Plasma androgen levels in men after oral administration of testosterone or testosterone undecanoate.

Plasma testosterone and androstenedione levels in men were measured after oral administration of free testosterone and testosterone undecanoate. Both androgens were determined by simultaneous, specific radioimmunoassays after separation and isolation by thin layer chromatography. While free unesterified testosterone had no effect on plasma androgen levels, a striking increase of both testosterone and androstenedione levels was noted after administration of testosterone undecanoate, which is otherwise only achieved by parenteral testosterone application. This effect of testosterone undecanoate is probably due to absorption via the lymph rather than via the portal vessels so that peripheral circulation is reached before metabolism in the liver. Testosterone undecanoate promises to be an effective medication for oral androgen replacement.     

Repeated intramuscular injections of testosterone undecanoate for substitution therapy in hypogonadal men

OBJECTIVE: To investigate the suitability of intramuscular testosterone undecanoate (TU) injections for substitution therapy in hypogonadal men. STUDY DESIGN: Clinical, open-label, non-randomized trial of 13 hypogonadal men receiving 4 intramuscular injections of 1000 mg TU in 4-ml castor oil at 6-week intervals. General wellbeing, sexual parameters, clinical chemistry, hormone levels, prostate size and prostate-specific antigen (PSA) were evaluated over 24 weeks and compared with baseline values. RESULTS: Testosterone serum levels were never found below the lower limit of normal and only briefly after the 3rd and 4th injection above the upper limit of normal, while peak and trough values increased over the 24-week observation period. Oestradiol and dihydrotestosterone followed this pattern, not exceeding the normal limits. No serious side-effects were noted. Slight increases in body weight, haemoglobin, haematocrit, prostate volume and PSA, suppression of gonadotrophins as well as increased ejaculation frequency occurred as signs of adequate testosterone substitution. CONCLUSION: Testosterone undecanoate is well tolerated by the patients. The injection intervals can be extended even beyond the 6-week periods chosen in the present study. Altogether, intramuscular testosterone undecanoate appears to be well suited for long-term substitution therapy in hypogonadism and hormonal male contraception.     

Changes in the bioactivity to immunoreactivity ratio of circulating luteinizing hormone in impotent men treated with testosterone undecanoate

Testosterone undecanoate was administered orally (80 mg twice daily) for 30 days to 10 impotent men with mild Leydig cell failure, age 28 to 42 years. Placebo was administered for 30 days both before and at the end of testosterone undecanoate therapy. Serum levels of bioactive LH, immunoreactive LH and testosterone were determined in basal conditions (day zero), 30 days after the first placebo administration, at the 15th and 30th day of testosterone undecanoate therapy, and at the end of the second treatment with placebo (90th day). Bioactive LH was measured by a sensitive and specific in vitro bioassay based on testosterone production by mechanically dispersed mouse Leydig cell preparations. Immunoreactive LH and testosterone were determined by a double-antibody RIA technique. The results were compared with those obtained in 30 untreated normal young men. In the basal state, serum concentrations of immunoreactive LH were significantly higher in the patients (P less than 0.02) than in control subjects, whereas testosterone levels were significantly lower (P less than 0.001) in the impotent men. In contrast, bioactive LH levels and the bioactive LH to immunoreactive LH ratios were similar in the two groups. In the patients, at the 15th day of treatment with testosterone undecanoate, serum levels of testosterone and bioactive LH were significantly higher (P less than 0.01) than basal values, whereas immunoreactive LH concentrations showed no significant changes. Consequently, the bioactive LH to immunoreactive LH ratios rose significantly (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Physiological testosterone replacement and arterial endothelial function in men

OBJECTIVE: The vascular effects of fluctuations in testosterone levels within the physiological range in otherwise healthy men are not known. We therefore aimed to study arterial function in hypogonadal men receiving long-term physiological androgen replacement therapy, at trough and peak testosterone levels. PATIENTS AND DESIGN: We recruited nine hypogonadal men (aged 35 +/- 4 years) receiving androgen replacement therapy, each treated with 800 mg testosterone (T) depot preparations every 6 months. MEASUREMENTS: Serum lipid and hormone levels and arterial reactivity were measured, prior to (trough T) and 2-4 weeks following testosterone administration (peak T). Each subject therefore served as their own control. Vessel diameter was measured by ultrasound at rest, during reactive hyperaemia [leading to flow-mediated dilatation (FMD), an endothelium-dependent response] and after sublingual nitroglycerin (GTN, an endothelium-independent dilator). RESULTS: Serum T (13 +/- 2 nmvs. 27 +/- 3 nm for trough and peak serum T, respectively, P < 0.001; normal adult male range 11-35 nm), and free T (195 +/- 23 pmvs. 510 +/- 93 pm, P < 0.005) significantly increased following subcutaneous depot T administration, as did serum oestradiol (100 +/- 10 pmvs. 175 +/- 9 pm, P = 0.001; normal adult male range < 250 pm). There was a significant decrease in FMD (3.6 +/- 1.1%vs. 3.0 +/- 0.8%, P < 0.01), but GTN responses were similar (9.5 +/- 0.8%vs. 10.4 +/- 1.0%, P > 0.2). Lipid, blood pressure and vessel diameter measurements were also similar before and after testosterone administration. CONCLUSION: Physiological replacement of testosterone is associated with decreased endothelium-dependent dilatation, in hypogonadal men.     

Androgen therapy of hypogonadal men with transscrotal testosterone systems

The need for improved controlled delivery of testosterone to hypogonadal men stimulated the development of a self-adherent transscrotal testosterone system to provide programmed testosterone delivery through the uniquely permeable scrotal skin. In this short- and long-term efficacy trial, the responses of testosterone and its metabolites to the application of transscrotal testosterone systems of varying testosterone content were compared with the response to 200 mg of testosterone enanthate. Daily transscrotal testosterone system administration resulted in a rapid increase of testosterone and bioavailable, non-sex hormone binding globulin-bound testosterone levels to normal, peaking at two hours, followed by a slow decline over 23 hours, resembling the diurnal variation of endogenous testosterone. One year of daily transscrotal testosterone system therapy demonstrated continued reliable absorption of testosterone and suppression to normal of the luteinizing hormone in two of three patients. There was a greatly disproportionate increase of serum dihydrotestosterone over testosterone, suggesting 5-alpha reduction at the scrotal site. The subjects reported marked subjective improvement. Thus, the transscrotal testosterone system is a novel, effective, and well-tolerated method of delivering testosterone to hypogonadal patients.     

Effects of testosterone replacement in hypogonadal men

Treatment of hypogonadal men with testosterone has been shown to ameliorate the effects of testosterone deficiency on bone, muscle, erythropoiesis, and the prostate. Most previous studies, however, have employed somewhat pharmacological doses of testosterone esters, which could result in exaggerated effects, and/or have been of relatively short duration or employed previously treated men, which could result in dampened effects. The goal of this study was to determine the magnitude and time course of the effects of physiological testosterone replacement for 3 yr on bone density, muscle mass and strength, erythropoiesis, prostate volume, energy, sexual function, and lipids in previously untreated hypogonadal men. We selected 18 men who were hypogonadal (mean serum testosterone +/- SD, 78 +/- 77 ng/dL; 2.7 +/- 2.7 nmol/L) due to organic disease and had never previously been treated for hypogonadism. We treated them with testosterone transdermally for 3 yr. Sixteen men completed 12 months of the protocol, and 14 men completed 36 months. The mean serum testosterone concentration reached the normal range by 3 months of treatment and remained there for the duration of treatment. Bone mineral density of the lumbar spine (L2-L4) increased by 7.7 +/- 7.6% (P < 0.001), and that of the femoral trochanter increased by 4.0 +/- 5.4% (P = 0.02); both reached maximum values by 24 months. Fat-free mass increased 3.1 kg (P = 0.004), and fat-free mass of the arms and legs individually increased, principally within the first 6 months. The decrease in fat mass was not statistically significant. Strength of knee flexion and extension did not change. Hematocrit increased dramatically, from mildly anemic (38.0 +/- 3.0%) to midnormal (43.1 +/- 4.0%; P = 0.002) within 3 months, and remained at that level for the duration of treatment. Prostate volume also increased dramatically, from subnormal (12.0 +/- 6.0 mL) before treatment to normal (22.4 +/- 8.4 mL; P = 0.004), principally during the first 6 months. Self-reported sense of energy (49 +/- 19% to 66 +/- 24%; P = 0.01) and sexual function (24 +/- 20% to 66 +/- 24%; P < 0.001) also increased, principally within the first 3 months. Lipids did not change. We conclude from this study that replacing testosterone in hypogonadal men increases bone mineral density of the spine and hip, fat-free mass, prostate volume, erythropoiesis, energy, and sexual function. The full effect of testosterone on bone mineral density took 24 months, but the full effects on the other tissues took only 3-6 months. These results provide the basis for monitoring the magnitude and the time course of the effects of testosterone replacement in hypogonadal men.     

Treatment of primary hypogonadism in men by the transdermal administration of testosterone

We tested the efficacy of a thin flexible testosterone-impregnated membrane applied to the scrotum for the long term treatment of male hypogonadism. Ten men with primary hypogonadism were treated for 3 months (2 men) or 13 months (8 men). Serum testosterone concentrations increased in all 10 men, to within the normal range in 8. Serum dihydrotestosterone concentrations increased to supranormal values in all of the men, decreased to the normal range in 6, indicating the biological effectiveness of the testosterone in those subjects. Two men whose serum LH concentrations did not fall to normal had small or distorted scrotal surfaces. Seven of the 8 men whose serum testosterone concentrations became normal said that their hypogonadal symptoms were corrected by this treatment. We conclude that the transdermal administration of testosterone is an effective means of treating the majority of hypogonadal men who have a normal scrotum.     

Intramuscular injection of testosterone undecanoate for the treatment of male hypogonadism: phase I studies

OBJECTIVE: In the search for long-acting testosterone preparations suited for substitution therapy of hypogonadal men, testosterone undecanoate (TU) dissolved in either tea seed oil or castor oil was investigated. DESIGN: In study I, 1000 mg TU in tea seed oil (125 mg/ml) were injected in equal parts into the gluteal muscles of seven hypogonadal men. In study II, 1000 mg TU in castor oil (250 mg/ml) were injected into one gluteal muscle of 14 patients. RESULTS: In comparison with published data on testosterone enanthate, most widely used for i.m. injections, the kinetic profiles of both TU preparations showed extended half-lives and serum levels not exceeding the upper limit of normal. The castor oil preparation had a longer half-life than TU in tea seed oil (33.9+/-4.9 vs 20.9+/-6.0 days (mean pm S.E.M.)). CONCLUSION: The longer half-life and the smaller injection volume make TU in castor oil a strong candidate for further applications in substitution therapy and in trials for male contraception.     

A biodegradable testosterone microcapsule formulation provides uniform eugonadal levels of testosterone for 10-11 weeks in hypogonadal men.

Limitations of presently available testosterone esters (enanthate and cypionate) include the fluctuating serum testosterone levels and the need for relatively frequent injections (every 10-21 days). These limitations of testosterone esters have prompted the development of more physiological and longer acting systems for androgen delivery. This paper reports pharmacokinetic and pharmacodynamic data with a second generation long-acting testosterone microcapsule formulation in hypogonadal men. This was a single dose, open label, nonrandomized study. Ten hypogonadal men with primary (n = 6) or secondary (n = 4) hypogonadism, otherwise in good health, received 630 mg microencapsulated testosterone in dextran solution (IM) on day 1. Serum total and free testosterone; LH; FSH; dihydrotesterone; estradiol; sex hormone-binding globulin; total cholesterol; high, low, and very low density lipoprotein cholesterol; triglycerides; and apoprotein-AII and -B were measured on multiple occasions during the 2-week control period and the 16-week treatment period. In addition, on days 0, 1, 28, 56, and 84, subjects were hospitalized for detailed hormone analyses over the 24-h period. Serum total and free testosterone levels rose quickly into the midnormal range and stayed uniformly in the eugonadal range for about 70-77 days, after which serum testosterone levels declined gradually into the hypogonadal range. Testosterone release from the microcapsule formulation over the first 10 weeks approximated zero order kinetics. Serum dihydrotestosterone levels rose into the normal range, and testosterone to dihydrotestosterone ratios remained in the physiological range. Serum estradiol levels rose and stayed in the midnormal male range. Serum sex hormone-binding globulin levels decreased significantly during treatment. Serum LH and FSH levels also significantly decreased in the six hypergonadotropic men. Total cholesterol low and very low density lipoprotein cholesterol and triglyceride levels did not change, but plasma high density lipoprotein cholesterol levels decreased significantly during treatment. These data indicate that testosterone microcapsule formulation provides uniform eugonadal levels of testosterone for about 10 weeks. The long duration and zero order kinetics make it an attractive alternative to existing methods of androgen replacement.     

WHICH TESTOSTERONE REPLACEMENT THERAPY?

Three different forms of testosterone (T) replacement therapy were compared; they were the intramuscular injection of mixed testosterone esters 250 mg; the subcutaneous implantation of 6 X 100 mg pellets of fused testosterone; and the oral administration of testosterone undecanoate (TU) 80 mg twice daily. Six hypogonadal males were treated with oral TU for an eight week period, during which time serial serum hormonal estimations were performed over 10 h at the initiation and after four and eight weeks of therapy. Serum T levels showed marked variability both between subjects and within the same subject on different occasions. We attribute this to variability in absorption of TU, which is formulated in oleic acid. The overall mean T level calculated from the areas under the profiles of TU was 12.0 nmol/l. Hormone responses to injected T esters were studied in nine hypogonadal males. Serum T rose to supraphysiological peak concentrations (mean 71 nmol/l) 24-48 h after an injection, followed by an exponential decay to reach baseline concentrations after 2-3 weeks. The overall calculated mean T level in subjects receiving testosterone esters 250 mg every three weeks was 27.7 nmol/l. Subcutaneous implantation of testosterone in six hypogonadal men produced a gradual rise in serum T followed by a slow decline, with T levels remaining within the normal range for 4-5 months. The calculated overall mean T level over 21 weeks after implantation was 17.0 nmol/l. Serum oestradiol (E2) levels remained within the normal male range throughout the study periods on both TU and T implant therapy but showed a supraphysiological peak (mean 347 pmol/l) 24-48 h after a T injection. 5 alpha-dihydrotestosterone (DHT) levels appeared to parallel those of T on the three forms of therapy, with DHT:T ratios being highest for TU therapy. This was also true for the target organ metabolite 5 alpha-androstane-3 alpha,17 beta-diol. At the doses studied drug costs were similar for T implantation (every 5 months) and T ester injections (every 3 weeks), but were 7-8 times higher for TU (80 mg twice a day). We conclude that T implantation remains overall the most physiological form of androgen replacement therapy, is generally well accepted and attended by few side effects; TU may have a useful role in the initial phases of therapy.     

Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low-normal gonadal status

BACKGROUND: Loss of muscle mass (sarcopenia) leads to frailty in older men. The decline in testosterone over the life span may contribute to this muscle loss. We studied the ability of oral testosterone to prevent muscle loss in older men over a 12-month period. METHODS: A standard dose (80 mg twice daily) of testosterone undecanoate or placebo was administered for 1 year to 76 healthy men aged 60 years or older. All men had a free testosterone index of 0.3-0.5, which represents a value below the normal lower limit for young men (19-30 years), but remains within the overall normal male range. Measurements of body composition, muscle strength, hormones, and safety parameters were obtained at 0, 6, and 12 months. RESULTS: Lean body mass increased (p =.0001) and fat mass decreased (p =.02) in the testosterone as compared with the placebo-treated group. There were no significant effects on muscle strength. There was a significant increase in hematocrit (0.02%) in the testosterone-treated group (p =.03). Plasma triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels were similar in both groups, but there was a decrease in high-density lipoprotein cholesterol (-0.1 mmol/L) at 12 months in the testosterone group as compared to the placebo group (p = 0.026). There were no differences in prostate-specific antigen or systolic or diastolic blood pressure between the groups. CONCLUSION: Oral testosterone administration to older relatively hypogonadal men results in an increase in muscle mass and a decrease in body fat.     

Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls

OBJECTIVE The potential use of testosterone preparations for substitution therapy for ageing men and for male contraception, In addition to the well established substitution therapy of male hypogonadism, make increased testosterone use likely. However, little clinical information is available on the effect of testosterone therapy on the prostate in hypogonadal men. DESIGN AND MEASUREMENTS In a controlled cross-sectional study, prostate volume measured by transrectal ultrasonography, serum levels of prostate-specific antigen (PSA) and sex hormones, and uroflow parameters were determined. PATIENTS Three groups of age-matched men were enrolled in the study: 47 newly diagnosed hypogonadal men before testosterone treatment, 78 hypogonadal men with at least 6 months of effective testosterone therapy and 75 normal men. RESULTS Regression analysis revealed a significant positive correlation of prostate volume with age in normal men and testosterone-treated hypogonadal men, whereas no significant correlation was detected in untreated hypogonadal men. Prostate volume was significantly lower in untreated hypogonadal men (12.2 (11.0–13.5) ml) (mean (95% confidence limits)) compared to both other groups. However, no significant difference in prostate volume was detected between testosterone-treated hypogonadal men (21.3 (19.9–22.8) ml) and normal men (22.9 (21.4–24.4) ml). Similar results were obtained for PSA with comparable values in the testosterone-treated hypogonadal men (0.98 (0.88–1.10) μg/l) and normal men (1.02 (0.91–1.14) μg/l), and significantly lower concentrations in the untreated hypogonadal men (0.64 (0.55–0.73) μg/l). No differences in uroflow parameters were detected between the three study groups. CONCLUSIONS Effective testosterone treatment of hypogonadal men results in prostate volume and prostate-specific antigen levels comparable to age-matched normal men. Therefore, testosterone-induced prostate growth should not preclude hypogonadal men from testosterone substitution therapy.     

Pharmacokinetics of a transdermal testosterone system in men with end stage renal disease receiving maintenance hemodialysis and healthy hypogonadal men

Androgen deficiency is common in men with end stage renal disease (ESRD) on maintenance hemodialysis. Pharmacokinetics of transdermal testosterone in men receiving maintenance hemodialysis have not been studied. Our objective was to compare the pharmacokinetics of a transdermal testosterone system in healthy hypogonadal men and in men with ESRD on maintenance hemodialysis. We recruited 10 healthy hypogonadal men and 8 medically stable men on maintenance hemodialysis, 18--70 yr old, who had serum testosterone less than 300 ng/dL. After baseline sampling during a 24-h control period, two testosterone patches were applied daily for 28 days, to achieve a nominal delivery of 10-mg testosterone daily. In addition to single, pooled samples on days 7, 14, and 21, blood was drawn at 0, 2, 4, 6, 8, and 24 h on day 28 in healthy hypogonadal men and on an interdialytic day (day 21 or 28) as well as a dialysis day (day 21 or 28) in men on hemodialysis. On the dialysis day (day 21 or 28), serum free and total testosterone levels were measured hourly for 4 h before hemodialysis and for 4 h during hemodialysis. The dialysate was sampled for testosterone measurement. Baseline mean + SD total (92 +/- 82 vs. 222 +/- 50 ng/dL) and free (11 +/- 9 vs. 27 +/- 6 pg/mL) testosterone concentrations were lower in healthy hypogonadal men than in men with ESRD. After application of two testosterone patches, serum total and free testosterone concentrations rose into the midnormal range in both groups of men. Time-average, steady state (total testosterone, 506 +/- 88 vs. 516 +/- 86 ng/dL; free testosterone, 55 +/- 9 vs. 67 +/- 11 pg/mL), minimum, and maximum total and free testosterone concentrations were not significantly different between the two groups of men during treatment. Increments in total and free testosterone concentrations above baseline, baseline-subtracted areas under the total and free testosterone curves, and half-life of testosterone elimination (t(1/2), 2.1 +/- 0.1 vs. 2.1 +/- 0.2 h, P = not significant) were not significantly different between the two groups. In men receiving hemodialysis, time-average, steady state, and maximal total and free testosterone concentrations and baseline-subtracted areas under the total and free testosterone curves were higher on dialysis day than on an interdialytic day. On the day of hemodialysis, time-average total and free testosterone concentrations were not significantly different during the 4 h before or during hemodialysis. The amount of testosterone removed in the dialysate (8.4 +/- 1.6 microg during 4 h of hemodialysis) was small compared with the daily testosterone production rates in healthy young men. Serum dihydrotestosterone and estradiol concentrations increased into the normal male range and were not significantly different between the two groups. Percent suppression of LH was greater in men with ESRD than in healthy hypogonadal men. A regimen of two Testoderm TTS testosterone patches (Alza Corp., Mountain View, CA) daily can maintain serum concentrations of total and free testosterone and its metabolites dihydrotestosterone and estradiol in the midnormal range in healthy hypogonadal men and men on hemodialysis. The amount of testosterone cleared by hemodialysis is small, and hemodialysis does not significantly affect serum total and free testosterone concentrations in men treated with the testosterone patch.     

Transdermal testosterone therapy in the treatment of male hypogonadism

Five hypogonadal men were treated with transdermal testosterone therapy, using a testosterone patch applied to the scrotal skin. Daily application of the patch, which contained 10 mg testosterone, produced an increase in serum testosterone concentrations from a pretreatment value of 45 +/- 12 (+/- SE; 1.5 +/- 0.4) to 436 +/- 80 ng/dL (15.1 +/- 2.8 nmol/L; P less than 0.001) after 4 weeks of treatment. Normal serum testosterone concentrations were achieved in all men after 6-8 weeks of therapy and were maintained during continued long term therapy for 9-12 months with a patch containing 15 mg testosterone. All men reported a subjective increase in libido and sexual function during therapy, and three men preferred it to testosterone injections. The serum testosterone and estradiol levels did not rise above the normal adult male range at any time during therapy. However, elevated serum dihydrotestosterone (DHT) concentrations occurred during treatment; the pretreatment DHT concentration was 95 +/- 3 ng/dL (3.3 +/- 0.1 nmol/L), and it increased to 228 +/- 40 ng/dL (7.8 +/- 1.4 nmol/L) after 4 weeks of treatment and remained elevated thereafter. The individual mean DHT to testosterone ratio increased from a pretreatment value of 0.2 (range, 0.1-0.3) to 0.6 (range, 0.4-0.7) after 2 weeks of therapy and remained high thereafter. Comparison of the serum DHT levels in patients during therapy with those in normal men who had similar testosterone concentrations [531 +/- 62 vs. 566 +/- 72 ng/dL (18.4 +/- 2.1 vs. 19.6 +/- 2.5 nmol/L); P greater than 0.05] revealed that the mean serum DHT concentration was significantly higher in the patients [315 +/- 69 vs. 87 +/- 6 ng/dL (10.8 +/- 2.4 vs. 2.9 +/- 0.2 nmol/L); P less than 0.001], as was the mean DHT to testosterone ratio [0.6 (range, 0.25- 1.1) vs. 0.16 (range, 0.09- 0.24); P less than 0.001]. The high serum DHT levels presumably were due to increased metabolism of testosterone to DHT by the 5 alpha-reductase in the scrotal skin. Serum 3 alpha-androstanediol glucuronide levels were not elevated in the patients. We conclude that transdermal testosterone therapy is an effective long term treatment for hypogonadism in men. It is, however, associated with high serum DHT levels, whose potential long term effects on the prostate and other tissues need to be investigated.     

Intramuscular testosterone undecanoate: pharmacokinetic aspects of a novel testosterone formulation during long-term treatment of men with hypogonadism

In an open-label, randomized, prospective trial, we investigated pharmacokinetics and several efficacy and safety parameters of a novel, long-acting testosterone (T) undecanoate (TU) formulation in 40 hypogonadal men (serum testosterone concentrations < 5 nmol/liter). For the first 30 wk (comparative study), the patients were randomly assigned to receive either 10 x 250 mg T enanthate (TE) im every 3 wk (n = 20) or 3 x 1000 mg TU im every 6 wk (loading dose) followed by 1 x 1000 mg after an additional 9 wk (n = 20). In a follow-up study, observation continued in those patients who completed the comparative part and opted for TU treatment (8 x 1000 mg TU every 12 wk in former TU patients and 2 x 1000 mg TU every 8 wk plus 6 x 1000 mg every 12 wk in former TE patients) for an additional 20-21 months. Here we report only the pharmacokinetic aspects of the new TU formulation for the first approximately 2.5 yr of treatment. At baseline, serum T concentrations did not significantly differ between the two study groups. In the TE group, mean trough levels of serum T were always less than 10 nmol/liter before the next injection, whereas in the TU group, mean trough levels of serum T were 14.1 +/- 4.5 nmol/liter after the first two doses (6-wk intervals) and 16.3 +/- 5.7 nmol/liter after the 9-wk interval at wk 30. The mean serum levels of dihydrotestosterone and estradiol also increased in parallel to the serum T pattern and remained within the normal range. In the follow-up study, the former TU patients (n = 20) received eight TU injections at 12-wk intervals, and the TE patients (n = 16) switched to TU and initially received two TU injections at 8-wk intervals (loading) and continued with six TU injections at 12-wk intervals (maintenance). This regimen resulted in stable mean serum trough levels of T (ranging from 14.9 +/- 5.2 to 16.5 +/- 8.0 nmol/liter) and estradiol (ranging from 98.5 +/- 45.2 to 80.4 +/- 14.4 pmol/liter). The present study has shown that 1000 mg TU injected into male patients with hypogonadism at 12-wk intervals is well tolerated and leads to T levels within normal ranges, using four instead of 17 or more TE injections per year. An initial loading dose of either 3 x 1000 mg TU every 6 wk at the beginning of hormone substitution or 2 x 1000 mg TU every 8 wk after switching from the short-acting TE to TU were found to be a adequate dosing regimens for starting of treatment with the long-acting TU preparation.     

Delta-4-androstene-3,17-dione binds androgen receptor, promotes myogenesis in vitro, and increases serum testosterone levels, fat-free mass, and muscle strength in hypogonadal men

Previous studies of Delta 4-androstene-3,17-dione (4-androstenedione) administration in men have not demonstrated sustained increments in testosterone levels, fat-free mass (FFM), and muscle strength, and failure to demonstrate androstenedione's androgenic/anabolic effects has stifled efforts to regulate its sales. To determine whether 4-androstenedione has androgenic/anabolic properties, we evaluated its association with androgen receptor (AR) and its effects on myogenesis in vitro. Additionally, we studied the effects of a high dose of 4-androstenedione on testosterone levels, FFM, and muscle strength in hypogonadal men. We determined the dissociation constant (K(d)) for 4-androstenedione using fluorescence anisotropy measurement of competitive displacement of fluorescent androgen from AR ligand-binding domain. AR nuclear translocation and myogenic activity of androstenedione were evaluated in mesenchymal, pluripotent C3H10T1/2 cells, in which androgens stimulate myogenesis through an AR pathway. We determined effects of a high dose of androstenedione (500 mg thrice daily) given for 12 wk on FFM, muscle strength, and hormone levels in nine healthy, hypogonadal men. 4-Androstenedione competitively displaced fluorescent androgen from AR ligand-binding domain with a lower affinity than dihydrotestosterone (K(d), 648 +/- 21 and 10 +/- 0.4 nm, respectively). In C3H10T1/2 cells, 4-androstenedione caused nuclear translocation of AR and stimulated myogenesis, as indicated by a dose-dependent increase in myosin heavy chain II+ myotube area and up-regulation of MyoD protein. Stimulatory effects of 4-androstenedione on myosin heavy chain II+ myotubes and myogenic determination factor expression were attenuated by bicalutamide, an AR antagonist. Administration of 1500 mg 4-androstenedione daily to hypogonadal men significantly increased serum androstenedione, total and free testosterone, estradiol, and estrone levels and suppressed SHBG and high-density lipoprotein cholesterol levels. 4-androstenedione administration was associated with significant gains in FFM (+1.7 +/- 0.5 kg; P = 0.012) and muscle strength in bench press (+4.3 +/- 3.1 kg; P = 0.006) and leg press exercises (+18.8 +/- 17.3 kg; P = 0.045). 4-androstenedione is an androgen that binds AR, induces AR nuclear translocation, and promotes myogenesis in vitro, with substantially lower potency than dihydrotestosterone. 4-androstenedione administration in high doses to hypogonadal men increases testosterone levels, FFM, and muscle strength, although at the dose tested, the anabolic effects in hypogonadal men are likely because of its conversion to testosterone.     

Physiologic testosterone therapy has no effect on serum levels of tumour necrosis factor-alpha in men with chronic heart failure

Physiological testosterone therapy increases exercise capacity and reduces symptom scores in men with chronic heart failure (CHF). Tumour necrosis factor-alpha (TNF-alpha) exerts a significant pathologic activity in CHF, and physiologic testosterone replacement therapy is associated with reduced serum levels of TNF-alpha in hypogonadal men with concomitant coronary artery disease. It is unknown whether testosterone exerts a similar immunomodulatory action in men with CHF. Testosterone therapy administered in three placebo-controlled studies, for either 6 hours (two 30-mg buccal tablets, n=12) or 3 months (fortnightly 100 mg intra muscular injection, n=20; or daily 5 mg transdermally, n=62). The effects of testosterone were also assessed on lipopolysaccharide (LPS)-induced TNF- production in whole blood obtained from 27 men with CHF. Incubation with testosterone (10 nM, 1 M, and 100 M) resulted in a reduction in LPS-induced TNF- production from 12.6 +/- 1.3 to 11.2 +/- 1.1 (P = 0.053), 10.3 +/- 1.1 (P = 0.0046), and 9.2 +/- 1.1 (P = 0.000066) ng/ml, respectively. However in men with CHF, serum levels of TNF- were similar before and after treatment with testosterone or placebo, irrespective of the length of study or route of administration. The clinically beneficial actions of testosterone in men with CHF are unlikely to be mediated by reducing TNF-alpha.     

Testosterone replacement therapy and sleep-related erections in hypogonadal men

Hypogonadal men usually have diminished libido and erectile dysfunction, and testosterone replacement therapy in these men increases sexual activity, erotic thoughts, and self-reported nocturnal erections. The polygraphic assessment of nocturnal penile tumescence (NPT) provides an objective index of erectile capability and is useful for differentiating psychogenic from organic erectile dysfunction. In this study we evaluated NPT in six hypogonadal adult men during and after termination of androgen therapy. Multinight sleep studies were conducted within 1 week and 7-8 weeks after each man received 20 mg testosterone cypionate, im. The mean serum testosterone level 4-7 days after testosterone injection was 35.9 +/- 3.4 (+/- SE) nmol/L, and it fell to 2.3 +/- 0.9 nmol/L after 7-8 weeks. Significant declines (P less than 0.05) in the number of NPT episodes (3.7 to 2.0), maximum penile circumference increase (24 to 13 mm), and total tumescence time (107 to 55 min) accompanied the fall in the serum testosterone level. No androgen-related changes in the amount or integrity of rapid eye movement sleep were found. Finally, the mean penile rigidity (buckling pressure) decreased from 770 +/- 98 to 590 +/- 81 g (P less than 0.05). Comparison of these results to those in normal men revealed that none of these men met all diagnostic criteria for organic impotence, even 7-8 weeks after discontinuation of testosterone administration. While men with androgen deficiency may have normal NPT, sleep-related erections increase in response to testosterone administration.     

Serum adiponectin levels in hypogonadal males: influence of testosterone replacement therapy

OBJECTIVE: Adiponectin is an adipocyte-specific secretory protein which exhibits antiatherogenic, anti-inflammatory and antidiabetic properties. We hypothesized that testosterone plays an important role in the regulation of its secretion in humans, as adiponectin concentrations are higher in women than in men and as testosterone administration is accompanied by a reduction in serum adiponectin in animals and by reduced protein secretion in cultured adipocytes. This study aimed to evaluate adiponectin levels in hypogonadal men prior to and during testosterone replacement therapy. SUBJECTS AND METHODS: In a retrospective study, adiponectin, total and free testosterone, oestradiol, SHBG, total cholesterol and triglyceride levels were evaluated in 31 hypogonadal men [HM; age, mean +/- SEM: 36.5 +/- 2.4 years; body mass index (BMI) 24.6 +/- 0.8 kg/m2] and 29 weight-matched eugonadal men (EM; age 30.8 +/- 1.5 years; BMI 23.4 +/- 0.6 kg/m2). In 13 HM (age 33.9 +/- 3.2 years; BMI 24.2 +/- 0.9 kg/m2) the same parameters were also evaluated after 6 months of testosterone replacement therapy. Correlation analysis between adiponectin and hormonal, biochemical and anthropometric parameters was performed in all subjects. RESULTS: Testosterone, free testosterone and oestradiol concentrations were significantly lower in HM than in EM (4.4 +/- 0.4 nmol/l, 78.4 +/- 10.9 pmol/l and 36.1 +/- 3.0 pmol/l, respectively, in HM vs. 21.9 +/- 0.7 nmol/l, 507.9 +/- 13.8 pmol/l and 65.2 +/- 1.8 pmol/l, respectively, in EM, P < 0.0001), while SHBG levels in HM were higher than in EM (54.4 +/- 7.5 vs. 30.9 +/- 2.2 nmol/l, P < 0.005). Serum adiponectin levels in HM were significantly higher than in EM (9.53 +/- 0.73 vs. 6.80 +/- 0.55 microg/ml, P < 0.01). Calculation of the Pearson coefficient showed that adiponectin levels in HM were not correlated with any of the anthropometric and hormonal parameters examined, but showed a significant negative correlation with serum triglycerides (r = -0.38, P < 0.05). Serum adiponectin levels were negatively correlated with body weight (r = -0.41, P < 0.05) in EM but not with other anthropometric, hormonal or biochemical parameters. Six months after initiation of testosterone replacement therapy, which increased testosterone and free testosterone levels to the normal range, adiponectin levels were significantly reduced in HM (6.37 +/- 0.93 vs. 9.26 +/- 1.01 microg/ml, P < 0.01) and similar to those recorded in EM. CONCLUSIONS: Compared to eugonadal subjects, hypogonadal men show higher adiponectin levels which are reduced by testosterone replacement therapy. This study indicates that testosterone exerts a regulatory role on adiponectin secretion in humans.     

Transdermal delivery of testosterone

We administered testosterone transdermally to six hypogonadal men by applying a thin flexible polymeric membrane containing testosterone to the scrotum. Each man wore a placebo membrane and three doses (5, 10, and 15 mg) of testosterone-containing membranes for 22 h/day. Each dose was worn for 1 week, and one dose was worn a second week. Blood was sampled frequently for one 22 h period on the seventh day of each treatment period. After the application of a membrane, the serum testosterone concentration rose rapidly, reached a peak in 2-3 h, and decreased slowly to 60-80% of the peak value by 22 h. The mean (+/- SE) 22-h average testosterone concentration during the wearing period was dependent on the testosterone content of the membrane (placebo, 135 +/- 38 ng/dl; 5 mg, 348 +/- 66 ng/dl; 10 mg, 455 +/- 77 ng/dl; and 15 mg, 624 +/- 65 ng/dl; P less than 0.001, by analysis of variance). When the same dose was worn twice, the mean coefficient of variation was 13.9%. We conclude that the transdermal application of testosterone to hypogonadal men reproducibly raises their serum testosterone concentrations to within the normal range, and that it, therefore, warrants evaluation as a treatment for male hypogonadism.