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Does long-acting testosterone injection (Nebido) have an impact on DHT?
... A study by von Eckardstein and Nieschlag, examining suitable LA-TU injection intervals, concluded that, after initial loading doses at 0 and 6 weeks, injection intervals of 12 weeks established eugonadal values of serum T [11]. Consequently, in an open-label, randomized, prospective study, Saad and colleagues compared LA-TU (TU 1000 mg 3 times every 6 weeks, thereafter every 9 weeks) with TE (250 mg every 3 weeks) in 40 hypogonadal men [12]. Trough T levels, measured prior to every injection, remained within the physiological range in patients treated with LA-TU in contrast to the group treated with TE. 2.5year follow-up data from this study demonstrated that both the group administered TU 1000 mg every 12 weeks (former LA-TU group) and the group administered 2× 1000 mg every 8 weeks followed by 1000 mg every 12 weeks (former TE group), resulted in stable mean serum concentrations of T and estradiol [13]. ...
Studies looking at the mode of action of LA-TU (molecular weight 456.7 Da) have shown that upon entry into the peripheral circulation, TU is hydrolyzed to T, which may then exert its androgenic role [1]. It is therefore believed that the toxicology of TU is the same as for other cleavable testosterone fatty acid esters such as T propionate (3 carbon atoms),-enanthate (7 carbon atoms),-cypionate (8 carbon atoms), and-undecanoic acid (11 carbon atoms). The use of T-undecanoic acid, which presents with a saturated aliphatic fatty acid, in contrast to using the fatty acid esters enumerated above, significantly improves the kinetics for side chain cleavage, thus permitting much longer intervals of injections, while at the same time maintaining balanced serum T levels [2]. Animal studies focusing on the use of injectable TU as T replacement have shown that, in orchiectomized male rats, a single injection of 125 mg/kg body weight can induce physiological T levels for a minimum of 4 weeks, while a maximum injection of 500 mg/kg body weight resulted in supraphysiological T serum concentrations for up to 6 weeks in non-orchiectomized rats. When compared to other T-releasing formulations, such as subcutaneous T pellets, T-filled subcutaneous Silastic® (Dow Corning Corp.) implants or subcutaneous T-propionate, TU was clearly superior regarding pharmacokinetic profile, safety, efficacy, and reduced side-effect profile [3]. Independent studies using cynomolgus monkeys (Macaca fascicularis) have addressed the pharmacokinetics of TU following administration of injectable TU 10 mg/kg body weight. One study revealed that with respect to pharmacokinetic and pharmacodynamic characteristics such as Area Under The Curve (AUC), residence time, terminal half-life, maximal T concentration, and time to maximal T concentration, in contrast to the administration of TE 10 mg/kg body weight, TU showed clear superiority [4]. A second study, comparing TU dissolved in soybean oil, castor oil or tea seed oil, showed no significant differences in the pharmacokinetics of the three TU formulations regarding plasma T and estradiol. The suppression of gonadotropin levels varied between individuals and despite increased prostate volumes after administration, these declined back to castrate levels after withdrawal [5]. In humans, several independent research groups have reported findings looking at pharmacokinetics of injectable TU in a variety of concentrations and using several delivery vehicles. The first pharmacokinetic investigation, lasting over 8-9 weeks, by Zhang and colleagues, concluded that, in hypogonadal men, administration of 500 mg injectable TU as first injection, followed by a 1000 mg injection 3 months later, provided more favorable peak testosterone values than when the 500 mg dose was administered as a second injection. The authors speculated that either long-term hypogonadism may induce faster cleavage or a clearance mechanism for TU and T by the time of the second injection or that residual endogenous T is suppressed by the first injection and that following the second injection, only exogenous T is measured [6]. Many pharmacokinetics studies of TU demonstrate that, after intramuscular injection of 1000 mg TU, serum T concentrations are still in the physiological range. One exception, a study of 10 hypogonadal men reported that 500
... The study concluded that after initial loading doses at 0 and 6-weeks, injection intervals of 12-weeks establish eugonadal values of serum testosterone in almost all men. A later study (Yassin and Saad 2005) analyzing 58 hypogonadal men receiving TU treatment every 3 months did not report elevations of DHT levels exceeding the physiological threshold. ...
Testosterone compounds have been available for almost 70 years, but the pharmaceutical formulations have been less than ideal. Traditionally, injectable testosterone esters have been used for treatment, but they generate supranormal testosterone levels shortly after the 2- to 3-weekly injection interval and then testosterone levels decline very rapidly, becoming subnormal in the days before the next injection. The rapid fluctuations in plasma testosterone are subjectively experienced as disagreeable. Testosterone undecanoate is a new injectable testosterone preparation with a considerably better pharmacokinetic profile. After 2 initial injections with a 6-week interval, the following intervals between two injections are almost always 12-weeks, amounting eventually to a total of 4 injections per year. Plasma testosterone levels with this preparation are nearly always in the range of normal men, so are its metabolic products estradiol and dihydrotestosterone. The "roller coaster" effects of traditional parenteral testosterone injections are not apparent. It reverses the effects of hypogonadism on bone and muscle and metabolic parameters and on sexual functions. Its safety profile is excellent due to the continuous normalcy of plasma testosterone levels. No polycythemia has been observed, and no adverse effects on lipid profiles. Prostate safety parameters are well within reference limits. There was no impairment of uroflow. Testosterone undecanoate is a valuable contribution to the treatment options of androgen deficiency.
Testosterone formulations have been available to patients since the 1930s but have proven less than ideal. Conventional injectable testosterone esters have been used as testosterone replacement but generate supraphysiological testosterone concentrations shortly after injection followed by a rapid decline, becoming subphysiological in the days before the next injection. These rapid fluctuations in plasma testosterone are subjectively experienced as disagreeable. Available since 2004, testosterone undecanoate is an injectable testosterone preparation with a considerably better pharmacokinetic profile. After two initial injections with a 6-week interval, the following intervals between injections are usually 12 weeks, amounting to a total of four injections per year. Plasma testosterone concentrations with this preparation are nearly always in the range of normal men, so are its metabolic products estradiol and dihydrotestosterone. Testosterone undecanoate, like other testosterone preparations, reverses the effects of hypogonadism on bone and muscle and significantly improves metabolic parameters and sexual functions, without the “roller coaster” effects of traditional testosterone injections. Other adverse effects, such as polycythemia and disturbed lipid profiles, have not been observed. Although some studies suggest a link between injectable testosterone and comorbidities such as prostate cancer, diabetes, and cardiovascular disease, conflicting data highlight the need for longer-term better controlled, randomized studies. Even though testosterone undecanoate stands out as a valuable contribution to the treatment options of androgen deficiency, a number of alternative therapies such as selective androgen receptor modulators are under development proving, from preliminary studies, as competitive testosterone replacement options.KeywordsTestosterone therapyInjectable androgensTestosterone undecanoateTestosterone enanthatePharmacokinetic profileClinical efficacyHypogonadismCardiovascular disordersProstate cancerSARMs
Testosterone formulations have been available to patients since the 1930s, but have proven less than ideal. Conventional injectable testosterone esters are being used as testosterone replacement, but generate supraphysiological testosterone concentrations shortly after injection followed by a rapid decline, becoming subphysiological in the days before the next injection. These rapid fluctuations in plasma testosterone are subjectively experienced as disagreeable. Available since 2004, testosterone undecanoate is an injectable testosterone preparation with a considerably better pharmacokinetic profile. After two initial injections with a 6-week interval, the future intervals between injections are usually 12 weeks, amounting to a total of four injections per year. Plasma testosterone concentrations with this preparation are nearly always in the range of normal men, so are its metabolic products estradiol and dihydrotestosterone. Testosterone undecanoate, like other testosterone preparations, reverses the effects of hypogonadism on bone and muscle and significantly improves metabolic parameters and sexual functions, without the “roller coaster” effects of traditional testosterone injections. Other adverse effects, such as polycythemia and disturbed lipid profiles, have not been observed. Although some studies suggest a link between injectable testosterone and comorbidities such as prostate cancer, diabetes, and cardiovascular disease, conflicting data highlight the need for longer-term better controlled, randomized studies. Although testosterone undecanoate stands out as a valuable contribution to the treatment options of androgen deficiency, a number of alternative therapies such as selective androgen receptor modulators are under development proving, from preliminary studies, as competitive testosterone replacement options.
Testosterone has a steeply dose-dependent effect on muscle mass and strength irrespective of gonadal status. So, for reasons of fairness, people who engage in competitive sports should not administer exogenous testosterone raising their blood testosterone levels beyond the range of normal. There is a ban on exogenous androgens for men and women in sports, but an exception has been made for men with androgen deficiency due to pituitary or testicular disease. Men who receive testosterone administration for the indication hypogonadism have an interest in the use of testosterone preparations generating blood testosterone levels within the normal range of healthy, eugonadal men. On the grounds of a positive correlation between blood testosterone concentrations muscle and volume/strength, they are best served with a parenteral testosterone preparation, rather than transdermal testosterone, but they should not run the risk of being excluded from competition because of supraphysiological testosterone levels. The latter is a realistic risk with the traditional parenteral testosterone esters. The new parenteral testosterone undecanoate preparation offers much better perspectives. Its pharmacokinetics have been investigated in detail and there is a fair degree of predictability of resulting blood testosterone levels with use of this preparation.
The efficacy and safety of androgen supplementation in older men remains controversial. Despite biochemical evidence of partial androgen deficiency in older men, controlled studies using T demonstrate equivocal benefits. Furthermore, the importance of aromatization and 5alpha reduction in androgen actions among older men remains unclear. Dihydrotestosterone is the highest potency natural androgen with the additional features that it is neither aromatizable nor susceptible to potency amplification by 5alpha reduction. Therefore, the effects of dihydrotestosterone may differ from those of T in older men. This study evaluated the efficacy and safety of 3 months treatment with transdermal dihydrotestosterone gel on muscle strength, mobility, and quality of life in ambulant, community-dwelling men aged 60 yr or older. Eligible men (plasma T < or =15 nmol/liter) were randomized to undergo daily dermal application of 70 mg dihydrotestosterone gel (n = 18) or vehicle (n = 19) and were studied before, monthly during, and 1 month after treatment. Among 33 (17 dihydrotestosterone, 16 placebo) men completing the study with a high degree of compliance, dihydrotestosterone had significant effects on circulating hormones (increased dihydrotestosterone; decreased total and free testosterone, LH, and FSH; unchanged SHBG and estradiol), lipid profiles (decreased total and low-density lipoprotein cholesterols; unchanged high-density lipoprotein cholesterol and triglycerides), hematopoiesis (increased hemoglobin, hematocrit, and red cell counts), and body composition (decreased skinfold thickness and fat mass; unchanged lean mass and waist to hip ratio). Muscle strength measured by isokinetic peak torque was increased in flexion of the dominant knee but not in knee extension or shoulder contraction, nor was there any significant change in gait, balance, or mobility tests, in cognitive function, or in quality of life scales. Dihydrotestosterone treatment had no adverse effects on prostate (unchanged prostate volumes and prostate-specific antigen) and cardiovascular (no adverse change in vascular reactivity or lipids) safety markers. We conclude that 3 months treatment with transdermal dihydrotestosterone gel demonstrates expected androgenic effects, short-term safety, and limited improvement in lower limb muscle strength but no change in physical functioning or cognitive function.
The objective of the study was to investigate the effects of dihydrotestosterone (DHT) gel on general well-being, sexual function, and the prostate in aging men. A total of 120 men participated in this randomized, placebo-controlled study (60 DHT and 60 placebo). All subjects had nocturnal penile tumescence once per week or less, andropause symptoms, and a serum T level of 15 nmol/liter or less and/or a serum SHBG level greater than 30 nmol/liter. The mean age was 58 yr (range, 50-70 yr). Of these subjects, 114 men completed the study. DHT was administered transdermally for 6 months, and the dose varied from 125-250 mg/d. General well-being symptoms and sexual function were evaluated using a questionnaire, and prostate symptoms were evaluated using the International Prostate Symptoms Score, transrectal ultrasonography, and assay of serum prostate-specific antigen. Early morning erections improved transiently in the DHT group at 3 months of treatment (P < 0.003), and the ability to maintain erection improved in the DHT group compared with the placebo group (P < 0.04). No significant changes were observed in general well-being between the placebo and the DHT group. Serum concentrations of LH, FSH, E2, T, and SHBG decreased significantly during DHT treatment. Treatment with DHT did not affect liver function or the lipid profile. Hemoglobin concentrations increased from 146.0 +/- 8.2 to 154.8 +/- 11.4 g/liter, and hematocrit from 43.5 +/- 2.5% to 45.8 +/- 3.4% (P < 0.001). Prostate weight and prostate-specific antigen levels did not change during the treatment. No major adverse events were observed. Transdermal administration of DHT improves sexual function and may be a useful alternative for androgen replacement. As estrogens are thought to play a role in the pathogenesis of prostate hyperplasia, DHT may be beneficial, compared with aromatizing androgens, in the treatment of aging men.
A role for 5α-reduction in androgen physiology was first established with the recognition that dihydrotestosterone, the 5α-reduced metabolite of testosterone, is formed in many androgen target tissues, binds to the androgen receptor with greater affinity than testosterone, and plays an essential role in virilization of the urogenital sinus and urogenital tubercle during male development. Two 5α-reductases perform this reaction, and both isoenzymes utilize NADPH as cofactor and have broad specificity for steroids containing a Δ⁴, 3-keto configuration. 5α-Reduction, which is essentially irreversible, flattens the steroid molecule because of altered relation of the A and B rings, and stabilizes the hormone–receptor complex. Studies involving in vitro reporter gene assays and intact mice in which both isoenzymes are disrupted, indicate that the fundamental effect of dihydrotestosterone formation is to amplify hormonal signals that can be mediated by testosterone at higher concentrations. 5α-Reduction also plays a role in the action of other steroid hormones, including the plant growth hormone, brassinolide, the boar pheromones, androstanol and androstenol, progesterone (in some species), and, possibly, aldosterone and cortisol. The fact that the reaction is important in plants and animals implies a fundamental role in steroid hormone action.
This paper reports the result of an open-label, non-randomized clinical trial investigating the efficacy and safety of an injectable preparation of testosterone undecanoate (TU) dissolved in castor oil and given over a 3.2-year period. In a previous study we demonstrated that injections of TU every 6 weeks resulted in satisfactory substitution but a tendency toward testosterone accumulation. Here we investigate prolonged TU treatment at extended injection intervals in 7 hypogonadal men. Injections were given at gradually increasing intervals between the fifth and 10th injection, and from then on every 12 weeks. Steady state kinetics were obtained after the 13th injection. Well-being, sexual activity, clinical chemistry, prostate volume, and prostate-specific antigen (PSA) and serum hormone levels were monitored. Patients were clinically well-adjusted throughout the study. Before the next injection, testosterone, dihydrotestosterone, and estradiol levels were mostly within the normal range and showed a tendency to decrease with increasing injection intervals. Body weight, hemoglobin, serum lipids, PSA, and prostate volume did not change significantly during the 3.2 years of treatment. PSA levels were always within the normal limit. Maximal testosterone levels during steady state kinetics were measured after 1 week with 32.0 +/- 11.7 nmol/L (mean +/- SD). Before the last injection, mean testosterone concentrations were 12.6 +/- 3.7 nmol/L. Compared with conventional testosterone enanthate or cypionate treatment requiring injection intervals of 2-3 weeks and resulting in supraphysiological serum testosterone levels, injections of TU at intervals of up to 3 months offer an excellent alternative for substitution therapy of male hypogonadism.
Prostate safety is a primary concern when aging men receive testosterone replacement therapy (TRT), but little information is available regarding the effects of TRT on prostate tissue in men.
To determine the effects of TRT on prostate tissue of aging men with low serum testosterone levels.
Randomized, double-blind, placebo-controlled trial of 44 men, aged 44 to 78 years, with screening serum testosterone levels lower than 300 ng/dL (<10.4 nmol/L) and related symptoms, conducted at a US community-based research center between February 2003 and November 2004.
Participants were randomly assigned to receive 150 mg of testosterone enanthate or matching placebo intramuscularly every 2 weeks for 6 months.
The primary outcome measure was the 6-month change in prostate tissue androgen levels (testosterone and dihydrotestosterone). Secondary outcome measures included 6-month changes in prostate-related clinical features, histology, biomarkers, and epithelial cell gene expression.
Of the 44 men randomized, 40 had prostate biopsies performed both at baseline and at 6 months and qualified for per-protocol analysis (TRT, n = 21; placebo, n = 19). Testosterone replacement therapy increased serum testosterone levels to the mid-normal range (median at baseline, 282 ng/dL [9.8 nmol/L]; median at 6 months, 640 ng/dL [22.2 nmol/L]) with no significant change in serum testosterone levels in matched, placebo-treated men. However, median prostate tissue levels of testosterone (0.91 ng/g) and dihydrotestosterone (6.79 ng/g) did not change significantly in the TRT group. No treatment-related change was observed in prostate histology, tissue biomarkers (androgen receptor, Ki-67, CD34), gene expression (including AR, PSA, PAP2A, VEGF, NXK3, CLU [Clusterin]), or cancer incidence or severity. Treatment-related changes in prostate volume, serum prostate-specific antigen, voiding symptoms, and urinary flow were minor.
These preliminary data suggest that in aging men with late-onset hypogonadism, 6 months of TRT normalizes serum androgen levels but appears to have little effect on prostate tissue androgen levels and cellular functions. Establishment of prostate safety for large populations of older men undergoing longer duration of TRT requires further study. Trial Registration clinicaltrials.gov Identifier: NCT00161304.
OBJECTIVE
Testosterone (T) substitution of hypogonadal men by conventional intramuscular injection of T esters is not considered optimal because it induces unphysiologically fluctuating serum T levels. In contrast, scrotal T patches produce normal serum (T) levels mimicking diurnal variations. In order to assess the quality of this new form of T substitution we followed hypogonadal men treated by transdermal T up to 10 years.PATIENTSEleven men aged 35.9 ± 9.8 years (mean ± SD) at the beginning of the study were treated with transscrotal T patches (Testoderm®) because of primary (n = 4) or secondary (n = 7) hypogonadism. Clinical examinations were performed every 3 months during the first 5 years and every 6 months thereafter. All 11 patients were seen for 7 years and some for longer periods: eight for 8 years, six for 9 years and four for 10 years.MEASUREMENTS AND RESULTSWith daily application of one patch T levels rose from 5.3 ± 1.3 nmol/l (mean ± SE) to 16.7 ± 2.6 nmol/l at month 3 and remained in the normal range throughout treatment. Serum 5α-dihydrotestosterone (DHT) rose from 1.3 ± 0.4 nmol/l to 3.9 ± 1.4 nmol/l and oestradiol from 52.3 ± 9.3 to 71.3 ± 9.6 pmol/l and remained stable without significant variations throughout the observation period. Patients reported absence of local side-effects except for occasional itching. No relevant changes occurred in clinical chemistry, including total cholesterol levels and triglycerides. Haemoglobin and erythrocyte counts remained normal. Bone density measured by QCT increased slightly from 113.6 ± 5.4 to 129.7 ± 9.3 mg/cm3 during the observation period (P = 0.028). In the nine patients aged < 50 years prostate volumes showed a small but insignificant increase from 16.8 ± 1.5 to 18.8 ± 2.1 ml during transscrotal T therapy. In the two older patients prostate volume remained constant or decreased slightly during T therapy after an initial increase in the previously untreated patient. Prostate specific antigen levels were constantly low in all patients.CONCLUSION
Transscrotal testosterone patches are well-accepted and safe in long-term testosterone substitution therapy for male hypogonadism.
Male ageing coincides on average with progressive impairment of testicular function. The most striking plasma changes are an increase in sex hormone binding globulin (SHBG) and a decrease in non SHBG-bound testosterone, which is the only testosterone subfraction effectively bioavailable for target tissues. In healthy subjects the bioavailable testosterone declines by approximately 1% per year between 40 and 70 years but a more pronounced decline has been observed in non-healthy groups, especially in high cardiovascular risks groups. Relative androgen deficiency is likely to have unfavourable consequences on muscle, adipose tissue, bone, haematopoiesis, fibrinolysis, insulin sensitivity, central nervous system, mood and sexual function and might be treated by an appropriate androgen supplementation. The potential risk for prostate has been the main reason for limiting indications of such treatment. Testosterone (T) and dihydrotestosterone (DHT) are two potent androgens which have opposite effects regarding aromatase activity, an enzyme present in prostate stroma and suspected to have a pathogenic influence through local oestradiol synthesis. T is the main substrate for aromatase and oestradiol synthesis while DHT is not aromatizable and, at sufficient concentration, decreases T and oestradiol levels. A 1.8 years survey of 37 men aged 55-70 years treated with daily percutaneous DHT treatment suggested that high plasma levels of DHT (> 8.5 nmol/l) effectively induced clinical benefits while slightly but significantly reducing prostate size. Early stages of prostate hypertrophy require synergic stimulation by both DHT and oestradiol, and suppressing oestradiol instead of DHT seems easier and better adapted to the specific situation of aged hypogonadic men.(ABSTRACT TRUNCATED AT 250 WORDS)
Androgen action differs from that of most hormones in the testosterone, the major androgen secreted from the testes and the most abundant androgen in the circulation of men, is not the principal androgen within target cells. Indeed, abundant evidence indicates that most androgen actions are mediated by the 5alpha-reduced metabolite dihydrotestosterone that is formed in target tissues. The conversion of testosterone to dihydrotestosterone is mediated by two isoenzymes; mutations in the steroid 5alpha-reductase 2 gene cause a rare autosomal-recessive form of male pseudohermaphroditism, and inhibition of this enzyme causes regression of the prostate gland. Dihydrotestosterone binds more tightly to the androgen receptor that does testosterone, but it is not clear whether this property is the sole explanation for its essential role in androgen action. Nor is it clear whether some androgenic effects may be mediated by circulating dihydrotestosterone acting as a hormone.
The pharmacokinetics, efficacy, and safety of the Androderm testosterone (T) transdermal system (TTD) and intramuscular T enanthate injections (IM) for the treatment of male hypogonadism were compared in a 24-week multicenter, randomized, parallel-group study. Sixty-six adult hypogonadal men (22–65 years of age) were withdrawn from prior IM treatment for 4–6 weeks and then randomly assigned to treatment with TTD (two 2.5-mg systems applied nightly) or IM (200 mg injected every 2 weeks); there were 33 patients per group. Twenty-six patients in the TTD group and 32 in the IM group completed the study.
TTD treatment produced circadian variations in the levels of total T, bioavailable T, dihydrotestosterone, and estradiol within the normal physiological ranges. IM treatment produced supraphysiological levels of T, bioavailable T, and estradiol (but not dihydrotestosterone) for several days after each injection. Mean morning sex hormone levels were within the normal range in greater proportions of TTD patients (range, 77–100%) than IM patients (range, 19–84%). Both treatments normalized LH levels in approximately 50% of patients with primary hypogonadism; however, LH levels were suppressed to the subnormal range in 31% of IM patients vs. 0% of TTD patients. Both treatments maintained sexual function (assessed by questionnaire and Rigiscan) and mood (Beck Depression Inventory) at the prior treatment levels.
Prostate-specific antigen levels, prostate volumes, and lipid and serum chemistry parameters were comparable in both treatment groups. Transient skin irritation from the patches was reported by 60% of the TTD patients, but caused only three patients (9%) to discontinue treatment. IM treatment produced local reactions in 33% of patients and was associated with significantly more abnormal hematocrit elevations (43.8% of patients) compared with TTD treatment (15.4% of patients). Gynecomastia resolved more frequently during TTD treatment (4 of 10 patients) than with IM treatment (1 of 9 patients).
Although both treatments seem to be efficacious for replacing T in hypogonadal men, the more physiological sex hormone levels and profiles associated with TTD may offer possible advantages over IM in minimizing excessive stimulation of erythropoiesis, preventing/ameliorating gynecomastia, and not over-suppressing gonadotropins.
The relative abundance and physiological role of 5alpha-reductase (5alphaR) isoforms in rat testis, in particular 5alpha-reductase Type 2 (5alphaR2) are poorly understood. Investigation of 5alphaR2 activity using enzyme kinetic studies was hampered by the high concentrations of 5alpha-reductase Type 1 (5alphaR1) in rat testis. Therefore, an assay was developed which exploited the differences in pH optima of the two isoforms. The 5alphaR assays measured the conversion of 3[H]-testosterone to 5alpha-reduced metabolites (dihydrotestosterone+3alpha-Androstanediol) at pH 5.0 and 7.0. To compensate for the overlap of 5alphaR1 activity at pH 5.0, the amount of 5alphaR1 activity at pH 5.0 was determined by measuring recombinant rat 5alphaR1 expressed in COS-7 cells at pH 5.0 and 7.0. The amount of activity at pH 5.0 that was attributed to 5alphaR1 was determined to be 12.4+/-1.4% (mean+/-S.D., n=14). The 5alphaR2 assay was validated by determining recombinant rat 5alphaR2 activity in the presence of recombinant rat 5alphaR1 activity in COS cells. A 99.3+/-14.7% recovery of 5alphaR2 activity was obtained when comparing 5alphaR2 activity recovered versus activity added. 5alphaR1 and 5alphaR2 activities were then assayed in rat testis extracts from 30, 75 and 147 days. Both isoforms markedly declined (50-100-fold) over this age range, with 5alphaR1 as the predominant isoform. In conclusion, an enzymatic assay that detects 5alphaR2 activity in the presence of high concentrations of 5alphaR1 was developed and is applicable in the measurement of 5alphaR2 activity in rat testis.
The major goal of androgen substitution is to replace testosterone at levels as close to physiological levels as is possible. For some androgen-dependent functions testosterone is a pro-hormone, peripherally converted to 5alpha-dihydrotestosterone (DHT) and 17beta-estradiol (E2), of which the levels preferably should be within normal physiological ranges. Furthermore, androgens should have a good safety profile without adverse effects on the prostate, serum lipids, liver or respiratory function, and they must be convenient to use and patient-friendly, with a relative independence from medical services. Natural testosterone is viewed as the best androgen for substitution in hypogonadal men. The reason behind the selection is that testosterone can be converted to DHT and E2, thus developing the full spectrum of testosterone activities in long-term substitution. The mainstays of testosterone substitution are parenteral testosterone esters (testosterone enantate and testosterone cipionate) administered every 2-3 weeks. A major disadvantage is the strongly fluctuating levels of plasma testosterone, which are not in the physiological range at least 50% of the time. Also, the generated plasma E2 is usually supraphysiological. A major improvement is parenteral testosterone undecanoate producing normal plasma levels of testosterone for 12 weeks, with normal plasma levels of DHT and E2 also. Subcutaneous testosterone implants provide the patient, depending on the dose of implants, with normal plasma testosterone for 3-6 months. However, their use is not widespread. Oral testosterone undecanoate dissolved in castor oil bypasses the liver via its lymphatic absorption. At a dosage of 80 mg twice daily, plasma testosterone levels are largely in the normal range, but plasma DHT tends to be elevated. For two decades transdermal testosterone preparations have been available and have an attractive pharmacokinetic profile. Scrotal testosterone patches generate supraphysiological plasma DHT levels, which is not the case with the nonscrotal testosterone patches. Transdermal testosterone gel produces fewer skin irritations than the patches and offers greater flexibility in dosage. Oromucosal testosterone preparations have recently become available. Testosterone replacement is usually of long duration and so patient compliance is of utmost importance. Therefore, the patient must be involved in the selection of type of testosterone preparation. Administration of testosterone to young individuals has almost no adverse effects. With increasing age the risk of adverse effects on the prostate, the cardiovascular system and erythropoiesis increases. Consequently, short-acting testosterone preparations are better suited for aging androgen-deficient men.
Chemoprevention may significantly impact the natural history of prostate cancer. The most potent intraprostatic androgen, dihydrotestosterone, has a significant role in the pathophysiology of prostate cancer. It represents a biologically plausible target for chemoprevention through the inhibition of 5alpha-reductase isoenzymes.
The Reduction by Dutasteride of Prostate Cancer Events clinical trial is an international, multicenter, double-blind, placebo controlled chemoprevention study designed to determine if dutasteride 0.5 mg daily decreases the risk of biopsy detectable prostate cancer. A total of 8,000 men will be randomized to receive dutasteride or placebo for 4 years. Eligible men must be 50 to 75 years old, have a serum prostate specific antigen of 2.5 to 10 ng/ml (ages 50 to 60 years) or 3.0 to 10 ng/ml (older than 60 years). Men must have a negative 6 to 12 core biopsy within 6 months prior to enrollment. Repeat biopsies will be taken at 2 and 4 years. The rates of prostate cancer for each treatment group will be compared. Genetic and protein biomarkers of prostate cancer, and the effect of dutasteride on benign prostatic hyperplasia and prostatitis symptomatology and histopathology will also be assessed.
Results remain to be determined.
The study will examine the effects of the dual 5alpha-reductase inhibitor dutasteride on the natural history of prostate cancer in men at increased risk for this malignancy. It affords a unique opportunity to examine biomarkers and genetic linkage for prostate cancer, and assess a range of prostate health outcome measures.
The number of men in the United States > or =65 years of age is projected to increase from 14,452,000 in 2000 to 31,343,000 in 2030. Approximately 30% of men 60-70 years of age and 70% of men 70-80 years of age have low bioavailable or free testosterone levels. Symptoms and findings of testosterone deficiency are similar to those associated with aging. They include loss of energy, depressed mood, decreased libido, erectile dysfunction, decreased muscle mass and strength, increased fat mass, frailty, osteopenia, and osteoporosis. Several small clinical trials indicate that testosterone replacement therapy can improve many of these findings; however, the studies have not been powered to assess potential risks, such as the need for invasive treatment of benign prostatic hyperplasia, development of a clinical prostate cancer, or cardiovascular events. Thus, the benefit/risk ratio of testosterone replacement therapy in aging men is not known.