November 26, 2004
Metformin Versus Flutamide in the Treatment of Metabolic Consequences of Non-Obese Young Women With Polycystic Ovary Syndrome: a Randomized Prospective Study
Key words: PCOS, INSULIN SENSITIVITY, ANDROGENS, METFORMIN, FLUTAMIDE
ABSTRACTIn addition to the reproductive consequences, polycystk ovary syndrome (PCOS) is characterized by a metabolic disorder in which hyperinsulincmia and insulin resistance are central features. The effects and possible benefits from insulin-sensitizing drugs are not well known, especially in non-obese women with PCOS. This study was designed to evaluate, the effects of metformin and flutamide on metabolic parameters and insulin resistance in non-obese women with PCOS. Thirty non-obese women newly diagnosed with PCOS and 15 age- and weight-matched healthy volunteers as controls were included in the study. Patients were assigned randomly to receive flutamide 250 mg daily or metformin 850 nig three times daily. Glucose, insulin, insulin resistance, androgen levels and glucose and insulin responses to an oral glucose tolerance tests (OGTT) were assessed before and after a 4-week therapy period. A positive correlation was found between body mass index and insulin level in patients with PCOS and controls. Follicle stimulating hormone, luteinizing hormone, free testosterone and dehydroepiandrosterone sulfate levels decreased significantly, but insulin resistance levels were not changed after flutamide therapy. Body weight, free testosterone, insulin and insulin resistance levels decreased significantly after metformin therapy. In conclusion, metformin treatment improved insulin sensitivity and decreased androgen levels, and flutamide decreased androgen levels but failed to improve insulin sensitivity in the non-obese women with PCOS.
Polycystic ovary syndrome (PCOS) is characterized by oligomenorrhea with variable degrees of ovarian and adrenal hyperandrogenism. This is an exceptionally common endocrine disorder among women of reproductive age and includes different pathologies1. In addition to the reproductive consequences, some studies also suggest that it may increase the risk of several conditions, including hyperinsulmemia, type 2 diabetes, dyslipidemia, hypertension and cardiovascular diseases2-4.
Numerous studies have shown that both lean and obese women with PCOS are insulin resistant5-9. The lean woman with PCOS seems to have a form of insulin resistance that is intrinsic to the syndrome. Recently, attention has been focused on the possible defect in post- receptor signal transduction. It has been shown that women with PCOS exhibit increased serine phosphorylation of insulin receptor substrate 1 (IRS-1), which appears to be a mechanism for tumor necrosis factor (TNF)-α mediated insulin resistance2.
It has been suggested that hyperinsulinemia may stimulate ovarian androgen production. It decreases the level of sex-hormone binding globulin (SHBG) and increases the gonadotropin releasing hormone (GnRH)-stimulated release of luteinizing hormone (LH) and causes hyperandrogenism10-15. It has become evident that insulin resistance is a key component in PCOS that could serve as the pathogenetic link between hyperandrogenemia and hyperinsulinemia. On the other hand, it is possible that hyperandrogenism may cause insulin resistance and hyperinsulinemia. Exogenous androgens reduce insulin sensitivity. Blockade of androgen receptors by flutamide or normalization of hyperandrogenism by GnRH analogs have been reported to improve insulin sensitivity. Therefore, it seems reasonable to postulate that the new therapeutic modalities that increase insulin sensitivity may be useful in preventing metabolic hazards such as insulin resistance and hyperandrogenism.
Metformin has been shown to improve ovarian function and glucose metabolism in women with PCOS16-24, but its effects and possible benefits in non-obese PCOS subjects, and whether or not metformm improves insulin sensitivity independently of weigh loss, are still not known25-29. Flutamide is known to be effective in reducing hirsutism in patients with ovarian hyperandrogenism"" . However, its effects on insulin resistance and the metabolic profile in non- obese PCOS women are controversial32-37.
We aimed to determine the effects of metformin, an insulin- sensitizing drug, and flutamide, a selective antiandrogen, on insulin resistance and glucose and androgen levels in non-obese women with PCOS.
DESIGN AND METHODS
Thirty non-obese women (body mass index (BMI)
The diagnosis of PCOS was made according to the characteristic clinical findings (oligomenorrhea, amenorrhea, hirsutism), the laboratory data (supranormal concentrations of total or free testosterone, LF/FSH ratio > 2) and ultrasonography (at least one ovary with volume of > 9 ml, having more than eight subcapsular cysts of 2-8 mm in the periphery of the ovary). PCOS was diagnosed if the patient had hirsutism and ultrasound features of polycystic ovaries, plus at least one of the following features: oligomenorrhea/ amenorrhea, or serum androgen concentrations at or above the upper limits of normal.
Hirsutism score was evaluated by a single examiner with the system of Ferriman and Gallwey as modified by Hatch et al. . Patients were assigned randomly to receive flutamide 250 mg daily or metformin 850 mg three times daily. Blood samples were drawn during the mid-follicular phase (days 37) of the menstrual cycle before and after the 4-week therapy period. After centrifugation the serum was stored at -20C until assayed.
Serum total testosterone, follicle stimulating hormone (FSH), LH, estradiol, dehydroepiandrosterone sulfate (DHEAS), cortisol and 17hydroxyprogesterone (17-OHP) levels were measured by an automated chemiluminescence system (ACS-180, Chiron, Emeryville, CA, USA). Intraassay coefficient of variance (CV) was 6.2%, 5.6%, 4.1%, 6.1%, 8.6%, 8.7% and 5.2%; and mterassay CV was 8.2%, 7.1%, 4.9%, 9.6%, 13.6%, 12.3% and 7.8%, for total testosterone, FSH, LH, estradiol, DHEAS, cortisol and 17-OHP, respectively. Serum free testosterone levels were measured by radioimmunoassay (Coat a Count, Diagnostic Products, Los Angeles, CA, USA). Intra-assay and interassay CV was 7.1% and 12.8%, respectively. Serum insulin levels were measured by radioimmunoassay (LINGO Research, St. Charles, MO, USA). Intraassay and interassay CV was 5.8% and 10.1%, respectively. Liver function parameters were carefully examined.
Each patient underwent an oral glucose tolerance test (OGTT) during the follicular phase of the menstrual cycle (days 3-7 of menstrual bleeding). Glucose levels, and glucose and insulin responses to the OGTT were assessed. Insulin resistance was calculated by the homeostasis model of assessment insulin resistance formulation39(HOMA-IR):
Fasting plasma insulin (U/ml) fasting plasma glucose (mmol/l)/ 22.5.
All values are expressed as means SD. A value of p
Women with PCOS and the control group did not differ significantly at baseline with respect to age, BMI, waist/hip ratio (WHR) or levels of FSH, total testosterone, estradiol, progesterone, DHEAS and fasting serum glucose. Hirsutism (Ferriman and Gallwey) score, and levels of LH, free testosterone and basal insulin were found to be higher in women with PCOS than in the controls (Table 1).
There were no statistically significant differences in the two study groups (group 1, metformin and group 2, flutamide) with respect to clinical characteristics, serum hormone concentrations and metabolic variables at baseline (p > 0.05) (Table 1 ). The Kolmogorov-Smirnov test yielded a normal distribution for our data.
A weak positive correlation between BMI and insulin level was found (r=0.31, p
In group 1 (metformin), the mean weight (66.73 12.69 vs. 65.40 12.44 kg; p
I\n group 1 (nietformin), there were significant decreases in levels of free testosterone, insulin and HOMA-IR (3.29 1.28 vs. 2.08 1.01 pg/ml; 12.52 6.24 vs. 5.94 2.52 U/ml; 2.30 1.22 vs.1.10 0.42, respectively) (Table 2) (Figure 1).
In group 2 (flutamide), there were significant decreases in FSH, LH, free testosterone and DHEAS (3.94 1.63 vs. 2.69 1.53 mIU/ml; 12.15 7.49 vs. 9.64 6.72 mIU/ml; 3.32 + 2.12 vs. 2.42 1.45 pg/ ml; 329.16 127.96 vs. 256.5 92.63 g/dl, respectively). Glucose, glucose response to the OGTT and HOMA-IR levels did not change after therapy (Table 3) (Figure 2).
PCOS, which affects about 6-10% of women of reproductive age, is characterized by chronic anovulation and hyperandrogenism . Its etiology remains unknown. However, an association between hyperinsulinemia, insulin resistance and PCOS was demonstrated clearly in the past decade. Moreover, it has been shown that hyperinsulinemia secondary to the insulin resistance plays an important role in the etiology of abnormalities in ovarian function. Therefore, the selection of drug type became an important issue in the management patients with PCOS8-10,40-42. In this study we aimed to compare the effect of the widely used antiandrogen drug flutamide and the anti-hyperglycemic drug metformin on insulin sensitivity and some metabolic parameters.
Previous studies revealed that 20-50% of women with PCOS have normal weight or are lean; insulin resistance in these non-obese PCOS women is controversial, but the results of several studies have suggested an intrinsic insulin resistance in non-obese PCOS women9,42-47. We also observed higher fasting insulin levels and decreased insulin sensitivity in women with PCOS compared to controls. BMI and WHR were similar in both groups, so this difference seems to be independent of obesity.
Table 1 Basal clinical characteristics, serum hormone concentrations, glucose and insulin response to the oral glucose tolerance test in both treatment groups and the control group
Metformin, a biguanide anti-hyperglycemic, has been used for the treatment of type 2 diabetes for more then 35 years. In our study, metformin therapy was accompanied by an increase in insulin sensitivity. We found that administration of metformin to women with PCOS resulted in a partial improvement of insulin resistance (hyperinsulinemia), and we observed a significant decrease in insulin levels at O min during the OGTT. Although the precise mechanism of action of metformin is incompletely defined, it appears to enhance insulin action without stimulating insulin secretion. Our results were similar to those of previous studies on obese insulin- resistant women with PCOS16,17,19, as well as those on non-obese subjects25,26. In obese women, the primary mechanisms of metfbrmin action have been suggested to be improvement of insulin sensitivity19,48. Some studies have stated that improvement of insulin action is secondary to reduction of central obesity24,49. On the other hand, whether or not metformm improves insulin sensitivity independent of weight loss is still controversial50,51.
Flutamide has serious side-effects such as skin dryiiess, gastrointestinal discomfort, breast tenderness, menstrual disturbances, fatal or non-fatal hepatotoxicity when it is used at doses of 500 mg or higher30,51. Severe hepatotoxicity has not been described when the daily flutamide dose is below 500 mg52,53. In this study, we used a low dose (250 mg) of flutamide. It was well tolerated without important side-effects.
Table 2 The effect of metformm on clinical characteristics, serum hormone concentrations, glucose and insulin response to the oral glucose tolerance test (n = 15)
Table 3 The effect of flutamide on clinical characteristics, serum hormone concentrations, glucose and insulin response to the oral glucose tolerance test (n = 15)
Figure 1 The effect of metformin therapy on gonadotropin, androgcn levels and the homeostasis model (HOMA). FSH, follicle stimulating hormone; LH, luteinizing hormone; T.test, total testosterone; F.test, free testosterone. *p
Figure 2 The effect of flutamide therapy on gonadotropin, androgen levels and the honieostasis model (HOMA). FSH, follicle stimulating hormone; LH, luteinizing hormone; T.test, total testosterone; F.test, free testosterone. *p
Flutamide is a non-steroidal androgen that conceivably exerts its major effect by blocking the nuclear binding of androgens to their receptor sites54. It has been reported that flutamide is a pure iion- steroidal anti-androgen that has no glucocorticoid, progestational, androgenic, estrogenic or antigonadotropic activity. However, in addition to its possible interaction with adrenal androgen secretion, a recent study also suggested that flutamide, when used alone in young hyperandrogenic women, reduces ovarian synthesis through restoration of the steroidogenic enzymes of androgen biosynthesis in ovarian thecal cells31.
The data with regard to the effect of flutamide on insulin resistance and the metabolic profile in nonobese PCOS women are controversial. Some reports have suggested that flutamide reduces both adrenal and ovarian androgen synthesis55-57, restores ovulation and ameliorates the metabolic profile of hyperandrogenic women30,31, whereas other reports have suggested no substantial effects on circulating androgens, lipids, or insulin sensitivity32-37. In our study, flutamide decreased androgen levels, but failed to improve insulin sensitivity in non-obese PCOS women after a short therapy period.
It is well known that androgens are involved in the feedback regulation of gonadotropin synthesis and secretion58-61. Specific androgen-receptor blockade by flutamide has been shown to increase gonadotropin synthesis in rats62-66 and men67-68 by reversing the effect of androgen. In PCOS, gonadotropin secretion is altered69 and the majority of patients have elevated LH levels in plasma and a persistent rapid frequency of LH (GnRH) pulse secretion70-72, the mechanisms of which are unclear. Studies regarding the effects of flutamide on gonadotropin levels in women with PCOS have yielded inconclusive results, possibly owing to the heterogeneity of the populations studied. Some reports stated that it has no effect on FSH and LH levels73,74, while some others stated that it decreases FSH and LH75 or decreases LH and increases FSH levels31. In our study, flutamide therapy decreased both FSH and LH levels significantly. This relation can be explained by restoration of the sensitivity of the GnRH pulse generator to sex hormones (estrogen and progesterone) in adult women by blocking the androgen action with antiandrogens. It is also suggested that reduction of excess androgen secretion or blockade of androgen action may be an important element in restoring normal ovarian regulation of GnRH secretion in PCOS and may have a place in therapeutic regimens aimed at establishing cyclic ovulation in women with PCOS76.
In conclusion, both drugs were found to be safe and supposed to be an effective approach in the patients with PCOS. Metformin treatment improved insulin sensitivity, but flutamide treatment failed to improve insulin sensitivity in non-obese PCOS women.
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I. Sahin, R. Serier[double dagger], F. Karakurt[double dagger], B. Demirbas[double dagger], C. Culha[double dagger], C. Taskapan*, F. Kosar[dagger] and Y. Aral[double dagger]
Department of Endocrinology and Metabolic Diseases, *Biochemistry and [dagger]Cardiology, Faculty of Medicine, Inonu University, Malatya; and [double dagger]Department of Endocrinology and Metabolic Diseases, Ankara Postgraduate Training Hospital, Ankara, Turkey
Correspondence: Assistant Professor I. Sahin, Department of Endocrinology and Metabolic Diseases, Faculty of Medicine, Inonu University, 44069 Malatya, Turkey
Copyright CRC Press Sep 2004