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

Evanthia Diamanti-Kandarakis, Asimina Mitrakou, Sotos Raptis, George Tolis and Antoni J. Duleba
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.

**The results of this study indicate that 1) flutamide treatment is associated with a significant reduction in total cholesterol, LDL, and triglycerides in young women with PCOS; 2) these effects occur in both obese and lean subjects; 3) the greatest effects of flutamide may be found in those with highest baseline levels of SHBG and androstenedione; and 4) the actions of flutamide on lipid metabolism appear not to be related to changes in circulating adrenaline and noradrenaline levels, glucose metabolism, or insulin sensitivity.
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.

http://jcem.endojournals.org/cgi/content/full/83/8/2699

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