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PubMedDate not supplied

Effects of flutamide and hydroxy-flutamide on the growth of human benign prostatic hyperplasia cells in primary culture: a preliminary report.

Tissues from human benign prostatic hyperplasia [BPH] were collected from twelve patients undergoing routine transurethral resection of the prostate to relieve urine out-flow obstruction. Viable epithelial organoids were obtained after enzymatic digestion of the tissue. Primary cultures of epithelium were successfully maintained on collagen gel for up to 21 days. Immunocytochemical staining revealed that there was no expression of either desmin or vimentin in these cells; however, the anticytokeratin antibodies LP-34 (cytokeratins 4, 5, 6, 10, 13, 16, 17 and 18), LE-61 (cytokeratin 18) and CAM 5.2 (cytokeratins 7 and 8) all showed positive responses, indicating the epithelial nature of the cells. Cell growth was significantly increased in the presence of 3 x 10(-10) M testosterone propionate [TP] in the culture medium. The presence of the non-steroidal anti-androgens, Flutamide and Hydroxy-Flutamide [Flu-OH], in the concentration range 1.0-0.001 micrograms per ml of medium inhibited the growth in the presence of androgens in a dose-dependent manner. The anti-androgens failed to affect cell growth in the absence of TP. In view of these preliminary findings, it is postulated that the antiandrogens might be acting either by displacing the androgen from its receptor or alternately by inhibiting the activity of prostatic 5 alpha-reductase.

Aged↗

PubMed1990

Flutamide has no effect on adrenal androgen response to acute ACTH stimulation in patients with prostatic cancer.

Basal levels and adrenocorticotropic hormone (ACTH)-induced increments (delta-values) of serum cortisol, dehydroepiandrosterone (DHA), dehydroepiandrosterone sulfate (DHAS), 4-androstene-3, 17-dione (A4), and 17-hydroxyprogesterone (170HP); basal testosterone (T), luteinizing hormone (LH), serum ASAT, gamma-GT, and albumin were measured in prostatic cancer patients before and after 6 months of treatment with LH-RH-agonist, with flutamide, and with LH-RH-agonist + flutamide, respectively. Basal DHA and DHAS were decreased during flutamide and LH-RH-agonist + flutamide treatment and basal A4 during treatment with LH-RH-agonist and with LH-RH-agonist + flutamide. Basal 170HP, T, and LH decreased during LH-RH-agonist and LH-RH-agonist + flutamide treatment and increased during single drug flutamide treatment. Slightly decreased delta cortisol values were observed during LH-RH-agonist and during flutamide treatment and slightly increased delta 170HP values during LH-RH-agonist and LH-RH-agonist + flutamide treatment. Values for delta DHA and delta A4 were completely unaffected by any of the treatment regimens. Elevated ASAT values were observed during treatment with flutamide and with LH-RH-agonist + flutamide. It is concluded that flutamide has no effect on the adrenal androgen response to acute ACTH stimulation.

Adrenocorticotropic Hormone↗

PubMed1990

Similarities and differences in progesterone and androgens in modulation of LH, FSH and PRL release: unexpected properties of flutamide.

The purpose of this study was to determine if the similarity of effect of progesterone and androgens on antagonism of estrogen-induced prolactin release also applied to the regulation of LH and FSH release. An additional objective was to examine the effect of the antiandrogen, flutamide, upon the ability of progesterone to induce gonadotropin secretion. Using the ovariectomized estrogen-primed immature rat, testosterone propionate suppressed LH and FSH secretion, whereas dihydrotestosterone only suppressed serum LH levels. In contrast, progesterone significantly elevated both serum LH and FSH levels. Thus, with respect to regulation of gonadotropin secretion, the effects of androgens and progesterone were dissimilar. In the estrogen-primed ovariectomized immature rat, flutamide was found to suppress LH, FSH and PRL secretion. Progesterone (0.8 mg/kg body wt) was incapable of overcoming this suppressive effect of flutamide. The effect of flutamide on gonadotropin secretion required estrogen priming. The effect of flutamide in suppressing LH, FSH and PRL release was not through suppression of an adrenal steroid as shown by adrenalectomy or the use of RU486. In the PMSG primed immature rat, flutamide had no effect on basal gonadotropin levels or ovulation. However, flutamide antagonized progesterone and triamcinolone acetonide-induced gonadotropin surges and blocked their ability to facilitate ovulation. These studies demonstrate that in the ovariectomized estrogen-primed immature rat flutamide has potent neuroendocrine regulatory ability leading to suppression of LH, FSH and PRL release. Flutamide also blocked progesterone and triamcinolone acetonide induced gonadotropin surges and ovulation in PMSG-primed immature female rats.

Adrenalectomy↗

PubMed1978

Flutamide therapy for carcinoma of the prostate.

In our three-year experience with the use of flutamide for the treatment of carcinoma of the prostate, 20 patients with previously untreated stage D carcinoma of the prostate were enrolled in a 12-week double-blind study. Seven patients received 1.5 gm of flutamide daily, seven patients received 0.75 gm of flutamide daily, and six patients received 1.0 mg of diethylstilbestrol daily. Two patients receiving flutamide did not complete the 12-week study. Six patients receiving flutamide and three patients receiving diethylstilbestrol had objective evidence of improvement. Of the patients receiving flutamide, 50% were alive at one year, and 43% were alive at two years. Three of the original 14 patients started on flutamide are alive at 36, 33, and 24 months. In addition, we continued clinical evaluation of flutamide as an open study, enrolling six other patients (four with stage D and two with stage C carcinoma of the prostate). All except one of these patients had received previous hormonal therapy. At present, four are still being followed up at 13, 15, 20 and 24 months, demonstrating that flutamide can give positive results to some patients whose condition is deteriorating despite diethylstilbestrol therapy.

Aged↗

PubMed1991

Testis and epididymis of the Indian wall lizard (Hemidactylus flaviviridis): effects of flutamide on FSH and testosterone influenced spermatogenesis, Leydig cell, and epididymis.

To determine the separate spermatogenic actions of FSH and testosterone, adult male lizards Hemidactylus flaviviridis with recrudescent testes were administered the non-steroidal antiandrogen flutamide either alone or in combination with FSH or testosterone, and the histology and histochemistry of the testes and ductus epididymides were studied. Flutamide-treated animals displayed a marked hypertrophy of Leydig cells. A few spermatids were also seen in testis of more than half the animals treated with flutamide. Flutamide also produced a significant increase of primary spermatocytes; no spermatids were observed in controls. A significant inhibition of spermatogenesis was noted in lizards treated either with testosterone alone or in combination with flutamide. Ovine FSH treatment caused a significant stimulation of spermatogenesis, as indicated by the increase of primary and secondary spermatocytes and the transformation of secondary spermatocytes into spermatids or, in a few cases, into spermatozoa. A considerable depletion of sudanophilic lipid and moderate delta 5-3 beta-hydroxysteroid dehydrogenase activity was noted in the Leydig cells of FSH-treated animals indicating enhanced steroidogenesis. Similar results were obtained when lizards were treated with flutamide + FSH. The effects of simultaneous treatment of flutamide with FSH or testosterone on ductus epididymidis revealed that flutamide markedly inhibited the epithelial cell height and lumen diameter with a loss of luminal content when compared to FSH or testosterone-treated lizards.

Animals↗

PubMed1992

Treatment of hirsutism in women with flutamide.

OBJECTIVE: To explore the clinical usefulness of the antiandrogen flutamide in the treatment modality for hirsutism in women. DESIGN: Nine women with hirsutism were assessed before and then monthly for 3 months on a regimen of flutamide 250 mg three times a day as the sole therapeutic agent. Blood samples were taken at each assessment time for a battery of androgenic parameters. SETTING: Patients were followed in the Out-Patient Department of the Hospital das Clinicas, Sao Paulo, Brazil. Hormonal assays were performed in the Hormone Laboratories of Hospital das Clinicas and the Endocrine Research Laboratory at Newark Beth Israel Medical Center, Newark, New Jersey. PATIENTS: Nine women with moderate hirsutism were treated with flutamide. Six women were previously diagnosed as having idiopathic hirsutism, and three women were diagnosed as having polycystic ovary syndrome. INTERVENTION: All women were treated with flutamide 250 mg three times a day for 3 months. MAIN OUTCOME MEASURE: Improvement of hirsutism was assessed using the Ferriman-Gallwey hair density index. Side effects of drug therapy (deterioration of menses and dry skin) were explored. Androgen parameters included testosterone (T), sex hormone-binding globulin, bound, nonbound, and free T, androstanediol glucuronide, and others. RESULTS: After 3 months of flutamide alone, Ferriman-Gallwey scores improved in seven of nine women with mean scores decreasing from 28.1 +/- 0.6 to 24.5 +/- 0.6. None of the androgenic parameters changed during this period of time. Follicle-stimulating hormone and luteinizing hormone response to gonadotropin-releasing hormone was unchanged after flutamide. CONCLUSION: Flutamide favorably influenced hirsutism in women, with differences noted after only 3 months of therapy. More prolonged and detailed studies of this drug as the sole therapeutic agent for treatment of hirsutism seems warranted.

Adult↗

PubMed1991

Perinatal flutamide and mounting and lordosis behavior in adult female Wistar and Sprague-Dawley rats.

The present study was designed to investigate the possible role of perinatal androgens acting via the androgen receptor, as opposed to the estrogen receptor, for the differentiation of adult mounting and lordosis behavior in female rats. Female Wistar (W) and Sprague-Dawley (SD) rats were exposed to the anti-androgen flutamide prenatally (days 11-22 of pregnancy) and/or neonatally (days 1-10). The females were ovariectomized in adulthood and repeatedly tested for mounting and lordosis behavior. Flutamide, given both pre- and neonatally to SD rats, reduced adult T-induced female mounting. Flutamide administered only prenatally or only neonatally did not lower adult mounting behavior of SD rats. Mounting behavior of female W rats, following pre- and/or neonatal flutamide treatment was not affected. Lordosis behavior was also not altered by perinatal flutamide treatment of either strain. The results of the present study, no effect of prenatal flutamide, do not support the hypothesis that female rats require prenatal androgen receptor-mediated actions of testosterone in the organization of neural tissues for the occurrence of adult mounting and lordosis behavior. Only in SD rats androgenic organization of adult mounting behavior via the androgen receptor seems to occur both pre- and neonatally. Since clear behavioral effects of prenatal flutamide treatment have been published earlier in Long-Evans females, we suggest strain differences in sensitivity for perinatal androgenization in female rats. Future research into that possibility is needed.

Animals↗

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↗

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↗

PubMed1992

Prenatal flutamide alters sexually dimorphic nuclei in the spinal cord of male rats.

The effects of prenatal exposure to the antiandrogen flutamide on two sexually dimorphic nuclei of the lumbar spinal cord, the dorsolateral nucleus (DLN) and the spinal nucleus of the bulbocavernosus (SNB), were investigated. Rat dams were given daily injections of 5 mg flutamide or vehicle alone from day 11 through 21 of pregnancy. The spinal cords and perineal morphology of their male and female offspring were examined in adulthood. Flutamide reduced the number of SNB and DLN neurons, reduced the somal and nuclear area of SNB neurons, and reduced the weight of the perineal muscles in males. Flutamide produced no effect in females. No sexual dimorphism was found in the mean somal area of DLN neurons, but a sexual dimorphism was found in the distribution of somal areas in our samples; females had proportionately more large neurons than males. Flutamide-treated males also had proportionately more large neurons than control males but fewer than females. A sexual dimorphism was found in the nuclear areas of DLN neurons but flutamide did not influence this trait.

Animals↗

PubMed1992

Comparison of the effects of the 5 alpha-reductase inhibitor finasteride and the antiandrogen flutamide on prostate and genital differentiation: dose-response studies.

Studies were performed to compare the effects of 5 alpha-reductase inhibition and antiandrogen receptor blockade on differentiation of male internal and external genital structures and prostate in the rat. Dose-response studies were performed on male rats treated in utero during the period of sexual differentiation with either the potent 5 alpha-reductase inhibitor finasteride or the antiandrogen flutamide. The treated animals were raised to adulthood and killed, and genital structures were evaluated. Treatment with the 5 alpha-reductase inhibitor finasteride at a dose of 25 mg/kg.day resulted in significant feminization of the external genitalia. There was no further feminization of the genitalia at doses up to 300 mg/kg.day. Wolffian ductal differentiation occurred at all doses evaluated. Seminal vesicle weight, however, significantly decreased at 25 mg/kg.day, but without a further decrease at higher doses of the 5 alpha-reductase inhibitor. Vas deferens and epididymal weights were unchanged at all doses evaluated. There was a significant decrease in prostate size at 25 and 50 mg/kg.day, with no further decrease at higher doses. In flutamide-treated animals, complete feminization of the genitalia occurred at 24 mg/kg.day in all animals. At 18 mg/kg.day, Wolffian ductal differentiation occurred, but seminal vesicle weight was decreased. At dosages of 100, 200, and 300 mg/kg.day flutamide, the vas deferens was absent unilaterally or bilaterally, with small remnants of epididymal head and tail present. At dosages of 24 mg/kg.day and above, the prostate was absent. Studies with the 5 alpha-reductase inhibitor finasteride demonstrate the dependency of prostate and male external genital differentiation on dihydrotestosterone (DHT). However, unlike androgen receptor blockade with flutamide, finasteride did not totally abolish prostate differentiation or completely feminize the external genitalia, despite increasingly higher doses. Since there is no evidence of multiple 5 alpha-reductase isoenzymes to date in the rat, these results suggest that testosterone (T) can compensate for DHT to some degree at the level of the androgen receptor. Wolffian differentiation, however, was not affected by inhibition of DHT, demonstrating its T dependency, but seminal vesicle growth was impaired. Thus, inhibition of 5 alpha-reductase activity limits seminal growth potential in adulthood. Studies with the antiandrogen flutamide show that at doses significantly above that required to completely block prostate differentiation and cause genital feminization, Wolffian ductal differentiation is significantly impaired. Thus, higher doses of flutamide are needed to block the paracrine effect of T on the Wolffian ducts.

5-alpha Reductase Inhibitors↗

PubMed1992

Incidence of liver toxicity associated with the use of flutamide in prostate cancer patients.

PURPOSE: The incidence of flutamide-related liver toxicity was studied in 1,091 consecutive patients treated for stage C or D prostate cancer with the antiandrogen flutamide and the luteinizing hormone-releasing factor (LHRH) agonist [D-Trp6, des-Gly-NH2(10)] LHRH ethylamide. PATIENTS AND METHODS: Liver function tests, namely measurement of serum aspartate amino-transferase (AST) and alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase (gamma-GT), and prothrombin and thromboplastin times, were performed at 4, 8, and 12 weeks and every 3 months thereafter. Clinical signs and symptoms of liver dysfunction were also sought. The causal link between the antiandrogen used and liver injury was assessed on the basis of the temporal relationship with the use of the drug in the absence of other possible causes and, in two patients, through rechallenge of the putative causative drug after a period of normalization of liver function. RESULTS: An increase in AST and ALT at fourfold or more above upper normal limits was observed in only four patients (0.36%). Total serum bilirubin and alkaline phosphatase were elevated in only one patient at 126 mmol/L and 640 IU/L, respectively. Among the four patients, only two developed clinical manifestations of liver disease (0.18%). Biopsy was performed in one patient, and the histopathologic findings showed a mixed pattern of cytotoxic and cholestatic changes. All clinical and biologic manifestations of liver toxicity rapidly disappeared upon discontinuation of flutamide alone. No sequelae were observed in the long-term follow-up at 18, 22, 31, and 62 months. The 1,087 remaining patients experienced no or mild (less than fourfold upper normal limit) and transient elevation in aminotransferase serum levels during the first 6 months of treatment, with normalization at later time intervals. CONCLUSION: Despite the fact that the cases reported so far, along with our large series, indicate that the incidence of flutamide-induced liver toxicity is very low, we recommend serial blood aminotransferase measurements at 2 and 4 weeks of treatment in order to detect early signs of possible flutamide-induced hepatic injury, thus avoiding the low potential risk of clinically significant liver toxicity.

Adenocarcinoma↗

PubMed1976

Percutaneous penetration and metabolism of topical (14C)flutamide in men.

This study was designed to determine the fate of the nonsteroid antiandrogen flutamide in men following a single 6-hr topical application of 5 mg 14C-labeled drug dissolved in 50% ethanol/50% propylene glycol. Analysis of 0-120 hr urine shows at least 16% of the applied flutamide is absorbed. Fifty-six percent of the dose is recovered from the site of application with cotton swabs moistened with 50% ethanol/50% propylene glycol. Flutamide plasma levels peak in 4 to 6 hr at about 1.3 ng/ml and then decline rapidly to about 0.08 ng/ml 24 hr after application. Only 13% of plasma 14C is associated with flutamide 6 hr after drug application. There are at least 10 plasma metabolites, 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-lactotoluidide (B); alpha, alpha, alpha-trifluoro-4'-nitro-m-acetotoluidide (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) is the major plasma metabolite, and its concentration exceeds flutamide's between 8 and 24 hr after drug. All the plasma metabolites are found in 0-24 hr urine in minor amounts. An additional metabolite, alpha, alpha, alpha-trifluoro-amino-5-nitro-p-cresol (G), accounts for 27% of urine 14C.

Administration, Topical↗

PubMed1975

The effects of a nonsteroid antiandrogen, flutamide, on sebaceous gland activity.

Flutamide (alpha,alpha,alpha-trifluoro-2-methyl-4'-nitro-m-propionotoluidide), at daily oral doses of 20 mg/day for 24 days, reduced the number and size of skin sebaceous gland cells, and reduced sebum production in ovariectomized, testosterone-stimulated rats. The weight of the preputial glands was also reduced. Unilateral topical application of flutamide (0.1-3.0 mg/day) to flank organs (androgen-sensitive cutaneous sebaceous structures) of testosterone propionate-treated female hamsters for 14 days resulted in bilateral reductions in flank organ weight and in inhibition of in vitro incorporation of 14-C from sodium [1--14C]acetate into lipids. Flutamide inhibition of flank organ weight paralleled the drug effect on lipogenesis. Unilateral topical application of flutamide to flank organs of intact male hamsters for 14 days resulted in significant bilateral reductions of flank organ weight at doses as low as 0.375 mg/day (the lowest dose tested). These weight changes were marked by reduction in sebaceous gland size, accompanied by focal cytoplasmic degeneration, and reductions in cytoplasmic organelles and in the size of the lipid bodies. Flutamide did not, however, seemingly alter the pattern of endogenous total lipids in sebaceous glands, nor did it alter the pattern of 14-C-incorporation into the lipids of male flank organ epidermis and isolated sebaceous glands, when compared to control, untreated preparations.

Acetates↗

PubMedDate not supplied

Effect of flutamide on the physiological status of epididymis and epididymal sperms.

Flutamide, a pure antiandrogen, increases the levels of plasma luteinizing hormone but antagonizes the biological expression of androgen on target organs. Flutamide was administered to rats to study the effect of altered availability of hormones on the functional status of epididymis. The weights of ventral prostate, seminal vesicles and epididymis showed antiandrogenic effects of flutamide. However, increased activity of kidney beta-glucuronidase reflected increased availability of testosterone. The concentrations of protein and DNA along with the activities of acid phosphatase and hyaluronidase decreased in flutamide-treated rats. The activities of acid phosphatase and hyaluronidase in epididymal sperms along with protein concentration increased in flutamide-treated rats. Alteration of epididymal function by treatments affecting lysosomal stability was indicated.

Acid Phosphatase↗

PubMed1979

Effect of flutamide on estradiol metabolism.

The effect of flutamide, a potent nonsteroidal antiandrogen, on the metabolism of iv tracers of [3H]estradiol was studied in five patients with advanced prostate cancer. The drug produced no change in the percentage of the injected radioactivity recovered in urine or in the glucuronide or nonglucuronide conjugate fractions. Of the five individual metabolites that were quantitated, estrone, estradiol, and estriol were unaffected by flutamide, but the drug caused striking decreases in conversion of estradiol to 2-hydroxyestrone (4.0% vs. 7.4%) (P less than 0.005) and 2-methoxyestrone (1.1% vs. 2.6%; P less than 0.05); every one of the patients showed a marked fall in recovery of both of these compounds. This depression of the formation of 2-oxygenated metabolites is reminiscent of the findings in liver disease; the same abnormality occurs regularly in cirrhosis and frequently in extrahepatic biliary obstruction. Taken together with our previous studies of the effects of flutamide on testosterone and cortisol metabolism, this study demonstrates that flutamide produces multiple functional, reversible, cirrhosis-like disturbances of steroid metabolism. Because these disturbances are universal in the patients studied regardless of whether they had clinical responses to flutamide, we doubt that the steroid metabolic changes play a role in the therapeutic effect of the drug.

Anilides↗

PubMed1992

Disturbed testicular descent in the rat after prenatal exposure to the antiandrogen flutamide.

Exposure of rats in utero to the anti-androgen flutamide resulted in feminization of the external genitalia that was noticeable at birth. This exposure also resulted in a high degree of cryptorchidism during adulthood. In most affected animals, testes were lying in 'ovary position' close to the caudal pole of the ipsilateral kidney. Cryptorchidism occurred despite normal prenatal development of the gubernacular cones and the transformation of these structures, postnatally, into muscular cremaster sacs. Inter- and intralitter variation in the response to prenatal exposure to flutamide was observed as well as intra-individual variation. Cryptorchidism frequently occurred unilaterally with right side cryptorchidism predominating. Cryptorchidism occurred in association with marked suppression of the growth of the ipsilateral epididymis and deferent duct. The possibility is considered that the poor development or absence of these structures contributes to cryptorchidism. Intra-individual variation supports the concept of the local nature of the influence of testis hormones in stabilization and further differentiation of the ipsilateral Wolffian duct derivatives. Cryptorchidism was enhanced when rats were treated postnatally with testosterone or oestradiol. The effect of testosterone was unexpected in view of the generally held hypothesis that androgens enhance testis descent. The effect of oestradiol was as expected: other animal models have been described in which induction of cryptorchidism by oestradiol occurs. Additional treatment with oestradiol caused further suppression of growth of the epididymis and deferent duct. The response to prenatal exposure to flutamide was not altered by further injections of flutamide postnatally. Such injections were without effect in males not exposed to flutamide prenatally except for minor, but statistically significant, testicular enlargement during adulthood. A model is thus presented that describes cryptorchidism as an endogenous developmental disorder.

Androgen-Insensitivity Syndrome↗