulfate (DHEAS), and 3-androstanediol glucuronide were measured using kits from Diagnostic Systems Laboratories (Webster, TX). For all determinations, the intra- and interassay coefficients of variation were 5–7% and 8–11%, respectively. Total cholesterol, triglycerides, and HDL were determined using techniques of Spectrum FPX (Abbott Laboratories, North Chicago, IL), whereas LDL was calculated by the Friedewald equation. Adrenaline and noradrenaline were determined using kits from DDN Diagnostika (Mirpurg, Germany).

Statistical analysis

The values were expressed as the mean ± SEM. Comparison of means was performed using Student’s t test or ANOVA, as appropriate. Baseline and posttreatment levels of lipids and hormones were compared using repeat measures ANOVA with one grouping factor (obese vs. lean). When appropriate, log transformation of variables was performed.

	Results

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Baseline and posttreatment levels of lipids

Treatment with flutamide resulted in marked changes in the lipid profile. Comparisons of lipid levels before treatment (baseline) and after the 12-week course of flutamide (posttreatment) are presented in Table 2. The results were analyzed using repeated measures ANOVA; this approach allows simultaneous evaluation of the effects of treatment, obesity, and the role of interaction between treatment and obesity. In the context of this study, the interaction component may be interpreted as a determination of whether the effect of treatment was altered by obesity. Flutamide treatment was associated with an average decline in cholesterol by 18%, in triglycerides by 23%, and in LDL by 13%. Treatment with flutamide was also associated with a trend (albeit not statistically significant) toward an increase in HDL by 14%. Ultimately, the LDL/HDL ratio declined by 23%. Effects of obesity on lipid profile were not statistically significant; nevertheless, there was a trend among obese patients to have higher levels of triglycerides and LDL. Comparable effects of flutamide were observed in both obese and lean patients.

View larger version (36K): [in this window] [in a new window]   Figure 1. Effect of a 12-week treatment with flutamide on lipid profile in lean and obese women with PCOS. Each line joins baseline and posttreatment values for each individual patient. Lipid levels are presented in Systeme International units. Normal ranges are: cholesterol, less than 5.2 mmol/L (multiply by 38.7 to convert to milligrams per dL); triglycerides, less than 1.8 mmol/L (multiply by 88.6 to convert to milligrams per dL); LDL, less than 3.36 mmol/L (multiply by 38.7 to convert to milligrams per dL); and HDL, more than 1.29 mmol/L (multiply by 38.7 to convert to milligrams per dL).

Table 3 presents comparisons of baseline and posttreatment levels of individual endocrine parameters. Treatment with flutamide was associated with an average decline in 3-androstanediol glucuronide by 21%, in androstenedione by 48%, and in DHEAS by 37%. Flutamide treatment had no significant effect on the level of total or free testosterone or estradiol. SHBG declined during flutamide treatment, on the average, by 18%. Flutamide had no demonstrable effect on levels of adrenaline and noradrenaline. Furthermore, flutamide treatment had no significant effect on fasting glucose levels, glucose AUC in response to oral glucose load, fasting insulin, insulin AUC in response to the glucose load, and glucose uptake during hyperinsulinemic, euglycemic clamp studies. Power analysis revealed that the present study had sufficient power (type II error <0.2 for type I error <0.05) to detect a 30% change in catecholamine levels or insulin sensitivity.

Hepatic function

Serum levels of hepatic enzymes were evaluated before and at the end of the treatment period (Table 4). Flutamide treatment was associated with modest increases in the results of liver function tests; however, these changes were not clinically significant.

	Discussion

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The foremost importance of the present findings is the potential for the development of new therapeutic strategies for the treatment of dyslipidemia. The effects of flutamide on lipid levels are consistent with a significant decline in the risk for development of atherosclerosis and consequent cardiovascular disease.

Most of the subjects in the present study did not have overt dyslipidemia. The potential therapeutic value of flutamide in the treatment of dyslipidemia has yet to be assessed in a broad population of subjects, over a longer treatment period, and with careful evaluation of possible adverse side-effects. Although significant complications due to flutamide use are uncommon, patients may develop elevations of liver transaminases; furthermore, isolated cases of cholestatic hepatitis and even liver failure have been documented in elderly patients treated for prostatic cancer (37). Furthermore, a case of serious hepatotoxicity was reported in a women treated with flutamide for hirsutism (38). In this study, flutamide produced no significant side-effects.

Flutamide is considered to be a "pure" androgen antagonist, acting by competitive inhibition of androgen receptors (39). Therefore, its actions on lipid profile may be most likely attributed to direct blockage of androgenic effects. As androgens are known to promote dyslipidemia, it is reasonable to expect that flutamide may promote a favorable lipid status by inhibiting these adverse actions of androgens. This line of reasoning is also supported by the findings of regression analysis, which indicate that the greatest improvement of total cholesterol may be found in patients with the highest pretreatment levels of androstenedione. In other words, the greatest improvement may be expected in those with the greatest initial androgenic effect.

Lipid metabolism may be affected by various interlinked and interdependent mechanisms (18, 40). Thus, androgens may affect lipids not only directly, but also by affecting obesity, catecholamines, and insulin. In this study, treatment with flutamide had little or no effect on weight; furthermore, the improvement of lipid profile was observed in both obese and lean patients and regardless of the WHR. Consequently, although obesity and high WHR are important risk factors for dyslipidemia, the actions of flutamide cannot be attributed to the effects on total body fat and its distribution. Treatment with flutamide also had no significant effect on adrenaline or noradrenaline; thus, it is unlikely that flutamide may have acted via modulation of metabolism of catecholamines. Furthermore, flutamide had no effect on fasting or post-OGTT insulin levels and glucose uptake during euglycemic clamp studies. Consequently, the effects of flutamide cannot be explained by the alterations in insulin sensitivity and its levels. Interestingly, Lovejoy et al. observed that administration of exogenous androgen to women led to increased visceral fat accumulation and decreased serum HDL without a change in fasting glucose or insulin sensitivity (28). Thus, androgens may affect lipid metabolism and fat deposition by mechanisms not involving insulin.

Actions of flutamide on lipid metabolism may not be universal to all pure antiandrogens. Casodex, another nonsteroidal agent that blocks androgen receptors, had no significant effect on total cholesterol, HDL, or LDL in men (41). In other studies on men, the use of cyproterone acetate, a synthetic steroid antiandrogen, resulted in adverse changes in the lipid profile, most notably a decrease in HDL (42, 43). These effects of cyproterone acetate may be due to its progestogenic properties.

Although flutamide is considered a pure antiandrogen, there is evidence that it has other biological activities and may, for example, inhibit adrenal 17–20-lyase (44). This activity may explain our present observation that flutamide treatment resulted in decreases in 3-androstanediol glucuronide, androstenedione, and DHEAS.

The present study revealed a complex and unexpected interrelationship between flutamide and SHBG. Treatment with flutamide led to a decrease in SHBG levels in both lean and obese patients; furthermore, high baseline SHBG level has been identified as one of the predictors of a greater decline in the total cholesterol level. Previous reports have demonstrated that hepatic production of SHBG may be inhibited by insulin and androgens (45, 46). Yet in this study, flutamide had no detectable effect on insulin. Furthermore, antiandrogenic properties of flutamide would be expected to increase, rather than decrease, the SHBG level. Thus, an observed decline in SHBG may be due to flutamide acting via mechanisms independent of its antiandrogenic properties. Another explanation of the suppression of SHBG involves the possibility that some actions of androgens may be independent of androgen receptors and thus not be inhibited by flutamide. Indeed, Brown et al. observed that testosterone may act on the liver by a mechanism independent of androgen receptors (47). In this context, it is important to note that although flutamide blocks androgen receptor-mediated effects, it has no significant effect on the levels of free and total testosterone. Thus, it is possible that in the presence of flutamide, testosterone may maintain suppressive activity on hepatic SHBG production. This explanation may also apply to the study by Winneker et al., who found that flutamide failed to increase SHBG after its suppression by androgen treatment (48).

The present study was limited to evaluation of a single dose of flutamide and did not include a placebo group. The dose of flutamide was selected on the basis of previous studies demonstrating its effectiveness in the treatment of hyperandrogenic conditions such as hirsutism, acne, and hair loss (23, 49, 50). Ideally, the effects of flutamide on lipid profile should be reevaluated in a placebo-controlled trial assessing several doses of the drug.

In conclusion, this report has demonstrated for the first time that treatment with the pure antiandrogen, flutamide, may improve the lipid profile. The beneficial actions of flutamide appear to be independent of obesity, catecholamine metabolism, and insulin resistance.

Received December 18, 1997.

Revised April 3, 1998.

Revised May 7, 1998.

Accepted May 7, 1998.

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