The potential application of finasteride for chemoprevention of prostate cancer.
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5-alpha Reductase Inhibitors↗
Biomedical subjects
G J Gormley
Publications and source records attributed to G J Gormley.
Finasteride: a clinical review.
Finasteride is the first of a new class of 5 alpha-reductase inhibitors which allows selective androgen deprivation affecting dihydrotestosterone (DHT) levels in target organs such as the prostate and scalp hair without effecting circulating levels of testosterone thus preserving the desired androgen mediated effects on muscle strength, bone density and sexual function. Finasteride has been demonstrated to produce significant effects in men with an enlarged prostate gland. The long-term data now emerging suggests that progression of benign prostatic hyperplasia (BPH) may be arrested providing additional long term benefits. Experimental uses in prostate cancer prevention and male pattern baldness offer new and exciting possibilities for this class of compounds.
Alopecia↗
Clinical experience of the detection of prostate cancer in patients with benign prostate hyperplasia treated with finasteride. The Finasteride Study Group.
The clinical experience relating to the detection of prostate cancer in patients participating in 2 large multicenter clinical trials of finasteride in the treatment of benign prostatic hyperplasia is reviewed. A total of 1,645 patients 40 to 83 years old with benign prostatic hyperplasia was randomized to receive 1 or 5 mg finasteride or placebo once a day for 12 months in a double-blind fashion followed by an open extension study in which all patients were treated with 5 mg finasteride daily. At entry, all patients were to have a maximum urinary flow rate of 15 ml per second or less with a voided volume of 150 ml or more, an enlarged prostate and symptoms of urinary obstruction. Patients with a prostate specific antigen level of 40 ng/ml or more, or any finding suggestive of prostate cancer were excluded. During the study period 32 cases of prostate cancer were diagnosed: 12 were detected during the 12 months of the controlled study and were evenly distributed among the treatment groups (4 on placebo, and 3 on 1 mg and 5 on 5 mg finasteride) and 20 cases were detected in the extension study. From these results we conclude that finasteride-treated patients should be evaluated periodically by digital rectal examination, careful monitoring of prostate specific antigen levels and appropriate investigation of any suspicious findings.
Aged↗
Effect of finasteride on prostate-specific antigen density.
OBJECTIVE: Prostate-specific antigen density (PSAD) has been proposed as a diagnostic marker for prostate cancer. Because treatment with finasteride may affect PSAD differently in men with BPH compared with men with BPH plus prostate cancer, we evaluated the diagnostic utility of PSAD in men treated with finasteride for twelve months. METHODS: Data for this analysis were obtained from 895 men with BPH enrolled in a twelve-month placebo-controlled North American study. Prostate volume was measured by magnetic resonance imaging and PSA was measured by the Hybritech immunoradiometric assay. RESULTS: Treatment with finasteride for twelve months increased the positive predictive value of PSAD for identifying the presence of prostate cancer from 14 percent to 30 percent. Using PSA values alone with a cutoff of 10 ng/mL at baseline and 5 ng/mL after twelve months of treatment, similar specificity and sensitivity could be achieved. CONCLUSION: The data suggest that adjustment of PSA values during treatment with finasteride can be used to maintain the diagnostic accuracy for prostate cancer while PSAD can be used to provide additional reassurance without requiring adjustment for treatment.
Adult↗
Clinical results with finasteride.
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Biomarkers↗
Endocrine therapies for BPH: scientific rationale, clinical results, and patient selection.
In 1993, medical therapy for BPH is a reality. Androgen deprivation therapy (LHRH agonists, antiandrogens, and 5 alpha-reductase inhibitors) has been shown to be effective by reducing the static component of BPH. Of these agents, the 5 alpha-reductase inhibitors have the greatest promise because of their low toxicity profile. Aromatase inhibitors, which function via a different mechanism, however, have not been demonstrated, as monotherapy, to be effective in the treatment of symptomatic BPH. It is still theoretically possible that aromatase inhibitors could have a role in the management of prostatism if they are utilized in conjunction with an antiandrogen or 5 alpha-reductase inhibitor. Although the early results for this endocrine therapies are encouraging, several issues relating to medical treatment remain unanswered. Not everyone with significant prostatism will respond to androgen deprivation therapy. How does the physician identify pre-treatment the patient most likely to achieve a significant improvement in voiding function with 5 alpha-reductase inhibitor therapy? At the present time, there is no method--based on symptoms, DRE findings, serum hormone and PSA levels, or histopathologic criteria--for recognizing the ideal patient for androgen deprivation therapy. Without question, it is a subjective decision. As a result, the benefits and risks of these medical approaches as well as those of the minimally invasive and surgical therapies must be discussed with the patient so that he can participate in the management decision. In this manner, the expectations and needs of the patient will be best served.
5-alpha Reductase Inhibitors↗
The effect of finasteride on prostate-specific antigen in men with benign prostatic hyperplasia.
Finasteride is a specific 5-alpha-reductase inhibitor that has been shown to reduce prostate size and decrease serum levels of prostate specific antigen (PSA). Among men who received finasteride (5 mg/day) for 12 months in North American clinical trials and in whom prostate cancer was not diagnosed the median percentage change in PSA was -50% (5-95% range: -81% to +20%). At baseline 72% had PSA < or = 4.0 ng/ml and 93% had PSA < or = 10.0 ng/ml. After 12 months on finasteride, 75% had PSA < or = 2.0 ng/ml and 95% had PSA < or = 5.0 ng/ml. Thus, the proportion of BPH patients with PSA levels of 2.0 ng/ml and 5.0 ng/ml after 12 months of treatment was comparable to the proportion with pretreatment PSA levels of 4.0 ng/ml and 10.0 ng/ml. Among the 10 men in these trials subsequently diagnosed with prostate cancer while on long-term finasteride therapy (5 mg/day), the median percentage change in PSA was -26% (range: -48% to +12%). Limited experience with finasteride in men with prostate cancer suggests that the reduction in PSA of malignant origin appears to be no greater than the percentage reduction in PSA of benign origin. These effects on PSA have not been shown to confer any therapeutic benefit. Physicians using finasteride should be aware of its effect on PSA levels.
5-alpha Reductase Inhibitors↗
Effect of finasteride on serum PSA concentration in men with benign prostatic hyperplasia. Results from the North American phase III clinical trial.
Finasteride, a 5-alpha reductase inhibitor recently introduced for the treatment of symptomatic benign prostatic hyperplasia, reduces prostate size and decreases serum PSA concentration. To interpret PSA in men treated with finasteride, it is necessary to take the reduction into account. This article describes the effect of finasteride on the serum PSA concentration in the North American Phase III clinical trial and discusses implications of these findings for the interpretation of serum PSA in men treated with finasteride.
Adult↗
The effect of finasteride in men with benign prostatic hyperplasia. The Finasteride Study Group.
BACKGROUND: Benign prostatic hyperplasia is a progressive, androgen-dependent disease resulting in enlargement of the prostate gland and urinary obstruction. Preventing the conversion of testosterone to its tissue-active form, dihydrotestosterone, by inhibiting the enzyme 5 alpha-reductase could decrease the action of androgens in their target tissues; in the prostate the result might be a decrease in prostatic hyperplasia and therefore in symptoms of urinary obstruction. METHODS: In a double-blind study, we evaluated the effect of two doses of finasteride (1 mg and 5 mg) and placebo, each given once daily for 12 months, in 895 men with prostatic hyperplasia. Urinary symptoms, urinary flow, prostatic volume, and serum concentrations of dihydrotestosterone and prostate-specific antigen were determined periodically during the treatment period. RESULTS: As compared with the men in the placebo group, the men treated with 5 mg of finasteride per day had a significant decrease in total urinary-symptom scores (P less than 0.001), an increase of 1.6 ml per second (22 percent, P less than 0.001) in the maximal urinary-flow rate, and a 19 percent decrease in prostatic volume (P less than 0.001). The men treated with 1 mg of finasteride per day did not have a significant decrease in total urinary-symptom scores, but had an increase of 1.4 ml per second (23 percent) in the maximal urinary-flow rate, and an 18 percent decrease in prostatic volume. The men given placebo had no changes in total urinary-symptom scores, an increase of 0.2 ml per second (8 percent) in the maximal urinary-flow rate, and a 3 percent decrease in prostatic volume. The frequency of adverse effects in the three groups was similar, except for a higher incidence of decreased libido, impotence, and ejaculatory disorders in the finasteride-treated groups. CONCLUSIONS: The treatment of benign prostatic hyperplasia with 5 mg of finasteride per day results in a significant decrease in symptoms of obstruction, an increase in urinary flow, and a decrease in prostatic volume, but at a slightly increased risk of sexual dysfunction.
5-alpha Reductase Inhibitors↗
Chemoprevention strategies for prostate cancer: the role of 5 alpha-reductase inhibitors.
Prostate cancer is a major health problem for the aging male population. Despite hormonal dependence, the inevitable emergence of androgen insensitive tumors, which have a dismal prognosis, highlights the need to develop prevention strategies such as chemoprevention. An acceptable agent must interfere with either the process of carcinogenesis or tumor growth, and have minimal toxicity. In clinical studies, 5 alpha-reductase inhibitors have been shown to suppress serum and intraprostatic levels of dihydrotestosterone, an important promoter of prostate cancer, leading to reduction in prostate size and suppression of glandular cell activity as measured by prostate specific antigen secretion. In addition, 5 alpha-reductase inhibitors have demonstrated an excellent safety profile and tolerability in 12 month controlled clinical trials. No significant metabolic effects have been observed in gonadotropin secretion, spermatogenesis, serum lipids or glucose tolerance. The efficacy and safety of 5 alpha-reductase inhibitors in studies to date, combined with the androgen dependence of tumor production, strongly supports investigating their use for chemoprevention of prostate cancer.
5-alpha Reductase Inhibitors↗
Multicenter, randomized, double-blind, placebo controlled study to investigate the effect of finasteride (MK-906) on stage D prostate cancer.
A total of 28 untreated patients with asymptomatic, stage D prostate cancer was randomized in a double-blinded fashion to receive finasteride (10 mg. per day), a 5 alpha-reductase inhibitor or placebo. Patients were evaluated at 3-week intervals by rectal examination, and serum prostate specific antigen (PSA) and prostatic acid phosphatase (PAP) levels, and at 6-week intervals by bone scan and transrectal ultrasound determinations of prostatic volume. Patients stopped the medication at week 6 at the discretion of the investigator when PSA levels increased from baseline. After 12 weeks all patients were reevaluated. Of the patients 13 received finasteride and 15 received placebo. The 2 groups did not differ statistically with respect to patient age, initial PSA and PAP level, or the extent of metastases on initial bone scan. A statistically significant decrease in the median percentage change from baseline in PSA at weeks 3 and 6 occurred in the finasteride group compared to the placebo group (-22.9% versus -2.9% and -15.1% versus +11.7%, respectively, p less than 0.05). Finasteride had no effect upon PAP, serum testosterone, prostatic volume or appearance of bone scans. A decrease in serum PSA in the finasteride treatment group suggests that finasteride exerts a minor effect in patients with prostate cancer. This effect does not approach that seen with medical or surgical castration yet because of the potency preserving feature and the lack of toxicity finasteride may warrant further study in the treatment of prostate cancer.
5-alpha Reductase Inhibitors↗
Effect of finasteride, a 5 alpha-reductase inhibitor, on serum gonadotropins in normal men.
Testosterone exerts negative feedback control on gonadotropin secretion either directly, after aromatization to estradiol, or after 5 alpha-reduction to dihydrotestosterone (DHT). Conflicting data exist as to the role of DHT in the modulation of this negative feedback. To determine whether suppression of endogenous DHT alters gonadotropin secretion, we gave the selective 5 alpha-reductase inhibitor finasteride (5 mg daily), or placebo, to 20 healthy men for 28 days. Basal and GnRH-stimulated LH, bioactive LH, FSH, testosterone, and DHT levels were measured before and after 14 and 28 days of treatment. Basal DHT fell from 1.1 +/- 0.2 to 0.15 +/- 0.04 nmol/L after 28 days of finasteride treatment. A significant rise in baseline testosterone from 17.6 +/- 2.0 to 18.3 +/- 2.3 nmol/L was seen at 14 days (P = 0.046), but not at 28 days. No significant changes were seen in either basal or GnRH-stimulated gonadotropin levels on any day. We conclude that suppression of serum DHT levels with 5 mg finasteride daily in healthy young men has no discernible effect on serum gonadotropin levels.
Adult↗
Role of 5 alpha-reductase inhibitors in the treatment of advanced prostatic carcinoma.
Everything we know about the biology of the prostate supports the concept that DHT is the obligate androgen responsible for normal and hyperplastic growth. Whether this selectivity is maintained during malignant transformation is unknown. The consistent emergence of androgen-insensitive disease highlights the spectrum of biologic evolution this cancer is capable of. If the tumor is dependent only on DHT for neoplastic growth, the unique characteristics of a 5 alpha-reductase inhibitor offer several potential actions that warrant a systematic evaluation.
5-alpha Reductase Inhibitors↗
Effects of finasteride (MK-906), a 5 alpha-reductase inhibitor, on circulating androgens in male volunteers.
Finasteride, a 5 alpha-reductase inhibitor, was administered to normal male volunteers in a blinded placebo-controlled study at daily oral doses of 25, 50, and 100 mg for 11 days (part 1) and daily oral doses of 0.04, 0.12, 0.2, and 1.0 mg for 14 days (part 2). Results from part 1 showed a significant reduction in dihydrotestosterone (DHT) at all doses and a significant increase in both testosterone (T) and delta 4-androstenedione at the 50- and 100-mg doses. No change was seen in LH, FSH, cortisol, or estradiol levels. Serum lipids, including total cholesterol, low density lipoprotein, high density lipoprotein, and triglycerides were not affected by treatment. Results from part 2 again showed significant reduction in DHT at all doses. DHT levels returned to pretreatment values within 14 days of discontinuing treatment. Significant increases in T were observed only in the 1.0 mg group and only during the first 8 days of treatment. The T/DHT ratio increased with all doses and returned to baseline when drug was discontinued. The DHT metabolites and androstanediol glucuronide and androsterone glucuronide were significantly reduced at all doses. There were no significant adverse experiences reported during part 1 or 2. In conclusion, finasteride is well tolerated by normal volunteers and results in significant suppression of serum DHT at all doses tested.
Adult↗
PhD faculty in the clinical department.
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Education, Graduate↗
Comparison of in vivo and in vitro glucocorticoid sensitivity in depression: relationship to the dexamethasone suppression test.
The effect of in vivo (1 mg) and in vitro (10(-7)-10(-10) M) dexamethasone administration on mitogen-induced lymphocyte proliferation was examined in drug-free depressed patients, nondepressed psychiatric patients, as well as normal controls, and was related to the results of a standard overnight Dexamethasone Suppression Test (DST). The effect of oral dexamethasone administration was also examined for its effect on lymphocyte cytosolic glucocorticoid receptor content. Oral dexamethasone administration significantly decreased both phytohemagglutinin (PHA) and concanavalin A (Con-A) induced lymphocyte proliferation, as well as glucocorticoid receptor number in suppressors, whereas dexamethasone failed to decrease these responses in nonsuppressors. Nonsuppressors had significantly lower serum dexamethasone levels compared to suppressors at both 8:00 AM and 4:00 PM. However, when differences in serum dexamethasone levels were covaried out, there were still significant differences between suppressors and nonsuppressors on the dexamethasone-induced mitogen changes, but the changes in glucocorticoid receptor content were no longer significant. In vitro incubation of lymphocytes with dexamethasone produced a dose-related decrease in mitogenesis, which was not different between the depressed and nondepressed groups. However, at physiologically relevant concentrations of dexamethasone (10(-9)-10(-10) M), nonsuppressors as compared to suppressors were more resistant to the immunosuppressive effects of in vitro dexamethasone on the Con-A response. The inhibitory effect of in vitro dexamethasone on Con-A-stimulated lymphocytes was positively correlated with basal 4:00 PM cortisol values. In conclusion, in vitro techniques are useful probes to assess glucocorticoid sensitivity in depression. The present results also further support the hypothesis that glucocorticoid insensitivity is associated with DST nonsuppression.
Adult↗
A controlled pore glass bead assay for the measurement of cytoplasmic and nuclear glucocorticoid receptors.
An assay for the quantitation of cytoplasmic and nuclear glucocorticoid receptors in lymphoid tissue has been developed using controlled pore glass (CPG) beads. Soluble receptor--3H-steroid complex (cytosol or nuclear extract) is adsorbed quantitatively within the crevasses of porous glass beads. Excess labeled steroid as well as most non-specifically bound steroid is easily washed away, leaving the hormone-receptor complex retained by the beads. Bound 3H-steroid is eluted with ethanol and measured for radioactivity. This procedure which is simple, rapid, and highly reproducible is carried out using frozen samples (stable for many months) containing as few as 1 X 10(7) cells. A comparison of the CPG assay to dextran coated charcoal and a whole cell assay demonstrates that CPG and dextran coated charcoal give equivalent measurements of cytosolic receptor concentration, while the CPG and whole cell assays provide equivalent values for total receptor content.
Adsorption↗
Glucocorticoid receptors in depression: relationship to the dexamethasone suppression test.
Cytoplasmic glucocorticoid receptor content wa quantitated in lymphocytes from unmedicated depressed patients and control subjects before and after a standardized dexamethasone suppression test. Depressed patients (N = 11) had significantly lower (32%) basal cytoplasmic glucocorticoid receptor content than the control group (N = 14). Suppression of serum cortisol (5.0 micrograms/dl or less) in both control and depressed subjects (N = 16) following dexamethasone (1 mg) was associated with a decrease in lymphocyte cytoplasmic glucocorticoid receptor number, whereas no such change occurred in cortisol nonsuppressors (N = 9). Changes in receptor concentration were positively correlated with postdexamethasone serum cortisol levels and with the inhibitory effect of dexamethasone on mitogen-induced lymphocyte proliferation.
Adult↗