RE: Effect of the dual 5alpha-reductase inhibitor dutasteride on markers of tumor regression in prostate cancer.
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5-alpha Reductase Inhibitors↗
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Dutasteride, cantharidin, atopiclair, cetuximab, sirolimus, AC-11 and dimericine reviewed in brief.
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Acne Vulgaris↗
The Use of Nomograms for Selecting BPH Candidates for Dutasteride Therapy.
Recent studies have discussed the benefits of medical therapy for benign prostatic hyperplasia (BPH), but have not provided physicians with the necessary tools needed to translate the information into individualized, evidence-based recommendations for clinically important questions. Nomograms can help physicians individualize their treatment decisions and predict a likely outcome by assessing the key risk factors for BPH progression.
Journal Article↗
Mass spectral fragmentation reactions of a therapeutic 4-azasteroid and related compounds.
Mass spectra were acquired for a therapeutic 4-azasteroid (dutasteride), and some related compounds, using various ionization conditions (EI, CI, APCI and ESI) in both positive and negative ion modes. The ionization and fragmentation behavior of the compound dutasteride, its precursors and several analogs is reported. Positive atmospheric pressure chemical ionization (APCI+) and positive electrospray ionization (ESI+) produced distinctive collision-induced dissociation (CID) spectra for the respective [MH]+ ions of dutasteride. The spectral differences are attributed to ion populations having either different structures or different internal energy distributions (as a consequence of the method of ionization). Irrespective of their origin, the protonated molecules undergo interesting fragmentation reactions when collisionally activated. The identity of the major fragmentation products was confirmed by accurate mass measurement. The negative APCI mass spectrum of dutasteride displays extensive dehydrohalogenation, apparently due to the thermal component of the APCI process. Some of the resulting radical anions display remarkable stability toward collisional decomposition. Details of the fragmentation behavior for the negative ion species and their relationship to the positive ion results are discussed.
5-alpha Reductase Inhibitors↗
Novel male hormonal contraceptive combinations: the hormonal and spermatogenic effects of testosterone and levonorgestrel combined with a 5alpha-reductase inhibitor or gonadotropin-releasing hormone antagonist.
We postulated that the addition of a combined types I and II, 5alpha-reductase inhibitor (dutasteride) or long-acting GnRH antagonist (acyline) to combination testosterone plus levonorgestrel treatment may be advantageous in the suppression of spermatogenesis for male contraception. This study aimed to examine effects of novel combination contraceptive regimens on serum gonadotropins and androgens and sperm concentration.This study was divided into three phases: screening (2 wk), treatment (8 wk), and recovery (4 wk). Twenty-two men (n = 5-6/group) received 8 wk of treatment with testosterone enanthate (TE, 100 mg im weekly) combined with one of the following: 1) levonorgestrel (LNG) 125 mug orally daily; 2) LNG 125 microg plus dutasteride 0.5 mg orally daily; 3) acyline 300 microg/kg sc every 2 wk (as a comparator for any additional progestin effects); or 4) LNG 125 microg orally daily plus acyline 300 microg/kg sc every 2 wk. Serum gonadotropin levels were similarly suppressed by all treatments, falling to a nadir between 1.2 and 3.4% and 0.5 and 0.8% baseline for FSH and LH, respectively (P < 0.05). Serum dihydrotestosterone levels were significantly (P < 0.05) decreased in the dutasteride group throughout the treatment period to a nadir of 31% baseline (wk 7). No significant differences in sperm concentrations among treatment groups were seen. Severe oligospermia (0.1-3 million/ml) or azoospermia was seen in none of five and four of five in TE + LNG; two of six and four of six in TE + LNG + dutasteride; two of six and four of six in TE + acyline; and one of five and three of five in TE + LNG + acyline groups, respectively. There was one nonresponder in each of the TE + LNG and TE + LNG + acyline groups.We conclude that the addition of a combined types I and II, 5alpha-reductase inhibitor or long-acting GnRH antagonist to a testosterone plus LNG regimen provides no additional suppression of gonadotropins or sperm concentration over an 8-wk treatment period. However, further evaluation of the effects of these regimens on the testis (including testicular steroid levels and germ cell maturation) and the treatment of larger numbers of men (and for longer periods) may provide data to support their place in contraceptive development.
Adult↗
Combined inhibition of types I and II 5 alpha-reductase selectively augments the basal (nonpulsatile) mode of testosterone secretion in young men.
CONTEXT: Testosterone (Te) is metabolized in the hypothalamus and pituitary gland, where untransformed steroid and activated products participate in feedback regulation of GnRH and LH secretion. Genetic inactivation of 5 alpha-reductase type I remains undescribed clinically, whereas deficiency of the type II isoenzyme elevates both LH and Te concentrations. OBJECTIVE: The aim of this study was to test the combined feedback contribution of 5 alpha-reduced steroids. SETTING/DESIGN/INTERVENTION: In a university setting, nine young men received placebo and a dual (type I/type II) 5 alpha-reductase inhibitor, dutasteride. METHODS/OUTCOMES: LH and Te dynamics were assessed by: 1) 10-min blood sampling for 26 h; 2) GnRH stimulation (100 ng/kg iv); 3) discrete peak detection; 4) deconvolution analysis; 5) cosinor analyses of 24-h rhythmicity; and 6) pattern regularity. RESULTS: Compared with placebo, dutasteride lowered 5 alpha-dihydro Te concentrations by 80% (P = 0.009), but did not alter any measure of LH dynamics. Conversely, dutasteride augmented: 1) total, bioavailable and free Te concentrations (0.002 < P < 0.032) without changing estradiol or SHBG concentrations; 2) nadir Te concentrations (P = 0.025); and 3) basal (P = 0.013) and thereby total (basal plus pulsatile) (P = 0.003) Te secretion. CONCLUSION: Combined antagonism of types I and II 5 alpha-reductase preferentially drives nonpulsatile Te secretion in healthy men. The concomitant stability of LH outflow could indicate that intragonadal 5 alpha-reduced androgens repress basal Leydig-cell steroidogenesis.
Adult↗
Validation of a population pharmacokinetic/pharmacodynamic model for 5 alpha-reductase inhibitors.
A population pharmacokinetic/dynamic model describing the conversion of testosterone to dihydrotestosterone (DHT) by 5alpha-reductases and the irreversible inhibition of 5alpha-reductase(s) by finasteride and dutasteride was validated. The model had been developed using data from a single dose study in healthy volunteers and was validated against data from a 28-day repeat dose study in patients with benign prostatic hyperplasia. Validation was carried out by comparing results of Monte Carlo simulations to the observed data, fitting the model to the repeat dose data and comparing with previously derived parameter values, and examining individual predictions of the model for the individuals in the repeat dose study for any bias. Simulations closely predicted the outcome of the repeat dose study, estimated parameters of the pharmacodynamic modelling were generally close to within 88 to 116% of those from the original model and the individual predictions did not indicate any bias. Thus the model derived from single dose data from healthy volunteers was considered to be valid for the prediction of DHT levels in the patient population after repeated dosing of dutasteride and finasteride.
5-alpha Reductase Inhibitors↗
Effects of testosterone and levonorgestrel combined with a 5alpha-reductase inhibitor or gonadotropin-releasing hormone antagonist on spermatogenesis and intratesticular steroid levels in normal men.
CONTEXT: Combination of a GnRH antagonist (acyline), types I and II, 5alpha-reductase inhibitor (dutasteride) or levonorgestrel (LNG) with testosterone (T) treatment may augment the suppression of spermatogenesis and intratesticular (iT) steroids. OBJECTIVE: The objective of this study was to assess the effects of combined hormonal contraceptive regimens on germ cell populations and iT steroids. DESIGN, SETTING, AND PARTICIPANTS: Twenty-nine normal health men enrolled in this prospective, randomized, 14-wk study at the University of Washington. INTERVENTION(S): Twenty-two men (n = 5-6/group) received 8 wk of T enanthate (TE; 100 mg, i.m., weekly) combined with 1) 125 microg LNG daily, orally; 2) 125 microg LNG plus 0.5 mg dutasteride daily, orally; 3) 300 microg/kg acyline twice weekly, s.c.; or 4) 125 microg LNG daily, orally, plus 300 microg/kg acyline twice weekly, s.c. Subjects then underwent a vasectomy and testicular biopsy. Control men (n = 7) proceeded directly to surgery. MAIN OUTCOME MEASURE(S): The main outcome measures were germ cells and iT steroids [T, dihydrotestosterone, 3alpha- and beta-androstanediol (Adiol), and estradiol (E2)]. RESULTS: High iT levels of all androgens (6- to 123-fold serum levels) and E2 (407-fold serum levels) were found in control men. iTT (1.9-2.6% control; P < 0.001) and iT3betaAdiol (16-34% control; P < 0.05) levels decreased with all treatments. iT dihydrotestosterone (13-29% control; P < 0.05) and iT3alphaAdiol (44-47% control; P < 0.05) levels decreased with all but the TE plus LNG treatment. iTE2 levels decreased only in the TE plus acyline group (28% control; P = 0.01). Germ cells from type B spermatogonia onward were suppressed, with no differences between groups found. Variable sites of impairment of germ cell progression were evident between men (spermagonial maturation, meiosis 1 entry, and spermiation). Other than a negative correlation between iT3alphaAdiol and haploid germ cell number (P < 0.006), no correlations between germ cell number and gonadotropins, sperm concentration, or iT steroids were found. CONCLUSIONS: A similar high testicular:serum gradient exists for E2 and T in normal men, and 8 wk of gonadotropin suppression markedly reduces iTT, with 5alpha-reduced androgens and E2 levels decreasing to a much lesser degree. The heterogeneity of the germ cell response, regardless of treatment, gonadotropins or iT steroids, points to the individual sensitivity of sites in germ cell development, which is worthy of additional exploration.
5-alpha Reductase Inhibitors↗
The interpretation of serum prostate specific antigen in men receiving 5alpha-reductase inhibitors: a review and clinical recommendations.
PURPOSE: We reviewed the effects of 5alpha-reductase inhibitors on prostate specific antigen and clarified the adjustments that should be made to compensate for these effects to ensure that the usefulness of prostate specific antigen for detecting prostate cancer is maintained. MATERIALS AND METHODS: We reviewed articles published in the scientific literature with relevance to the effects of 5alpha-reductase inhibitors on the usefulness of prostate specific antigen for detecting prostate cancer. RESULTS: A total serum prostate specific antigen of 4.0 ng/ml has traditionally been used as the threshold for triggering prostate biopsy. However, clinical trials of finasteride and dutasteride have shown that 5alpha-reductase inhibitors decrease serum prostate specific antigen in patients with and without prostate cancer. To compensate, the doubling rule has been applied in clinical trials and clinical practice. However, doubling serum prostate specific antigen may overestimate actual prostate specific antigen in some patients receiving 5alpha-reductase inhibitors for up to 6 to 9 months, accurately estimate prostate specific antigen from 1 to 3 years and underestimate it thereafter. An increase in prostate specific antigen of 0.3 ng/ml from nadir as a trigger for biopsy maintains 71% sensitivity for prostate cancer in men receiving dutasteride with 60% specificity, similar to the 4.0 ng/ml prostate specific antigen cutoff using placebo. CONCLUSIONS: We propose that a prostate specific antigen increase from nadir of 0.3 ng/ml or greater could represent an alternative to the doubling rule for monitoring prostate specific antigen in patients on 5alpha-reductase inhibitors. The prostate specific antigen increase from nadir appears to be a more accurate cancer indicator than a doubled value in some patients.
Cholestenone 5 alpha-Reductase↗
Benign prostatic hyperplasia progression and its impact on treatment.
PURPOSE OF REVIEW: Management of men with benign prostatic hyperplasia should reduce the lifetime risk of acute urinary retention and the need for benign prostatic hyperplasia-related surgery. A number of recent studies demonstrate that 5alpha-reductase inhibitors are unique in providing a long-term combination of improvements in symptoms and flow, and reductions in the risks of acute urinary retention and surgical intervention. RECENT FINDINGS: The 5alpha-reductase inhibitor finasteride was shown to reduce the risk of retention and surgery in men with large prostate volumes and/or high PSA. Recent studies have examined the role of adding an alpha1-blocker to 5alpha-reductase inhibitor in short- or long-term combination. The Medical Therapy of Prostatic Symptoms study randomised 3,047 men with benign prostatic hyperplasia to treatment with a 5alpha-reductase inhibitor (finasteride), an alpha1 blocker (doxazosin), a combination of both, or placebo. Only treatment arms containing 5alpha-reductase inhibitor therapy were associated with longer-term significant reductions in the risk of acute urinary retention and invasive therapy for benign prostatic hyperplasia. Three randomised, two-year, placebo-controlled studies have assessed the clinical relevance of the >93% DHT suppression provided by dutasteride. Dutasteride was also associated with a reduction in the risk of acute urinary retention of 57%, and a reduction of 48% in the risk of surgical intervention compared with placebo after 2 years. SUMMARY: Short-term combination of 5alpha-reductase inhibitor and alpha-blockade are optimal in providing symptomatic improvement among patients who require symptom relief, while enabling the initiation of 5alpha-reductase inhibitor therapy to reduce the risk of subsequent acute urinary retention or benign prostatic hyperplasia-related surgery in men who are at greater risk of disease progression.
Adrenergic alpha-Antagonists↗
Phase III prostate cancer prevention trials: are the costs justified?
One randomized, prospective clinical trial for chemoprevention of prostate cancer has been completed, and two additional trials are ongoing. The investment, time, and effort for these trials are substantial. We reviewed the outcomes of these trials to address the value of the investment. The outcomes of the Prostate Cancer Prevention Trial (testing finasteride) and the design of the Selenium and Vitamin E Cancer Prevention Trial (SELECT; testing vitamin E and selenium) trial as well as the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial (testing dutasteride) were reviewed. From a public health standpoint, there is tremendous potential for benefit from large-scale cancer prevention trials. Because of the volume of data that are collected, potential discoveries related to the biology of the disease are substantial. Translational scientific efforts are direct outgrowths of these studies. Prospective, randomized chemoprevention trials for prostate and other cancers are expensive and require long periods of time to conduct, yet the rewards are on a par with the investment.
Clinical Trials, Phase III as Topic↗
[Novel therapeutics strategies in benign hypertrophy of prostate management].
The benign hypertrophy of prostate (BPH) is a progressive disease which can assign all the men to various degrees, involving an unquestionable repercussion on the quality of life. The two types of drugs commonly used for the treatment of the symptomatic BPH are the inhibitors of 5-alpha-reductase and the alpha-blockers. They last one relatively long action, making it possible to prevent occurred of complications like the acute urinary retention or the prostatic recourse to the surgery. A risk of progression and development of urinary complications can require an association of these two therapeutic agents in order to obtain a faster and durable improvement of symptomatology. The results of various studies are reported which highlight the interest of this therapeutic combination and underline the contribution of an inhibitor of 5-alpha-reductase among patients presenting a significant prostatic volume and a high PSA. Taking into account the risk of bad compliance and side effects with the long course, after a treatment combined for six months by tamsulosine and dutasteride, the stop of the alpha-blocker allows a maintenance of the situation obtained. Lastly, several clinical studies made it possible to draw the attention to the potentially preventive action of the inhibitors of 5-alpha-reductase in the development of the prostate cancer by its action to the DHT. These observational studies left the place to the PCPT study which made it possible to confirm a reduction in the prevalence of the cancer of prostate in a group of patients treated by finasteride compared with a placebo group. Currently, the preventive potential role of the dutasteride is also the subject of a study (REDUCE). These results are necessary in order to better define the interest and the role of the inhibition of 5-alpha-reductase in a strategic attitude of prostate cancer prevention.
5-alpha Reductase Inhibitors↗
Chemopreventive trials in urologic cancer.
Cancer prevention uses natural, synthetic, or biological chemical agents to reverse, suppress, or prevent carcinogenic progression. Chemoprevention trials are based on the hypothesis that interruption of the biological process involved in carcinogenesis will inhibit this process and, in turn, reduce cancer incidence. Bladder cancer chemoprevention trials demonstrate conflicting findings. Dietary fat, soy protein, garlic, and selenium have been reported to possess anticancer properties in the bladder, but they still remain largely unstudied in vivo. Regarding prostate cancer, vitamin D deficiency was reported to increase risk for the disease, and sunlight exposure is inversely proportional to prostate cancer mortality. The Prostate Cancer Prevention Trial reported a 24.4% prostate cancer incidence with placebo, compared with 18.4% with finasteride, and a reduction of 24.8% over 7 years. Dutasteride, a dual inhibitor of type 1 and type 2 5alpha-reductase, is the subject of the Reduction by Dutasteride of Prostate Cancer Events trial. Results are awaited from that study.
Journal Article↗
[Chemoprevention of prostate cancer].
Despite advances in the detection and management of prostate cancer, this disease remains a major cause of morbidity and mortality in men. Increasing attention has focused on the role of chemoprevention for prostate cancer, i.e., the administration of agents that inhibit one or more steps in the natural course of prostate carcinogenesis. We review prostate cancer chemoprevention studies in Europe. Published studies were identified in a search of MEDLINE. Information about ongoing studies was provided by author access to protocols. A variety of chemoprevention studies have focused on the role of dietary factors, vitamins, and trace elements in prostate cancer. Some of these studies have been prospective, randomized, and double-blinded, while others have used retrospective or epidemiological approaches. Large-scale randomized studies are also evaluating the role of 5alpha-reductase inhibitors, which inhibit the conversion of testosterone to the more potent androgen dihydrotestosterone. Robust evidence is lacking for the value of chemopreventive agents in prostate cancer. Current evidence does suggest that vitamin E and selenium may have a role in prostate cancer chemoprevention. Data from two studies, one examining the type 1 5alpha-reductase selective inhibitor finasteride and the other using the dual 5a-reductase inhibitor dutasteride, will determine the benefits of androgen inhibition strategies for prostate cancer chemoprevention.
Anticarcinogenic Agents↗
Actions of 5alpha-reductase inhibitors on the epididymis.
Testosterone is converted to the more biologically active androgen, dihydrotestosterone (DHT), by steroid 5alpha-reductase. Two isozymes of 5alpha-reductase, types 1 and 2, are abundantly expressed in the epididymis. DHT is the androgen found in the nuclei of epididymal cells and is essential for the maturation of spermatozoa. Thus, one approach to block androgen action in the epididymis is to inhibit DHT formation. Several compounds have been reported to inhibit either one or both forms of 5alpha-reductase in many tissues. The first commercially available inhibitor of 5alpha-reductase, finasteride, has a predominant effect on the type 2 isozyme, while more recently developed agents, such as dutasteride, PNU157706 and FK143, act as dual inhibitors. We found that the treatment of adult rats with such agents results in pronounced effects on the expression of genes essential to the formation of the optimal luminal microenvironment that is required for proper sperm maturation. Furthermore, drug treatment caused a significant decrease in the percentage of progressively motile and morphologically normal spermatozoa in the cauda epididymides. Mating females to treated males resulted in fewer successful pregnancies and a higher rate of pre-implantation loss. Thus, there may be a role for dual 5alpha-reductase inhibitors as potential components of a male contraceptive.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
[Use of 5-alpha-reductase inhibitors in the prevention of prostate cancer].
5-alpha-reductase inhibitors are now in widespread use for the treatment of benign prostatic hyperplasia (BHP) and these molecules have recently come under the spotlight in prostate cancer. Their peripheral "hormonal" action inducing reduced intraprostatic DHT synthesis seems to involve them in this hormone-dependant disorder. Finasteride evaluated in the treatment of BPH (PLESS study) was found to have a preventive effect on the incidence of cancer and this activity was assessed in a specific trial (PCPT study). Nevertheless, in the latter randomized study with a 7-year follow-up period, a reduction in the global incidence of the number of cases of cancers was associated with an increase in the number of high-grade cancers. A slight reduction in prostate cancer was also noted in the studies with dutasteride in BPH (ARIA3001, ARIA3002 and ARIB3003). An international multicenter study (REDUCE) is currently being conducted to confirm the preventive value of this molecule which has a more complete activity than finasteride with its inhibitory action on the two 5-alpha-reductase iso-enzymes, and may therefore have a clearer efficiency and rule out the risk of onset of high-grade cancer.
Aged↗
A model for the turnover of dihydrotestosterone in the presence of the irreversible 5 alpha-reductase inhibitors GI198745 and finasteride.
OBJECTIVE: To develop a pharmacokinetic-pharmacodynamic model that characterizes the conversion of testosterone to dihydrotestosterone (DHT) by 5 alpha-reductase types 1 and 2 and the irreversible inhibition of 5 alpha-reductase by finasteride, a 5 alpha-reductase type 2 inhibitor and by GI198745 (dutasteride), a potent and specific dual 5 alpha-reductase inhibitor. METHODS: Healthy men (n = 48) received doses of 0.1 to 40 mg GI198745 (n = 4 subjects per dose), 5 mg finasteride (n = 8), or placebo (n = 8) in a parallel-group study. Plasma concentrations of GI198745, finasteride, and DHT were measured frequently up to 8 weeks after dosing. Models were fitted with mixed-effects modeling with the NONMEM program. RESULTS: The pharmacodynamics were well described with a model that accounted for the rates of DHT formation and elimination, 5 alpha-reductase turnover, relative capacity of the 2 5 alpha-reductase isozymes, and the rates of irreversible inhibition of one (finasteride) or both (GI198745) types of 5 alpha-reductase. The model indicated that type 2 5 alpha-reductase contributed approximately 80% of plasma DHT. GI198745 was about 3-fold more potent than finasteride on 5 alpha-reductase type 2. Nearly full blockade of both isozymes was achieved at doses of 10 mg or more GI198745, although the potency of this agent on 5 alpha-reductase type 1 was less than on type 2. CONCLUSIONS: A physiologically based model for the turnover and irreversible inhibition of 5 alpha-reductase and for formation and elimination of DHT described the data well. This model helps explain differences in the rates of onset and offset of effect and offers a way to determine the relative potency of the irreversible 5 alpha-reductase inhibitors.
5-alpha Reductase Inhibitors↗