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PubMed1987

Clinical evaluation of flutamide and estramustine as initial treatment of metastatic carcinoma of prostate.

The efficacy and side effects of flutamide were compared with estramustine in patients with advanced prostatic carcinoma. Thirty patients with metastatic cancers but with no serious cardiovascular (CV) conditions were randomly assigned to receive treatment either with flutamide (250 mg X 3) or with estramustine (280 mg X 2). Clinical examination, bone scan, laboratory measurements, including coagulation studies were performed prior to randomization, every three months during year one, and at six-month intervals thereafter. The two groups were comparable with respect to age and tumor characteristics. However, more patients presented with skeletal pain among those later treated with flutamide. During an observation period of between one and two and one-half years, flutamide was discontinued in 1 case (7%) because of icterus, and estramustine in 3 cases (20%) because of CV complications. Of the remaining 14 flutamide-treated patients, 13 responded initially. Eleven of them relapsed, and 5 died of cancer. In the corresponding group of 12 estramustine-treated patients, there were 11 primary responders. Of these, only 2 relapsed and died as did the only nonresponder. The difference between the two groups with regard to relapse is significant (P less than 0.01), but not with regard to mortality. All estramustine-treated patients lost their libido, whereas only 20 per cent of the patients treated with flutamide did so. In the present limited material there was an initial favorable response to flutamide without signs of CV complications and with maintained libido in most cases. However, due to significantly increased risk for relapse compared with estramustine, flutamide cannot be recommended as single therapy except in cases where estrogens are contraindicated or when interference with libido and potency is unacceptable.

Adenocarcinoma↗
PubMed1986

Characteristics of interaction of the antiandrogen flutamide with the androgen receptor in various target tissues.

In rat adenohypophysial cells in primary culture, the specific uptake of [3H] testosterone (T) is completely blocked by increasing concentrations of the pure antiandrogen flutamide-OH, the active metabolite of flutamide at an IC50 value of 50 nM while unlabeled T causes a similar inhibition at an IC50 value of 0.5 nM. After 210 min of incubation of 3 nM [3H]T with the anterior pituitary cells, 80% of radioactivity is still present as unchanged T. Direct binding studies show that flutamide-OH and flutamide interact with the rat anterior pituitary androgen receptor at Ki values of 55 and 1275 nM, respectively. In rat ventral prostate (cytosolic and nuclear fractions) and cytosol from human prostatic carcinoma, rat uterus and mouse Shionogi mammary carcinoma, the Ki values ranged from 0.1 to 0.47, 0.6 to 2.7, 62 to 205 and 1450 to 7550 nM for dihydrotestosterone, T, flutamide-OH and flutamide, respectively . Since the ability of flutamide-OH to inhibit the uptake of [3H]T in intact adenohypophysial cells and to compete for binding to the adenohypophysial androgen receptor shows almost identical values at approximately 1% of the potency of T itself, it is most likely that the antiandrogen activity of flutamide-OH can be completely explained by the ability of the pure antiandrogen to displace androgen from their specific receptor in target tissues. In addition, the finding of similar binding characteristics in a series of other tissues suggests that a similar potency of the antiandrogen can be expected in the other androgen-target tissues.

Anilides↗
PubMed1993

Clinical and endocrine effects of flutamide in hyperandrogenic women.

OBJECTIVE: To investigate the clinical and endocrine effects of the antiandrogen flutamide in hirsute women. DESIGN: Hirsutism was assessed before and after 3 months of treatment with flutamide 500 mg/d. Endocrine evaluations were performed before and during the 2nd month of treatment with flutamide 500 mg or 750 mg/d. SETTING: Department of Obstetrics and Gynecology, Pisa, Italy. PARTICIPANTS: Eighteen hirsute women were studied: nine women were hyperandrogenic, and the other 9 had an idiopathic hirsutism. INTERVENTIONS: Women were randomly treated with flutamide 500 mg/d (9 patients) or 750 mg/d (9 patients) for 3 and 2 months, respectively. Six received placebo 1 month before flutamide treatment. MAIN OUTCOME MEASURES: Hirsutism was assessed by measuring hair diameter. Follicle-stimulating hormone and LH responses to GnRH were evaluated. Basal plasma levels of T, androstenedione (A), 17-hydroxyprogesterone (17-OHP), DHEAS, cortisol (F), and sex hormone-binding globulin (SHBG) were evaluated. The same hormones were determined after a single dose of flutamide (250 or 500 mg) or placebo throughout a 12-hour period and in samples collected 60 and 120 minutes after ACTH intravenous injection. RESULTS: Hair diameter was reduced by 30%. Both dosages of flutamide did not change basal and stimulated gonadotropin, T, A, 17-OHP, F, and SHBG levels. Both dosages reduced stimulated DHEAS levels. CONCLUSIONS: Flutamide may have a beneficial effect on hirsutism. This effectiveness is mainly due to its peripheral antiandrogen action. However, an effect on the adrenal gland seems to be present.

17-alpha-Hydroxyprogesterone↗
PubMed1996

Maximal androgen blockade for patients with metastatic prostate cancer: outcome of a controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy. Casodex Combination Study Group.

OBJECTIVES: To review the outcome of therapy with maximal androgen blockade and compare the efficacy and safety of bicalutamide and flutamide, each used in combination with luteinizing hormone-releasing hormone analogue (LHRH-A) therapy, in patients with untreated metastatic (Stage D2) prostate cancer. METHODS: Randomized, double-blind (for antiandrogen therapy), multicenter study with a 2 x 2 factorial design. A total of 813 patients were allocated 1:1 to bicalutamide (50 mg once daily) or flutamide (250 mg three times daily), plus 2:1 to goserelin acetate (3.6 mg every 28 days) or leuprolide acetate (7.5 mg every 28 days). RESULTS: At the time of analysis (median follow-up, 49 weeks), bicalutamide plus LHRH-A was associated with a statistically significant improvement in time-to-treatment failure, the primary endpoint, when compared with flutamide plus LHRH-A. The results with longer follow-up (median, 95 weeks) support previous findings of an improved time-to-treatment failure with bicalutamide plus LHRH-A; however, the difference between groups was not statistically significant. A treatment failure endpoint was reached by 68% of patients in the bicalutamide plus LHRH-A group, compared with 72% of patients in the flutamide plus LHRH-A group. The hazard ratio of bicalutamide plus LHRH-A to flutamide plus LHRH-A was 0.87 (95% confidence interval [CI], 0.74-1.03; P = 0.10). The upper one-sided 95% confidence limit for survival was 1.00, meeting the definition for equivalence (< 1.25). With longer follow-up, overall mortality was 34%, with equivalent survival between groups: 32% of patients in the bicalutamide plus LHRH-A group died, compared with 35% in the flutamide plus LHRH-A group. The hazard ratio of bicalutamide plus LHRH-A to flutamide plus LHRH-A was 0.88 (95% CI, 0.69-1.11; P = 0.29). The upper one-sided 95% confidence limit for survival was 1.07, meeting the definition for equivalence (< 1.25). Diarrhea occurred in 24% of patients in the flutamide plus LHRH-A group compared with 10% of patients in the bicalutamide plus LHRH-A group (P < 0.001). CONCLUSIONS: In patients with metastatic prostate cancer, bicalutamide plus LHRH-A is effective and well tolerated. Because of its efficacy and tolerability profile, together with its convenient once-daily dosing formulation, bicalutamide represents a prime candidate for antiandrogen of first choice in combination with LHRH-A therapy in the treatment of men with metastatic prostate cancer.

Adult↗
PubMed1997

Finasteride and flutamide as potency-sparing androgen-ablative therapy for advanced adenocarcinoma of the prostate.

OBJECTIVES: Androgen ablation with luteinizing hormone-releasing hormone (LHRH) agonists, orchiectomy, or oral estrogens has significant untoward sexual side effects. We evaluated a combination of finasteride and flutamide as potency-sparing androgen ablative therapy (AAT) for advanced adenocarcinoma of the prostate. In addition, we evaluated whether finasteride provided additional intraprostatic androgen blockade to flutamide. METHODS: Twenty men with advanced prostate cancer were given flutamide, 250 mg orally three times daily. Serum prostate-specific antigen (PSA) values were measured weekly. At a nadir PSA value, finasteride, 5 mg orally every day, was added. PSA values were then measured weekly until a second nadir PSA value was achieved. Sexual function was evaluated at baseline, at the second nadir PSA value, and every 3 months thereafter. Testosterone, dihydrotestosterone (DHT), and dehydroepiandrostenedione (DHEA) levels were measured at baseline and at the first and second nadir PSA values. RESULTS: The median follow-up period was 16.9 months. Therapy failed in 1 patient with Stage D2 disease at 12 months, but an additional response to subsequent LHRH agonist therapy was observed. One patient developed National Cancer Institute grade 3 diarrhea and was withdrawn from the study. Seven of 20 men developed mild gynecomastia, and 3 of 20 developed mild transient liver function test elevations. Mean PSA levels were 94.6 +/- 38.2 ng/mL at baseline and 7.8 +/- 2.7 and 4.7 +/- 2.2 ng/mL at the first and second PSA nadir values, respectively (P = 0.034). Mean percent decline in PSA value from baseline was 87.0 +/- 3.1% with flutamide alone and 94.0 +/- 1.9% with both flutamide and finasteride (P = 0.001). Eleven of 20 men were potent at baseline. At the second nadir PSA value, 9 (82%) of 11 were potent, whereas 2 (18%) of 11 were impotent. With longer follow-up (median 16.4 months), 6 (55%) of 11 men were potent, 2 (18%) of 11 were partially potent, and 3 (27%) of 11 were impotent. With flutamide alone, testosterone rose a mean of 77 +/- 14.7% of baseline (P = 0.0001), DHEA fell a mean of 32.4 +/- 4.6% (P = 0.0001), and DHT was unchanged. With the addition of finasteride, testosterone rose another 14 +/- 6% (P = 0.06, not significant), DHEA was unchanged, and DHT fell a mean of 34.8 +/- 4.7% (P = 0.0009). CONCLUSIONS: Finasteride and flutamide were safe and well tolerated as AAT for advanced prostate cancer. Finasteride provided additional intraprostatic androgen blockade to flutamide, as measured by additional PSA suppression. Sexual potency was preserved initially in most patients, although there was a reduction in potency and libido in some patients on longer follow-up. Further evaluation of this therapy is needed.

Adenocarcinoma↗
PubMed1997

Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Casodex Combination Study Group.

OBJECTIVES: To compare the efficacy and tolerability of bicalutamide and flutamide, each combined with luteinizing hormone-releasing hormone analogue (LHRH-A) therapy, in patients with metastatic (Stage D2) prostate cancer. METHODS: This was a randomized, double-blind (for antiandrogen therapy), multicenter study with a two-by-two factorial design. Eight hundred thirteen patients were allocated 1:1 to bicalutamide (50 mg once daily) and flutamide (250 mg three times daily) and 2:1 to goserelin acetate (3.6 mg every 28 days) and leuprolide acetate (7.5 mg every 28 days). RESULTS: The median times to progression and death were 97 and 180 weeks for the bicalutamide plus LHRH-A group compared with 77 and 148 weeks for the flutamide plus LHRH-A group. The hazard ratio for time to progression for bicalutamide plus LHRH-A to flutamide plus LHRH-A was 0.93 (95% confidence interval [CI] 0.79 to 1.10, P = 0.41) and that for survival time was 0.87 (95% CI 0.72 to 1.05, P = 0.15). The therapies were generally well tolerated. The most common adverse event in the two groups was hot flashes. The incidence of hematuria was significantly higher for the bicalutamide plus LHRH-A group than for the flutamide plus LHRH-A group (12% versus 6%, P = 0.007), but no patient withdrew from therapy because of hematuria. There was a significantly (26% versus 12%, P < 0.001) higher incidence of diarrhea and more withdrawals for diarrhea (25 patients versus 2) for the flutamide plus LHRH-A group relative to the bicalutamide plus LHRH-A group. CONCLUSIONS: With a median follow-up time of 160 weeks, the combination of bicalutamide plus LHRH-A was well tolerated and had equivalent time to progression and survival compared with flutamide plus LHRH-A. Treatment with bicalutamide plus LHRH-A resulted in longer median survival than treatment with flutamide plus LHRH-A.

Adult↗
PubMed1997

Daily dosing with flutamide or Casodex exerts maximal antiandrogenic activity.

OBJECTIVES: Because the large increase in luteinizing hormone secretion induced by flutamide in the intact rat is not found in men, we have used castrated rats and mice supplemented with androstenedione (4-dione) instead of intact animals to measure the activity of the pure antiandrogens flutamide and Casodex. METHODS: We first compared the effect of different schedules of administration of various doses of the two antiandrogens on prostate and seminal vesicle weights in the castrated rat and mice models. RESULTS: For both flutamide and Casodex, no consistent difference was found between the effects of once daily and thrice daily oral dosing in the rat. It was observed, however, that flutamide, especially at the high and therapeutically more effective doses, is about three times more potent than Casodex under both schedules of dosing. When flutamide was administered subcutaneously three times a day, twice a day, once a day, or once every second day in rats and mice, no difference was observed in the degree of inhibition achieved on prostate and seminal vesicle weights. CONCLUSIONS: The present data show that Casodex is about three times less potent than flutamide on the well-recognized parameters of androgen responsiveness in the rat, namely prostate and seminal vesicle weights. Another finding is that once daily dosing with flutamide exhibits an effectiveness comparable to thrice daily dosing; such data may have potential significance in facilitating compliance by administration of flutamide once daily instead of the current thrice daily schedule in men. Moreover, these data, if obtained in a reliable in vivo model, should be helpful in determining the choice of an appropriate dose of Casodex for the treatment of prostate cancer.

Androgen Antagonists↗
PubMed1998

Effects of flutamide on pituitary and adrenal responsiveness to corticotrophin releasing factor (CRF).

OBJECTIVE: Flutamide is a non-steroid antiandrogen that specifically blocks the androgen receptor. We have investigated the effect of flutamide treatment on the adrenal androgen response to corticotrophin releasing factor (CRF) in eight patients with polycystic ovary syndrome (PCOS). PATIENTS: Eight women with moderate to severe hirsutism, ranging in age from 19 to 23 years were enrolled in the study. Basal hormonal pattern showed anovulatory cycles, increased concentrations of LH, androstenedione and testosterone and increased LH/ FSH ratio. A baseline ultrasound scan revealed polycystic ovaries in all patients. Each received 250 mg of Flutamide twice a day for 6 months. MEASUREMENTS: Before treatment and at the end of the sixth month, women were evaluated for hirsutism score and a CRF test was performed to evaluate ACTH, cortisol and adrenal androgen responses. RESULTS: Androstenedione (delta 4), DHEA-S, 17-hydroxy-progesterone, testosterone and free-testosterone showed significantly reduced responses after six months of flutamide therapy whereas ACTH and cortisol response were similar to those before treatment. Clinical improvement in the degree of hirsutism was observed in all patients. The Ferriman-Gallwey scores decreased from a mean of 22 +/- 2 to 8 +/- 1.5. CONCLUSION: Flutamide induces a significant reduction in adrenal androgen response to the CRF test but not in the response of ACTH and cortisol. The finding that flutamide does not alter the pituitary-adrenal axis shows that flutamide acts by reducing adrenal androgens. These results demonstrate that flutamide is not only effective in the treatment of hirsutism but also reduces adrenal androgen secretion.

17-alpha-Hydroxyprogesterone↗
PubMed1998

Bilateral orchiectomy with or without flutamide for metastatic prostate cancer.

BACKGROUND: Combined androgen blockade for the treatment of metastatic prostate cancer consists of an antiandrogen drug plus castration. In a previous trial, we found that adding the antiandrogen flutamide to leuprolide acetate (a synthetic gonadotropin-releasing hormone that results in medical ablation of testicular function) significantly improved survival as compared with that achieved with placebo plus leuprolide acetate. In the current trial, we compared flutamide plus bilateral orchiectomy with placebo plus orchiectomy. METHODS: We randomly assigned patients who had never received antiandrogen therapy and who had distant metastases from adenocarcinoma of the prostate to treatment with bilateral orchiectomy and either flutamide or placebo. Patients were stratified according to the extent of disease and according to performance status. RESULTS: Of the 1387 patients who were enrolled in the trial, 700 were randomly assigned to the flutamide group and 687 to the placebo group. Overall, the incidence of toxic effects was minimal; the only notable differences between the groups were the greater rates of diarrhea and anemia with flutamide. There was no significant difference between the two groups in overall survival (P=0.14). The estimated risk of death (hazard ratio) for flutamide as compared with placebo was 0.91 (90 percent confidence interval, 0.81 to 1.01). Flutamide was not associated with enhanced benefit in patients with minimal disease. CONCLUSIONS: The addition of flutamide to bilateral orchiectomy does not result in a clinically meaningful improvement in survival among patients with metastatic prostate cancer.

Adenocarcinoma↗
PubMed1994

Surprising activity of flutamide withdrawal, when combined with aminoglutethimide, in treatment of "hormone-refractory" prostate cancer.

BACKGROUND: The best treatment for patients with "hormone-refractory" metastatic prostate cancer is unclear, particularly in patients for whom suramin and hydrocortisone have failed. PURPOSE: We investigated a combination of flutamide withdrawal and aminoglutethimide in suramin- and hydrocortisone-pretreated patients with "hormone-refractory" prostate cancer. METHODS: Twenty-nine patients with metastatic prostate cancer were treated with simultaneous flutamide withdrawal and aminoglutethimide (250 mg given orally four times daily). All patients were taking flutamide at the time of entry, and previous treatments with medical or surgical castration, flutamide, suramin, and hydrocortisone had failed in all of these patients. Because of suramin-induced adrenal insufficiency, all patients had previously received, and continued to receive, physiological doses of hydrocortisone. Treatment of all non-surgically castrated patients had previously failed; however, these patients continued to receive depot leuprolide. RESULTS: In 14 (48%) of 29 patients, the prostate-specific antigen (PSA) decreased by more than 80% for 4 or more weeks. Improvements in anemia, thrombocytopenia, soft-tissue masses, bone scans, and symptoms were also noted. Factors associated with response included prolonged flutamide pretreatment, a markedly elevated pretreatment PSA, and the absence of soft-tissue disease. CONCLUSIONS: Flutamide withdrawal, when combined with the simultaneous administration of aminoglutethimide, is a therapeutically active approach in patients with "hormone-refractory" prostate cancer. IMPLICATIONS: On the basis of these and additional data, we hypothesize that prolonged exposure to flutamide results in the selective proliferation of cancer cells containing a mutant androgen receptor that aberrantly recognizes flutamide metabolites and nonandrogenic steroids as androgenic stimuli.

Aged↗
PubMed2004

Effect of flutamide and metformin administered alone or in combination in dieting obese women with polycystic ovary syndrome.

BACKGROUND: Hyperandrogenism, hyperinsulinaemia and obesity play a key and coordinating roles in the pathogenesis of polycystic ovary syndrome (PCOS), contributing in different ways to the clinical expression of the syndrome. Weight loss is beneficial, but the additional administration of insulin-lowering drugs, such as metformin, and antiandrogens may produce further benefits, due to their different spectrum of action. The effects of long-term metformin and flutamide, an antiandrogen drug, added alone or in combination with a low-calorie diet, on body weight and fat distribution, androgens, metabolic parameters and clinical status in obese women with PCOS were investigated. METHODS: Forty obese women with PCOS were enrolled in the study. After a 1-month diet, according to single-blind design, the patients were allocated to treatment with placebo, metformin (850 mg/orally, twice daily), flutamide (250 mg/orally, twice daily) or metformin (850 mg/orally, twice daily) + flutamide (250 mg/orally, twice daily) for the following 6 months, while continuing hypocaloric dieting. At baseline and at the end of the study, sex hormone, SHBG, lipid, insulin and insulin sensitivity determinations were evaluated. At the same time, clinical parameters such as anthropometry, total (TAT), visceral (VAT) and subcutaneous (SAT) adipose tissue, hirsutism and menses were also measured. RESULTS: We found that, in obese PCOS women, following a hypocaloric diet the addition of metformin, flutamide or the combined metformin + flutamide treatment had some specific additional favourable effects with respect to the low-calorie diet alone. In particular, flutamide treatment seemed to add a significant effect in decreasing visceral fat, androstenedione, DHEA-S, total and low density lipoprotein (LDL) cholesterol and in improving hirsutism. Conversely, metformin had significant benefits on the menstrual status. The two drugs showed an additive effect in reducing testosterone concentrations and a synergistic effect in increasing high density lipoprotein (HDL) cholesterol and SHBG levels. Improvement of insulin sensitivity and hyperinsulinaemia appeared to depend on hypocaloric diet, without any further significant effect of the pharmacological treatments, either alone or in combination. CONCLUSIONS: We conclude that, in obese PCOS women, following a hypocaloric diet the addition of metformin, flutamide or the combined metformin + flutamide treatment appears to have a more favourable outcome on body fat distribution, androgens, lipids, hirsutism and menses. However, our data emphasize the dominant role of hypocaloric dieting in improving insulin resistance and hyperinsulinaemia. Therefore, this study provides a rationale for specifically targeting different therapeutical options for PCOS according to the required outcomes.

Adult↗
PubMed1996

Flutamide-associated liver toxicity during treatment with total androgen suppression and radiation therapy for prostate cancer.

PURPOSE: To examine the frequency and severity of toxicity associated with flutamide inpatients treated with total androgen suppression before and during pelvic radiation therapy (RT) for prostate cancer. MATERIALS AND METHODS: Sixty-five patients with T2b-T4 prostate cancer received flutamide and goserelin acetate for 4 months, with RT beginning at the 3rd month. Treatment records including liver function test (LFT) results at baseline and during treatment were reviewed and toxicities noted. RESULTS: In 30 (46%) of 65 patients, flutamide was discontinued prematurely. Primary reasons included elevation in LFT levels (n=14); gastro-intestinal toxicity (n=9); decreased hemoglobin level (n=2); patient refusal (n=2); and arthralgia, rash, and malaise (n=1 each). Hepatotoxicity generally was manifest as asymptomatic transaminase level elevation. Grade 3-4 hepatotoxicity was noted in four of 65 patients. Mean aspartase aminotransferase increased from 23 (baseline) to 67 U/L (during flutamide treatment) (P<.02); mean alanine aminotransferase level increased from 26 (baseline) to 94 U/L (during flutamide treatment) (P<.005). CONCLUSION: Flutamide toxicity was common. LFTs should be monitored during flutamide therapy. The role of flutamide in this treatment regimen may need to be reevaluated.

Aged↗
PubMed2001

Optimal starting time for flutamide to prevent disease flare in prostate cancer patients treated with a gonadotropin-releasing hormone agonist.

OBJECTIVE: Flare-up phenomena, such as an increase in prostate-specific antigen (PSA) and/or deterioration of symptoms, are observed in some patients undergoing gonadotropin-releasing hormone (GnRH) agonist therapy. This study was carried out to determine the optimal time for starting the administration of flutamide to prevent flare-up phenomena. PATIENTS AND METHODS: Twenty-six patients with prostate cancer and elevated serum levels of PSA were randomly assigned to 5 groups. Group A patients (n = 6) were treated with a subcutaneous injection of 3.75 mg leuprorelin acetate depot alone. Group B, C, D and E patients (5 patients in each group) were treated with 375 mg/day of orally administered flutamide combined with leuprorelin. Flutamide was initiated on the day of leuprorelin injection in group B, and at 1, 2 and 4 weeks before leuprorelin injection in groups C, D and E, respectively. Serum PSA and testosterone levels were measured in each patient. RESULTS: Pretreatment with flutamide increased the serum testosterone level, but the testosterone surge after leuprorelin administration was almost the same in all 5 treatment groups. In patients who had been treated with flutamide in combination with leuprorelin, the mean PSA level did not exceed the pretreatment levels after leuprorelin administration. The rate of decrease in PSA in the group receiving simultaneous administration of flutamide with leuprorelin showed a decline comparable to that during the period before leuprorelin administration in the flutamide pretreatment groups. CONCLUSION: Simultaneous administration of flutamide with a GnRH agonist is sufficient to prevent flare-up phenomena.

Adenocarcinoma↗
PubMed2003

Flutamide-metformin therapy to reduce fat mass in hyperinsulinemic ovarian hyperandrogenism: effects in adolescents and in women on third-generation oral contraception.

Adolescents and young women with menstrual irregularities and hyperinsulinemic hyperandrogenism, so-called polycystic ovary syndrome, have abnormalities in body composition, even when nonobese. The combination of flutamide (125-250 mg/d) and metformin has additive benefits on endocrine- metabolic indices in women with polycystic ovary syndrome. However, it is unknown whether this combination also reverses the abnormalities in body composition in this population, especially if the flutamide dose is further reduced, the combination is given at a young age, and an oral contraceptive (OC) is added. Two randomized 3-month studies with flutamide-metformin were conducted in nonobese patients (n = 45) with hyperinsulinemic ovarian hyperandrogenism. In teenagers [n = 21; approximately 15 yr; no use of OC (OC-)], we determined whether a minidose combination (flutamide 62.5 mg/d) improved body composition and endocrine-metabolic indices, and in young women (n = 24; approximately 18 yr; OC+), we determined whether the addition of the minidose combination to a gestodene-containing OC exerted additive effects on the same variables. In OC- teenagers, flutamide-metformin improved fasting insulin/glucose ratio; serum IGF-binding protein-1, testosterone, SHBG, androstenedione, triglycerides, low- density lipoprotein and high-density lipoprotein cholesterol; lean mass, total fat, and abdominal fat (all P < 0.01). In OC+ women, the addition of flutamide-metformin was associated with gain of lean mass and loss of total fat (P < 0.01 vs. OC alone), but the addition failed to reduce abdominal fat. In conclusion, in nonobese adolescents with hyperinsulinemic ovarian hyperandrogenism, minidose flutamide-metformin reversed endocrine-metabolic anomalies and the excess of fat, including abdominal fat; in women, adding flutamide- metformin to a third-generation OC was also effective in improving body composition, but abdominal adiposity was not improved.

Abdomen↗
PubMed2000

Treatment of hirsutism, hyperandrogenism, oligomenorrhea, dyslipidemia, and hyperinsulinism in nonobese, adolescent girls: effect of flutamide.

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.

Adolescent↗
PubMed1999

Comparison of finasteride versus flutamide in the treatment of hirsutism.

OBJECTIVE: To compare the effectiveness of finasteride and flutamide in the treatment of hirsutism in patients with polycystic ovary syndrome (PCOS) and with idiopathic hirsutism. DESIGN: Randomized study. PATIENTS: One hundred and ten hirsute patients were selected: 64 women with PCOS and 46 with idiopathic hirsutism. METHODS: Patients were assigned randomly to receive 5mg finasteride once daily or 250mg of flutamide twice daily, for 12 consecutive months. Hirsutism was evaluated at 12 months of therapy, with the Ferriman-Gallwey score and with measurement of the terminal hair diameters (microm) taken from four different body areas. Blood samples were taken for assessment of endocrine and hematochemical parameters. Side effects were monitored during the treatment. RESULTS: Both finasteride and flutamide induced a significant decrease in the hirsutism scores and hair diameters at the end of 12 months. Finasteride reduced the Ferriman-Gallwey score by 31.4% in the PCOS cases and by 34.2% in the idiopathic hirsutism cases, and hair diameter by 27.0-34.1% in PCOS and by 29.6-37.9% in idiopathic hirsutism. Flutamide reduced the Ferriman-Gallwey score by 56.7% in PCOS and by 50.9% in idiopathic hirsutism, and hair diameter by 50. 3-60.0% in PCOS and by 47.7-56.5% in idiopathic hirsutism. Flutamide did not induce hormone variations, while finasteride increased testosterone levels by 40% in PCOS and by 60% in idiopathic hirsutism and decreased 3alpha-androstanediol glucuronide (3alpha-diolG) by 66.7% in PCOS and by 69.5% in idiopathic hirsutism. No important side effects or changes in the hematochemical parameters were observed with finasteride, while two patients (3.6%) in the flutamide group expressed abnormal transaminase levels after 6 months of treatment. Dry skin also appeared significantly more with flutamide (67.3%) than with finasteride (23.6%). CONCLUSIONS: Both drugs are effective in the treatment of hirsutism but flutamide is more effective than finasteride.

Adolescent↗
PubMed1999

Combined treatment with the 5 alpha-reductase inhibitor PNU 157706 and the antiandrogen flutamide on the Dunning R3327 prostatic carcinoma in rats.

The steroid 5 alpha-reductase enzyme catalyzes the conversion of testosterone to the potent androgen 5 alpha-dihydrotestosterone (DHT). PNU 157706, a novel, potent and selective dual 5 alpha-reductase inhibitor, was reported to be effective in inhibiting the growth of established tumors in the Dunning R3327 rat prostatic carcinoma model. We have studied the efficacy of combined treatment with PNU 157706 and the antiandrogen flutamide in this prostatic tumor in rats. Rats with tumor diameters of about 1 cm were treated orally 6 days a week for 9 weeks with PNU 157706 (10 mg/kg per day) alone or in combination with flutamide (1 and 5 mg/kg per day). Animals were killed 24 h after the last treatment and ventral prostates were removed for testosterone and DHT determination. PNU 157706 reduced the growth of established tumors by 36%; flutamide showed a slight effect at 1 mg/kg per day (24% inhibition), while at the dose of 5 mg/kg per day it reduced tumor growth by 48%. The combination of PNU 157706 with the lower dose of flutamide caused an additive tumor growth inhibition (60%) and the combination with the higher dose of flutamide resulted in a better inhibition of tumor growth (68%) than did either treatment alone. Castration resulted in marked tumor growth inhibition (76%). Ventral prostate weight was more markedly reduced by PNU 157706 treatment than by flutamide; combined treatment was as effective as castration. Prostatic DHT content was markedly reduced by PNU 157706 (93%), whereas prostatic testosterone increased (137%). Concomitant treatment with flutamide partially antagonized the testosterone increase induced by PNU 157706 and did not modify the already considerable suppression of DHT. These data show that the inhibitory effects of PNU 157706 and flutamide on Dunning prostatic tumor growth are additive, thus supporting the rationale of this combination therapy in advanced prostate cancer, in order to achieve adequate androgen blockade with minimal side-effects.

Androstenes↗
PubMed2005

Influence of ovariectomy and flutamide treatment on vaginal tissue and body weight.

OBJECTIVE: To determine the effect of flutamide on vaginal histology, and to ascertain whether flutamide regulates body weight gain in the ovariectomized rat model. METHODS: We chose 36 sexually mature female Wistar-Albino rats in this study. The study took placed in the Department of Medical Science Application and Research Center of Dicle University, Diyarbakir, Turkey, in 2002. We divided the model rats into 3 groups: group 1--control group, group 2--sham-operated group and group 3--bilaterally ovariectomized group. In addition, we gave flutamide to group 3. RESULTS: We found that the body weight was higher in the ovariectomized rats than the control rats. Furthermore, the body weight decreased a little after flutamide therapy. The thickness in the vaginal epithelium of the control group decreased, moreover, the appearance of stromal tissue was rather loose. After flutamide applications, infiltration of the stromal cells increased, the vaginal epithelial layer thickened and became keratinized. Microscopic papillae and anatomical processes appeared in the flutamide treated group. CONCLUSION: We observed that the antiandrogen drug flutamide is hormonally active and may exhibit estrogenic-antiestrogenic activity in rats. Our study may be a source for further research examining the relationship between the androgen receptor antagonist flutamide and reproductive function in female rats.

Androgen Antagonists↗