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PubMed1988

Effects of an antiandrogen, flutamide, on oocyte quality and embryo development in rats superovulated with pregnant mare's serum gonadotropin.

Increased oocyte degeneration in rats is associated with enhanced ovarian androgen secretion following superovulation with pregnant mare's serum gonadotropin (PMSG). To determine whether androgens may be causally related to oocyte degeneration, we examined the effects of an antiandrogen, flutamide, on oocyte quality and embryo development after induction of superovulation with PMSG. Immature female Sprague-Dawley rats were used for two experiments. In the first experiment, the females received either 5 mg flutamide or vehicle alone 30 and 36 h after 40 IU PMSG and were killed at 48, 60, and 72 h. Although total number of oocytes was not significantly different between the two groups, flutamide significantly reduced the percentage of degenerate oocytes ovulated at all the time intervals examined (p less than 0.01). In the second experiment, the females were given 4 IU PMSG (control) or 40 IU PMSG with either 5 mg flutamide or vehicle. The rats were mated and then killed on Days 2, 3, 4, and 5 of pregnancy. Compared to control, flutamide did not effectively prevent the early loss of preimplantation embryos nor the developmental retardation which took place in the vehicle-treated rats after Day 2. However, flutamide treatment was associated with a significant decrease in embryo degeneration and a significant increase in the percentage of cleaved embryos on Day 2 (p less than 0.01). Compared to levels associated with the vehicle regimen, ovarian and/or serum androgen levels in the flutamide-treated rats significantly decreased at 60 h (p less than 0.01) and on Day 2 (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Androgens↗
PubMed2004

Direct gastrointestinal toxicity of flutamide: comparison of irradiated and nonirradiated cases.

PURPOSE: Gastrointestinal (GI) side effects of flutamide in cases treated for advanced prostate cancer are well documented. Proposed mechanisms for these side effects include increased serum blood levels, direct vehicle effects and/or local toxicity. If local toxicity, the focus of this study, mediates GI side effects of flutamide then cases exposed to external beam radiation (XRT) should have more symptoms. We hypothesize that GI side effects of flutamide are not a direct local toxic effect resulting in a similar side effect profile for irradiated and nonirradiated cases. Thus, the present study compares GI effects of flutamide in irradiated and nonirradiated cases. MATERIALS AND METHODS: We identified 106 of 440 cases from a prior flutamide dose comparison study as having undergone XRT (56 cases) or radical prostatectomy (50 patients). The prevalence of GI side effects (abdominal pain/distention, diarrhea, constipation, nausea/vomiting and anorexia) was tallied for each treatment group and/or dosing regimen, 250 mg every 8 hours or 500 mg daily. Chi-square analysis with Yates' correction was performed for statistical analysis. RESULTS: The overall prevalence in 106 cases of GI side effects with flutamide was 22%. Treatment specific differences revealed no differences between the XRT and radical prostatectomy groups at 21% and 22%, respectively. Furthermore, independent analysis of treatment groups for each distinct side effect and dosing regimen did not identify significant differences. CONCLUSIONS: Irradiated cases are not at greater risk for the development of GI side effects from flutamide, suggesting that drug induced local toxicity does not mediate GI distress.

Aged↗
PubMed1993

The impact of a pure anti-androgen (flutamide) on LH, FSH, androgens and clinical status in idiopathic hirsutism.

OBJECTIVES: We assessed in women the effects of androgen suppression on gonadotrophin secretion and the therapeutic efficacy of the pure anti-androgen flutamide (2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide). DESIGN AND SUBJECTS: Ten women, aged 28-35 years, using an intrauterine device for contraception, were selected for this study. All women had idiopathic hirsutism with or without acne and seborrhoea. Flutamide was administered orally in a dose of 250 mg twice daily for 1 year. Basal body temperature was recorded and pelvic ultrasonography performed before and every 3 months during treatment. LH pulse frequency and amplitude (Cluster analysis) and basal and GnRH-stimulated plasma LH and FSH levels were determined on day 5 of the cycle prior to flutamide treatment, and after 6 and 12 months of therapy. Plasma total testosterone (T), non-SHBG bound T, androstenedione (A), dehydroepiandrosterone sulphate (DHEAS), androstanediol glucuronide (3 alpha-diol G) and sex hormone binding globulin (SHBG) levels were measured before and every 3 months during therapy, on day 5 of the cycle. Plasma oestradiol and progesterone levels were determined on day 22 of the studied cycles. RESULTS: Disappearance of acne and seborrhoea occurred after 2 months with a marked improvement of hirsutism at 6 months. At 12 months, hirsutism had disappeared with a Ferriman and Gallwey score < 7. No adverse side-effects, apart from transient diarrhoea in two patients, were reported with this flutamide dose. None of the patients had any disturbance of menstrual cycles which remained ovulatory. The pure anti-androgen flutamide induced no significant change in LH pulsatile profile, nor in LH and FSH responsiveness to GnRH. Plasma concentrations of steroids were not altered. Plasma SHBG and 3 alpha-diol G levels did not change during flutamide treatment. CONCLUSION: Flutamide, which interacts only with the androgen receptor, is effective for hirsutism, acne and seborrhoea, and does not disturb menstrual cyclicity or ovulation. It may represent a treatment of choice for essential hirsutism in women using safe contraceptive methods.

Acne Vulgaris↗
PubMed2006

Effects of prenatal flutamide on testicular development, androgen production and fertility in rats.

INTRODUCTION: To investigate the effects of blocking prenatal androgen with the anti-androgen flutamide on testicular weight (TW), seminiferous tubular diameter (STD), testicular biopsy score (TBS), testicular testosterone (TT), and fertility. MATERIALS AND METHODS: Ten pregnant Wistar albino rats were injected with flutamide (100 mg/kg) on gestational days 16 and 19. Rats injected with the solvent were used as controls. Male pups from these dams were evaluated for testicular descent on postnatal day 22. The ability of each male to produce offspring was tested when the animals were aged 130 days. The rats were killed when 180 days old, and the testes were removed. RESULTS: Sixteen of the 24 male rats (66.6%) exhibited cryptorchidism (6 unilateral, 10 bilateral) in the flutamide-treated group. Three of the rats with normally descended testicles were fertile, but none of the cryptorchid rats was fertile in flutamide-treated group. The average TW, mean STD, TBS and TT levels of the flutamide-treated rats was significantly lower than in the solvent-injected rats. However, there was no significant difference in these values between descended and undescended testes in flutamide-treated rats. CONCLUSION: Blocking of prenatal androgen with flutamide interferes with testicular development by inhibiting testicular descent, and also effects testicular morphology and function in both the descended and undescended testes of rats.

Androgen Antagonists↗
PubMed1990

Flutamide: an antiandrogen for advanced prostate cancer.

Flutamide is a nonsteroidal pure antiandrogen that acts by inhibiting the uptake and/or binding of dihydrotestosterone to the target cell receptor, thus interfering with androgen action. Flutamide is well absorbed orally and extensively metabolized; its active metabolite, 2-hydroxyflutamide, is formed rapidly and excreted almost entirely by the kidneys. Clinical studies in prostate cancer patients have demonstrated efficacy with flutamide monotherapy in patients who had received no prior treatment, in untreated patients with combined androgen blockade concomitantly with a luteinizing hormone-releasing hormone (LHRH)-agonist, and in relapsed patients. A randomized, placebo-controlled trial demonstrated a 26 percent increase in median survival for patients treated with leuprolide plus flutamide compared with leuprolide plus placebo. When given as monotherapy and in combination with an LHRH-agonist, flutamide is well tolerated. The usual adverse effects are gynecomastia and mild diarrhea when given as a single agent. In combination with an LHRH-agonist, hot flashes, loss of libido, impotence, mild nausea and vomiting, gynecomastia, and diarrhea are commonly reported. However, only diarrhea occurred more frequently in patients treated with leuprolide plus flutamide than in those treated with leuprolide plus placebo. Flutamide is indicated in combination with an LHRH-agonist (e.g., leuprolide) as initial therapy in metastatic (stage D2) prostate cancer. The usual dose is 250 mg po tid given at eight-hour intervals and started concurrently with the LHRH-agonist. Formulary addition is recommended.

Anilides↗
PubMed2005

Mechanism of the salutary effects of flutamide on intestinal myeloperoxidase activity following trauma-hemorrhage: up-regulation of estrogen receptor-{beta}-dependent HO-1.

Hemeoxygenase (HO)-1 induction following adverse circulatory conditions is known to be protective, and precastrated males have less intestinal damage than sham-operated males following trauma-hemorrhage (T-H). Previous studies have also shown that administration of flutamide up-regulated estrogen receptor (ER) expression in males following T-H. We hypothesized that flutamide administration in males following T-H up-regulates HO-1 via an ER-dependent pathway and protects against intestinal injury. Male Sprague-Dawley rats underwent T-H [mean blood pressure (MBP) 40 mmHg for 90 min and then resuscitation]. A single dose of flutamide (25 mg/kg body weight), with or without an ER antagonist (ICI 182,780), a HO enzyme inhibitor [chromium-mesoporphyrin (CrMP)], or vehicle, was administered subcutaneously during resuscitation. At 2 h after T-H or sham operation, intestinal myeloperoxidase (MPO) activity, intercellular adhesion molecule (ICAM)-1, cytokine-induced neutrophil chemoattractant (CINC)-1, and CINC-3 levels were measured. Intestinal ER-alpha, ER-beta, androgen receptor, and HO-1 mRNA/protein levels were also determined. Results showed that T-H increased intestinal MPO activity, ICAM-1, CINC-1, and CINC-3 levels. These parameters were improved significantly in the flutamide-treated rats subjected to T-H. Flutamide treatment increased intestinal HO-1 and ER-beta mRNA/protein levels as compared with vehicle-treated T-H rats. Administration of the ER antagonist ICI 182,780 or the HO inhibitor CrMP prevented the flutamide-induced attenuation of shock-induced intestinal damage. Thus, the salutary effects of flutamide administration on attenuation of intestinal injury following T-H are mediated via up-regulation of ER-beta-dependent HO-1 expression.

Animals↗
PubMed1993

Flutamide withdrawal syndrome: its impact on clinical trials in hormone-refractory prostate cancer.

PURPOSE: To evaluate the effect of discontinuation of the antiandrogen, flutamide, in patients with metastatic prostate cancer who are progressing on hormonal therapy. PATIENTS AND METHODS: Thirty-six patients with progressive disease on hormonal treatment that included flutamide had discontinuation of the antiandrogen. Thirty-five (95%) had progressive increases in prostate-specific antigen (PSA) levels, despite castrate levels of testosterone. Twenty-five patients (69%) were treated with combined androgen blockade (orchiectomy or gonadotropin-releasing hormone [GnRH] analog plus flutamide) as initial therapy and 11 (31%) were started on monotherapy alone. Patients who had not undergone a previous orchiectomy were continued on the GnRH analog. Patients were monitored clinically and with serial PSA measurements, radionuclide scans, and radiographs as indicated to assess response. RESULTS: Considering the 35 patients with increasing PSA values, 10 (29%) showed a significant decline (> or = 80% in seven, and > or = 50% in three) in PSA from baseline. All 10 had received combined androgen blockade as initial therapy. The duration of decline was short (median, 5+ months; range, 2 to 10+), but was associated with improvement in clinical symptoms, while one patient had a partial response in an epidural mass with parallel decline in PSA. None of the patients started on single hormone therapies responded. CONCLUSION: Discontinuation of flutamide was associated with a significant decrease in PSA values in 10 of 25 patients (40%; 95% confidence interval, 21% to 59%) and clinical improvement in a subset of patients who had an initial response, but later progressive disease on combined androgen blockade. A trial of flutamide withdrawal should be considered in patients progressing on total androgen blockade before the initiation of more toxic therapies. It is likely that flutamide withdrawal has contributed to the observed responses in phase II trials of both second-line hormonal therapies and new cytotoxic agents. Future phase II trials in hormone-refractory prostatic cancer must control for this observation, and insure that progression off flutamide is documented before initiation of alternative treatment.

Aged↗
PubMed2004

Effects of dehydroepiandrosterone and flutamide on hippocampal CA1 spine synapse density in male and female rats: implications for the role of androgens in maintenance of hippocampal structure.

The effects of androgens and the androgen antagonist, flutamide, on the density of dendritic spine synapses in the CA1 subfield of the hippocampus were studied in gonadectomized male and female rats. Treatment of orchidectomized male rats with dehydroepiandrosterone (DHEA; 2 d, 1 mg/d sc) increased the density of CA1 spine synapses observed 2 d later, by 106%, without significantly affecting ventral prostate weight. The hippocampal response to DHEA was unaffected by blockade of intracerebral estrogen biosynthesis using the aromatase inhibitor, letrozole. By contrast, flutamide alone (2 d; 5 mg/d, sc) increased CA1 spine synapse density by 66%, whereas in combination the effects of flutamide and DHEA were additive rather than inhibitory. Additive effects on CA1 synapse density were also observed in males using combinations of flutamide with 5alpha-dihydrotestosterone (2 d, 500 microg/d, sc). At the same doses, flutamide had no effect on prostate weight and completely blocked the effects on the prostate of treatment with 5alpha-dihydrotestosterone. Treatment of ovariectomized females with DHEA increased CA1 spine synapse density to a level similar to that observed in the male. As in males, flutamide in females increased CA1 spine synapse formation and further augmented the response to DHEA. These results demonstrate that flutamide and DHEA have positive effects on hippocampal CA1 spine synapse density in both sexes. They also suggest that conventional measures of androgen agonist or antagonist activity, exemplified by ventral prostate growth, may not be indicative of effects on hippocampal CA1 synaptogenesis.

Adjuvants, Immunologic↗
PubMed2003

Low-dose flutamide-metformin therapy reverses insulin resistance and reduces fat mass in nonobese adolescents with ovarian hyperandrogenism.

Ovarian hyperandrogenism is a common disorder often presenting post menarche with anovulatory oligomenorrhea and signs of androgen excess. Associated hyperinsulinemic insulin resistance, dyslipidemia, and central fat excess herald long-term disease risk. Combined antiandrogen (flutamide 250 mg/d) and insulin-sensitizing (metformin) therapy has beneficial effects, in particular on dyslipidemia and androgen excess in young women. We studied the effects of low-dose flutamide-metformin combination on metabolic variables and body composition in adolescent girls with ovarian hyperandrogenism. Thirty teenage girls (age range, 13.6-18.6 yr) with hyperinsulinemic hyperandrogenism participated in a 12-month pilot study with a 3-month off-treatment phase and a 9-month treatment phase (randomized sequence) on combined flutamide (125 mg/d) and metformin (1275 mg/d). Body composition was assessed by dual-energy x-ray absorptiometry; endocrine-metabolic state and ovulation rate were screened every 3 months. Insulin sensitivity was assessed by homeostasis model assessment (HOMA). Overnight GH and LH profiles were obtained pretreatment and after 6 months on treatment (n = 8). Over the 3-month pretreatment control phase (n = 14) all study indices were unchanged. Flutamide-metformin treatment (n = 30) was followed within 3 months by marked decreases in hirsutism score and serum androgens, by a more than 50% increase in insulin sensitivity and by a less atherogenic lipid profile (all P < 0.0001). After 9 months on flutamide-metformin, body fat decreased by 10%, with a preferential 20% loss of abdominal fat; conversely lean body mass increased, and total body weight remained unchanged; ovulation rate increased from 7-87% after 9 months. Baseline GH hypersecretion and elevated serum IGF-1 normalized after 6 months on flutamide-metformin. Within 3 months post treatment (n = 16), a rebound was observed for all assessed indices. In conclusion, in teenage girls with ovarian hyperandrogenism, low-dose combined flutamide-metformin therapy attenuated a spectrum of abnormalities, including insulin resistance and hyperlipidemia. Improved insulin sensitivity and reduced androgen activity led to a marked redistribution of body fat and lean mass, resulting in a more feminine body shape.

Adipose Tissue↗
PubMed2004

Ethinylestradiol-drospirenone, flutamide-metformin, or both for adolescents and women with hyperinsulinemic hyperandrogenism: opposite effects on adipocytokines and body adiposity.

Hyperinsulinemic hyperandrogenism with anovulation, the so-called polycystic ovary syndrome (PCOS), is the most frequent endocrine disorder of young women. One of the stigmata of PCOS is a deficit of lean mass and an excess of fat, in particular, abdominal fat, even in the absence of obesity. Adiponectin and IL-6 are among the adipocytokines that have recently been related to abdominal fat excess, insulin resistance states, and cardiovascular disease risk. We studied the effects of two new treatment options, ethinylestradiol-drospirenone and flutamide-metformin, and of their combination on adipocytokinemia and body adiposity in adolescents and women with PCOS. Adolescents with PCOS (n = 32; age, approximately 15 yr; body mass index, approximately 22 kg/m(2)) were randomly assigned to receive the oral contraceptive (OC) ethinylestradiol-drospirenone, or the low-dose generic duo of flutamide (62.5 mg/d) plus metformin (850 mg/d). Young women with PCOS (n = 22; age, approximately 19 yr; body mass index, approximately 22 kg/m(2)) were randomized to receive the same OC, either alone or with flutamide-metformin. Fasting blood glucose, serum insulin, lipids, androgens, IL-6, adiponectin, and body composition (by absorptiometry) were assessed at the start, and after 3 and/or 9 months. At the start, serum concentrations of the proinflammatory IL-6 were high, and those of the antiinflammatory adiponectin were low; body composition was adipose in each subpopulation. Abnormal adipocytokine levels, hypertriglyceridemia, and body adiposity diverged further from the norm in adolescents on OC; in contrast, girls on flutamide-metformin reverted all study indices toward normal, lost part of their fat excess, and reduced their lean mass deficit. In comparison to the girls on OC, those on flutamide-metformin lost a mean of approximately 4 kg of fat and gained approximately 4 kg of lean mass. Similarly, abnormal adipocytokine levels and adiposity were aggravated in women on OC alone and improved in women on OC plus flutamide-metformin; within 9 months, the latter subgroup lost a mean of approximately 3 kg of fat and gained approximately 3 kg of lean mass, in comparison to women on OC alone. In conclusion, young and nonobese PCOS patients were found to be in a low-grade, chronic inflammation state, and to have a body adiposity that evolves according to the balance of circulating adipocytokines and lipids, rather than to androgen excess or fasting hyperinsulinemia. Monotherapy with ethinylestradiol-drospirenone may not be a prime choice for PCOS, given its inefficacy to attenuate abnormal adipocytokine levels and body adiposity; ethinylestradiol-drospirenone plus flutamide-metformin, however, is a first OC combination that was found capable of reverting both the adipocytokine balance and the body composition toward normal, and that may therefore improve the long-term cardiovascular perspectives of women with PCOS.

Adiponectin↗
PubMed2005

Circulating antiandrogenic activity in children with congenital adrenal hyperplasia during peroral flutamide treatment.

CONTEXT: The degree of androgen receptor blockade achieved with peroral flutamide is unknown. OBJECTIVE: The aim of this study was to examine the contribution of flutamide to circulating antiandrogenic activity in children with congenital adrenal hyperplasia using a recombinant cell bioassay. DESIGN: We describe an open-label, prospective clinical study. SETTING: The study was conducted at the Hospital for Children and Adolescents, University of Helsinki, or the Turku University Hospital, Finland. PARTICIPANTS: Seven children, age 7.2-10.5 yr, were included. INTERVENTION: As an experimental approach to improve control of height velocity and the rate of bone maturation, the patients received letrozole (2.5 mg/d) and flutamide (10 mg/kg.d) and were followed up at 3-month intervals for 3-12 months. Before employing the bioassay, two pools of sera (obtained before and during flutamide treatment) were supplemented with increasing amounts of testosterone, and all sera (n = 27) of individual patients were supplemented with a constant amount of exogenous testosterone. MAIN OUTCOME MEASURE: The main outcome measure was circulating antiandrogenic activity. RESULTS: Flutamide and/or its metabolites shifted the dose-response curve of testosterone, in that only the highest testosterone concentration, corresponding to 1803 ng/dl (62.5 nm) in human serum, was measurable by the bioassay. In individual sera supplemented with testosterone, flutamide treatment suppressed androgen bioactivity from 378 +/- 20 ng/dl (13.1 +/- 0.7 nm) (mean +/- sem) (pretreatment) to 110 +/- 20 ng/dl (3.8 +/- 0.7 nm) (3 months), 83.7 +/- 12 ng/dl (2.9 +/- 0.4 nm) (6 months), 46.2 +/- 6 ng/dl (1.6 +/- 0.2 nm) (9 months), and 57.7 +/- 9 ng/dl (2.0 +/- 0.3 nm) (12 months) testosterone equivalents (P < 0.01). CONCLUSIONS: A dose of flutamide less than 10 mg/kg.d appears sufficient to inhibit AR in children. The recombinant cell bioassay employed herein offers a novel means to monitor the treatment of patients receiving antiandrogens.

Administration, Oral↗
PubMed2006

Treatment with flutamide, metformin, and their combination added to a hypocaloric diet in overweight-obese women with polycystic ovary syndrome: a randomized, 12-month, placebo-controlled study.

CONTEXT: The few controlled trials performed so far indicate that the addition of metformin and/or flutamide to a hypocaloric diet in obese women with polycystic ovary syndrome (PCOS) effectively influences different phenotypic aspects of the syndrome. All these studies are, however, characterized by a short to medium period of treatment. OBJECTIVE: Our objective was to investigate the long-term effects of these therapies. DESIGN AND SETTING: We conducted a prospective, randomized, placebo-controlled trial at a medical center. PATIENTS: Of 80 overweight-obese women with PCOS, 76 completed the study. INTERVENTIONS: Patients were placed on a hypocaloric diet for the first month and then on a hypocaloric diet plus placebo, metformin (850 mg, orally, twice a day), flutamide (250 mg, orally, twice a day), or metformin plus flutamide for the subsequent 12 months (20 subjects in each group). MAIN OUTCOME MEASURES: We assessed clinical features, computerized tomography measurement of fat distribution, androgens, lipids, and fasting and glucose-stimulated glucose and insulin levels at baseline and after 6 and 12 months of treatment. RESULTS: After 6 months, compared with placebo, flutamide further decreased visceral/sc fat mass (P = 0.044), androstenedione (P < 0.001), dehydroepiandrosterone sulfate (P < 0.001), and hirsutism score (P < 0.001), whereas metformin further increased frequency of menstruation (P = 0.039). After 12 months, flutamide maintained the effects observed after 6 months on visceral/sc fat mass (P = 0.033) and androstenedione (P < 0.001), whereas it produced an additional decrease in dehydroepiandrosterone sulfate (P = 0.020) and hirsutism score (P = 0.019); metformin further improved the menstrual pattern (P = 0.013). Moreover, after 12 months, flutamide improved more than placebo the menstrual pattern (P = 0.008), glucose-stimulated glucose levels (P = 0.041), insulin sensitivity (P < 0.001), and low-density lipoprotein cholesterol levels (P = 0.003), whereas metformin decreased glucose-stimulated insulin levels (P = 0.014). The combination of the two drugs maintained the specific effect of each of the compounds, without any additive or synergistic effect. CONCLUSIONS: These findings add relevance to the usefulness of metformin and flutamide in the treatment of dieting overweight-obese PCOS women and provide a rationale for targeting different therapeutic options according to the required outcomes in the long term.

Adipose Tissue↗
PubMed1975

Disposition of a new, nonsteroid, antiandrogen, alpha,alpha,alpha-trifluoro-2-methyl-4'-nitro-m-propionotoluidide (Flutamide), in men following a single oral 200 mg dose.

A single oral 200 mg dose of tritium-labeled alpha,alpha,alpha-trifluoro-2-methyl-4'-nitro-m-propionotoluidide (flutamide) was given to 3 men. Analysis of plasma, urine and feces shows flutamide is rapidly and completely absorbed and excreted mainly through the kidneys. Analysis of plasma radioactivity shows flutamide is rapidly and extensively metabolized--only 2.5% of plasma radioactivity 1 h after dosing is associated with flutamide. At least 10 other metabolites are present, of which 6 have been tentatively identified. These are alpha,alpha,alpha-trifluoro-4'-amino-m-acetotoluidide (A); alpha,alpha,alpha-trifluoro-4'-amino-2-methyl-m-lactotoluidede (B); alpha,alpha,alpha-trifluoro-4'-nitro-m-acetotoluidede (C); alpha,alpha,alpha-trifluoro-2-methyl-4'-nitro-m-lactotoluidide (D); alpha,alpha,alpha-trifluoro-4'-amino-2-methyl-m-propionotoluidide (E); and alpha,alpha,alpha-trifluoro-6-nitro-m-toluidine (F). (D) represents 23% of plasma tritium 1 h after drug and is a major metabolite at all other measured times. Each of the other metabolites accounts for less than 10% of plasma radioactivity. Minor amounts of flutamide and (A) through (F) are found in 0-24-h urine. An additional metabolite, alpha,alpha,alpha-trifluoro-2-amino-5-nitro-p-cresol, constitutes 25% of urine tritium. The rapid conversion of flutamide to (D) and the high plasma levels of (D) suggest (D) might be the active form of flutamide.

Administration, Oral↗
PubMed1991

Comparative effects of chronic administration of the non-steroidal antiandrogens flutamide and Casodex on the reproductive system of the adult male rat.

The effects of chronic blockade of androgen action by the antiandrogens flutamide and Casodex on serum and pituitary concentrations of LH and FSH, serum and testicular androgen levels, reproductive organ weights, and on spermatogenesis were compared in the adult rat. Animals were treated for 3 and 8 weeks with vehicle, Casodex (20 mg.kg-1.(day)-1, flutamide (20 mg.kg-1.(day)-1) and GnRH antagonist (150 micrograms/day, Detirelix). Treatment with GnRH antagonist suppressed gonadotropin and testosterone production, reduced the weights of testes, epididymides and seminal vesicles, and inhibited germ cell development. Flutamide administration markedly elevated serum and pituitary levels of gonadotropins as well as serum and testicular androgen concentrations. Casodex-induced elevation of gonadotropin concentrations was less pronounced and serum and testicular levels of androgens did not change significantly. The reduction of seminal vesicle weights was similar after Casodex and GnRH antagonist treatment, whereas flutamide was less effective. Testicular weight and spermatogenesis (assessed by light microscopical and flow-cytometric analysis) remained unaffected by Casodex and flutamide. It is concluded, that 1. Casodex, in contrast to flutamide, is a peripherally selective antiandrogen, and 2. Casodex influences release of gonadotropins into circulation less than flutamide. Therefore this antiandrogen might be useful clinically for selectively blocking androgen actions in the accessory sex glands.

Androgen Antagonists↗
PubMed2003

Effects of perinatal exposure to flutamide on sex hormone responsiveness in F1 male rats.

Pregnant rats were administered flutamide (0 and 10 mg/kg, p.o.) from gestation Day 14 to post-parturition Day 3 and effects on responsiveness to androgens (testosterone propionate, TP; dihydrotestosterone, DHT) in male offspring were examined with a Hershberger assay. Male pups of each group were assigned to 6 subgroups as follows: Group 1, castration and euthanized at postnatal Day 46 (PND 46); Group 2, castration + vehicle; Group 3, castration + TP; Group 4, castration + DHT; Group 5, vehicle; Group 6, DHT. After castrations were conducted at PND 36, animals were treated with TP (2 mg/kg in corn oil, s.c.) or DHT (1.25 mg/kg in corn oil, s.c.) once a day for 10 days, beginning at PND 46. At PND 56, the following organs/tissues were removed and weighed: ventral prostate, dorso-lateral prostate, seminal vesicles with coagulating glands, levator ani muscle plus bulbocavernosus muscle, Cowper's gland, and glands penis. Analysis of serum testosterone, LH and FSH in Groups 2, 3, 4, 5 and 6, and RT-PCR using prostate tissue from Groups 2, 3 and 4 were carried out. Perinatal exposure to flutamide caused decreased weights of androgen-dependent organs. Responses to androgens were recognized in organs of all castrated groups, with increased organ weights, especially in animals administered TP where values were essentially equal to or greater than those of intact animals in both the control and the 10 mg/kg group. On the other hand, the degree of weight increase of the ventral prostate and seminal vesicles with TP or DHT treatment in castrated animals was smaller in the flutamide administration group than in the controls. In hormone assays, castrated + vehicle animals showed higher serum LH than the other groups. Serum FSH was high in the castrated groups (Group 2>Group 4>Group 3), while in the noncastrated group a constant level was noted, with or without flutamide. No effect of flutamide administration was observed regarding sex hormone. RT-PCR using ventral prostate tissue revealed no significant differences in expression of AR, C3, VEGF, TGF-beta1, beta2, KGF and CK8 mRNA after androgen treatment between the control and flutamide treatment groups. C3 mRNA was increased in androgen-treated animals, whereas AR, TGF-beta and KGF mRNAs were decreased. Perinatal exposure to anti-androgen causes irreversible abnormalities in male pups. Concerning the responsiveness to TP and DHT, the degrees of weight changes in ventral prostate and seminal vesicles in castrated animals were decreased. However, the other organ weights, the sex hormone levels and androgen-reactive gene expression in the ventral prostate were not influenced by perinatal flutamide treatment in the present study.

Androgen Antagonists↗
PubMed2005

Evaluation of general behavior, memory, learning performance, and brain sexual differentiation in F1 offspring males of rats treated with flutamide during late gestation.

Flutamide is a drug with antiandrogen effects that are mediated through androgen receptors (ARs). In this study, flutamide was subcutaneously administered to female rats (3, 10 or 30 mg/kg/day) on gestation Days 16-21 to evaluate effects on memory and learning performance in F1 offspring. Brain sexual differentiation was also evaluated by measuring the volume of the sexual dimorphic nucleus of the preoptic area (SDN-POA) and analyzing levels of androgen receptor (AR) mRNA expression in the prostate, hypothalamus and hippocampus. In F1 offspring exposed in utero to flutamide, evaluation of motor activity, learning performance and spatial perception showed that flutamide tended to exert a dose-dependent increase on the motor activity in F1 males, but no significant differences were identified in the other measurements. Prominent changes in development of the SDN-POA were apparent in males after maturation. Doses of > or =3 mg/kg/day resulted in significantly decreased length and volume of the SDN-POA compared to controls. These differences tended to become more marked at higher doses. Volumes of the SDN-POA did not differ significantly between F1 males and females exposed to flutamide at 30 mg/kg/day. AR mRNA was assayed using the dot-blotting method in F1 animals. In flutamide dose groups, AR mRNA expression tended to be increased in the prostate gland and decreased in the hippocampus. These results might suggest that exposure to flutamide in utero might affect controlling AR expression on a hormonal signal transduction system mediated by testosterone. However, these changes were not clearly correlated to learning performance in male offspring other than motor activity.

Androgen Antagonists↗
PubMed1987

Effects of flutamide, a pure antiandrogen, on endocrine parameters, in the adult female rat.

Since antiandrogens having mixed agonistic-antagonistic activities on the androgen receptor have shown benefits in the treatment of hirsutism, the availability of a pure antiandrogen is of particular interest. As a first step, we have thus investigated in detail the effect of the pure antiandrogen Flutamide on endocrine parameters in the female rat. Treatment with the antiandrogen (5 mg, twice daily) for 4 cycles did not affect the 4-day estrous cycle. The antiandrogen had no significant effect on the ovarian level of cytosolic total and available as well as nuclear estrogen receptors in the uterus, and did not affect the concentration of LH and FSH ovarian receptors. The ovarian level of progestins was minimally affected or unchanged on estrus and diestrus I, while an increase was observed under treatment with Flutamide on diestrus II and proestrus. In the plasma, however, there was small or no effect of Flutamide treatment on the concentration of pregnenolone, 17-OH pregnenolone, progesterone and 17-OH-progesterone. The ovarian levels of testosterone (T) and of its two metabolites androstane-3 alpha,17 beta-diol and androstane-3 beta,17 beta-diol were increased by treatment with Flutamide on the morning of diestrus II and proestrus. This was reflected by a 30-100% increase of the levels of plasma T on proestrus. The increase in the ovarian concentration of 5-androstene-3 beta,17 beta-diol (delta 5-diol) and androstenedione observed on diestrus II and on proestrus did not lead to any change in the plasma level of these steroids, which remained normal throughout the estrous cycle during treatment with Flutamide. The ovarian and plasma levels of 17 beta-estradiol were not affected by treatment with the antiandrogen. The present data show that treatment of intact adult female rats with the pure antiandrogen Flutamide has no effect on the estrous cycle, with no significant change in the plasma concentration of the most important estrogenic compound in the rat, namely, 17 beta-estradiol. The present observation of minor endocrine effects of Flutamide in the intact adult female rat supports clinical trials on the use of this antiandrogen, a potential drug of choice for the treatment of hirsutism, acne and alopecia in women.

17-alpha-Hydroxyprogesterone↗
PubMed1993

Fatal and nonfatal hepatotoxicity associated with flutamide.

OBJECTIVE: To identify and describe patients with hepatotoxicity possibly caused by flutamide, an antiandrogen drug. DESIGN: Case series of reports, submitted to the Adverse Drug Event Reporting System of the Food and Drug Administration. SETTING: Outpatient clinics and physicians' offices in the United States. PATIENTS: Nineteen patients treated with flutamide for prostate cancer or benign prostatic hypertrophy (for Investigation of a New Drug or off-label use). MEASUREMENTS: Evidence of increased liver enzyme levels, hyperbilirubinemia, associated clinical symptoms, and diagnoses of cholestatic hepatitis. Autopsy reports were used when available. RESULTS: From the time of marketing of flutamide in February 1989 through March 1991, the Food and Drug Administration received reports of 19 patients in the United States who developed serious hepatotoxicity while using flutamide. Fourteen patients had resolution of abnormal liver function test results after discontinuing or decreasing the dose of flutamide, but five patients died of progressive liver disease. Autopsy reports from three patients and abnormal pathologic results from three other patients (reported to the Food and Drug Administration or in the medical literature) showed hepatocellular necrosis and possibly cholestasis. Thorough work-ups excluded other possible causes than flutamide. CONCLUSIONS: Flutamide appears to cause hepatotoxic effects in certain patients. Physicians should tell patients to immediately report to physicians nausea, vomiting, fatigue, jaundice, and other signs and symptoms of liver injury.

Adverse Drug Reaction Reporting Systems↗