Measurement of thyroid stimulating immunoglobulins using a novel thyroid stimulating hormone receptor-guanine nucleotide-binding protein, (GNAS) fusion bioassay.

Hyperthyroidism, defined by overproduction of thyroid hormones, has a 2-3% prevalence in the population. The most common form of hyperthyroidism is Graves' disease. A diagnostic biomarker for Graves' disease is the presence of immunoglobulins which bind to, and stimulate, the thyroid stimulating hormone receptor (TSHR), a G-protein coupled receptor (GPCR). We hypothesized that the ectopically expressed TSHR gene in a thyroid stimulating immunoglobulin (TSI) assay could be engineered to increase the accumulation of the GPCR pathway second messenger, cyclic AMP (cAMP), the molecule measured in the assay as a marker for pathway activation. An ectopically expressing TSHR-mutant guanine nucleotide-binding protein, (GNAS) Chinese hamster ovary (CHO) cell clone was constructed using standard molecular biology techniques. After incubation of the new clone with sera containing various levels of TSI, GPCR pathway activation was then quantified by measuring cAMP accumulation in the clone. The clone, together with a NaCl-free cell assay buffer containing 5% polyethylene glycol (PEG)6000, was tested against 56 Graves' patients, 27 toxic thyroid nodule patients and 119 normal patients. Using receiver operating characteristic analysis, when comparing normal with Graves' sera, the assay yielded a sensitivity of 93%, a specificity of 99% and an efficiency of 98%. Total complex precision (within-run, across runs and across days), presented as a percentage coefficient of variation, was found to be 7·8, 8·7 and 7·6% for low, medium and high TSI responding serum, respectively. We conclude that the performance of the new TSI assay provides sensitive detection of TSI, allowing for accurate, early detection of Graves' disease.

Effects of testosterone replacement in human immunodeficiency virus-infected women with weight loss.

The objective of this study was to determine whether physiological testosterone replacement increases fat-free mass (FFM) and muscle strength and contributes to weight maintenance in HIV-infected women with relative androgen deficiency and weight loss. Fifty-two HIV-infected, medically stable women, 18-50 yr of age, with more than 5% weight loss over 6 months and testosterone levels below 33 ng/dl were randomized into this double-blind, placebo-controlled trial of 24-wk duration. Subjects in the testosterone group applied testosterone patches twice weekly to achieve a nominal delivery of 300 mug testosterone over 24 h. Data were evaluable for 44 women. Serum average total and peak testosterone levels increased significantly in the testosterone group, but did not change in the placebo group. However, there were no significant changes in FFM (testosterone, 0.7 +/- 0.4 kg; placebo, 0.3 +/- 0.4 kg), fat mass (testosterone, 0.3 +/- 0.7 kg; placebo, 0.6 +/- 0.7 kg), or body weight (testosterone, 1.0 +/- 0.9 kg; placebo, 0.9 +/- 0.8 kg) between the two treatment groups. There were no significant changes in leg press strength, leg power, or muscle fatigability in either group. Changes in quality of life, sexual function, cognitive function, and Karnofsky performance scores did not differ significantly between the two groups. High-density lipoprotein cholesterol levels decreased significantly in the testosterone group. The patches were well tolerated. We conclude that physiological testosterone replacement was safe and effective in raising testosterone levels into the mid to high normal range, but did not significantly increase FFM, body weight, or muscle performance in HIV-infected women with low testosterone levels and mild weight loss. Additional studies are needed to fully explore the role of androgens in the regulation of body composition in women.

Transdermal testosterone gel: pharmacokinetics, efficacy of dosing and application site in hypogonadal men.

OBJECTIVE: To determine the regimen that would most effectively maintain serum testosterone concentrations in treated hypogonadal men within the normal reference range of 3-11.4 microg/L. PATIENTS AND METHODS: Eighteen men aged 24-69 years with either primary or secondary hypogonadism participated in and 16 completed a randomized, six-treatment regimen, three-period (phase), three-way matrix-type crossover study. A 1% and 2% testosterone gel (CP601, Cellegy Pharmaceuticals, Inc., San Francisco, USA) was administered either once or twice daily transdermally at different body sites to determine optimal dosing, application sites, and its pharmacokinetics and tolerability in hypogonadal men. Treatments A-F included 1 g of 1% and 2% gel that was equivalent to 10 or 20 mg of testosterone, applied once or twice daily to the skin of either the thigh or the upper arm. Six men also participated in a study of 3 g of 2% gel that was equivalent to 60 mg of testosterone applied once daily, half on each thigh. Pharmacokinetic variables were calculated for testosterone for each man in each treatment period and the results analysed by anova. RESULTS: In general the higher dose regimens produced higher serum concentrations of testosterone; the 3 g/2% dose was most successful in maintaining serum testosterone within the normal reference range. The average testosterone concentration (C(avg)) was 6.52 microg/L and all men had a C(avg) of > 3.0 microg/L. The prediction of all men achieving a C(avg) of > 3.0 microg/L was 96%. The mean minimum concentration (C(min)) was 3.83 microg/L and half the patients had a C(min) of > 3.0 microg/L. Most men had serum testosterone levels within the normal reference range throughout the 24 h, and the treatment was well tolerated. CONCLUSIONS: The 3 g/2% dose applied to the skin daily resulted in serum testosterone in the normal reference range in most hypogonadal men. Dose adjustments to either a lower or higher dose should shift serum testosterone concentration to the desired range in those who do not achieve this range with this dose.

Pituitary radiographic abnormalities and clinical correlates of hypogonadism in elderly males presenting with erectile dysfunction.

The prevalence of erectile dysfunction rises rapidly with age and is a frequent complaint presented in clinical practice. Although the etiology of erectile dysfunction is multifactorial, 10-20% of evaluations demonstrate testosterone deficiency. Testosterone deficiency due to secondary hypogonadism increases with age. Despite a higher prevalence of secondary hypogonadism in the elderly, there are no studies addressing hypothalamic-pituitary structural abnormalities in elderly impotent men with testosterone deficiency. We retrospectively reviewed the records of all elderly men who presented for general outpatient evaluation of erectile dysfunction from 1996 to 1999. To obtain a cohort control population, the records of 300 patients without erectile dysfunction were also reviewed. Amongst the erectile dysfunction patients, 225 were found to be testosterone deficient (testosterone < 300 ng/dl). Of these patients, 29 were additionally diagnosed with secondary hypogonadism based on a luteinizing hormone (LH) < 13 mIU/ml. Magnetic resonance imaging (MRI) or computed tomography (CT) imaging was available and reviewed in all patients diagnosed with secondary hypogonadism. Ten per cent of these patients had hypothalamic-pituitary imaging abnormalities. The prevalence of pituitary tumors within our population was not significantly elevated compared to the previous general population studies. Small-vessel white matter disease, hyperlipidemia and history of compression fractures were significantly increased in both univariate and multivariate analysis in the erectile dysfunction group compared with the control cohort. This study does not suggest that the use of hypothalamic-pituitary imaging in the evaluation of impotence in elderly men, in the absence of clinical characteristics of other hormonal loss or sella compression symptoms, will increase diagnosis of structural hypothalamic-pituitary abnormalities over that of the general population. However, the yield may increase with very low testosterone levels. These data suggest that there is an increase in ischemic white matter disease in elderly men with hypogonadism that may reflect microvascular injury to the hypothalamic-pituitary. Furthermore, these data confirm that low testosterone is associated with hyperlipidemia in the elderly. Future studies are required to assess the role of hypogonadism and hyperlipidemia, and to determine if treatment of the hormone deficiency improves the lipid profile.

Interrelationships among lipoprotein levels, sex hormones, anthropometric parameters, and age in hypogonadal men treated for 1 year with a permeation-enhanced testosterone transdermal system.

Serum lipoproteins and cardiovascular risk are affected by endogenous and exogenous sex hormones. As part of a multicenter evaluation of a permeation-enhanced testosterone transdermal system (TTD), the interrelationships among serum lipoproteins, hormone levels, anthropometric parameters, and age were investigated in 29 hypogonadal men. Subjects (aged 21-65 yr) were first studied during prior treatment with im testosterone esters (IM-T), then during an 8-week period of androgen withdrawal resulting in a hypogonadal state (HG), and finally during a 1-yr treatment period with the TTD. Compared with treatment with IM-T, the HG period produced increases in high density lipoprotein [HDL; 12.0 +/- 1.6% (+/-SEM); P<0.001] and total cholesterol (4.2 +/- 1.9%; P: = 0.02) and a decrease in the cholesterol/HDL ratio (-9.7 +/- 2.8%; P = 0.02). Compared with the HG period, TTD treatment produced decreases in HDL (-7.6 +/- 2.5%; P = 0.002) and increases in the cholesterol/HDL ratio (9.0 +/- 2.5%; P = 0.01) and triglycerides (20.7 +/- 6.4%; P: = 0.03). Small decreases in total cholesterol (-1.2 +/- 1.8%; P: = 0.1) and low density lipoprotein (-0.8 +/- 2.6%; P = 0.07) were also observed during TTD, but did not reach statistical significance. Likewise, there were no significant differences between the IM-T and TTD treatments. Serum HDL levels showed a strong negative correlation with body mass index and other obesity parameters in all three study periods (r < -0.45; P < 0.02). During treatment with TTD, serum testosterone levels also correlated negatively with body mass index (r = -0.621; P < 0.001). As a consequence of these relationships, a positive trend was observed between HDL and testosterone levels during TTD treatment (r = 0.336; P = 0.07). Interestingly, the changes in lipoprotein levels during TTD treatment indicated a more favorable profile (decrease in cholesterol and low density lipoprotein levels) with increasing age of the patients. In hypogonadal men the effects of transdermal testosterone replacement on serum lipoproteins appear consistent with the physiological effects of testosterone in eugonadal men.

Vitamin E and other antioxidants inhibit human prostate cancer cells through apoptosis.

BACKGROUND: Many human prostate cancer cells have escaped the apoptotic effects of natural regulators of cell growth such as transforming growth factor betal (TGF beta-1) and tumor necrosis factor (TNF). METHODS: Prostate cancer cell growth was investigated by treating with antioxidants. DU-145 (androgen-unresponsive), LNCaP (androgen-responsive), and ALVA-101 (androgen moderately responsive) were grown in RPMI-1640 medium supplemented with bovine fetal calf serum and antibiotics, and were treated with various antioxidants for 1-7 days. Cell growth was then determined with the Cell Titer 96 AQ assay, and apoptosis was assessed by cell death detection ELISA, nuclear morphology, and TUNEL techniques. RESULTS: Cells treated with or without (+/-)-alpha-tocopherol (vitamin E) for 1-7 days at concentrations from 0.078-2.5 microg/ml modestly affected cell growth compared to other antioxidants tested. Tocopherol produced a significant (P < 0.01) inhibition of ALVA-101 and LNCaP (10-24% of control; 0.078-2.5 microg/ml; at 6 days; n = 6). DU-145 cells were not growth-inhibited significantly. However, pyrrolidinedithiocarbamate (PDTC) produced a significant (P < 0.01, n = 6; 17-80% of control; 2.5-20 microg/ml; 1-7 days) inhibition of DU-145 and ALVA-101 cells. A significant (P < 0.01) and maximum inhibition of LNCaP cells occurred at all concentration of PDTC (2. 5-20 microg/ml). A third compound, diethyldithiocarbamic acid (DETC), incubated for 1-7 days, produced a significant dose response suppression of cell growth of DU-145 and ALVA-101 cells (P < 0.01; 14-88% of control; 1.25-80 microg/ml; n = 6). LNCaP cells were inhibited by DETC (P < 0.01; 28% of control; 1.25-80 microg/ml; n = 6). All three antioxidants tested stimulated apoptosis in actively dividing ALVA-101, DU-145, and LNCaP cells (P < 0.01; n = 6), but confluent cells were affected less. Testosterone had additive inhibitory effects when combined with PDTC in ALVA-101 cells; however, the other cell lines were not influenced. CONCLUSIONS: These results demonstrate that antioxidants modulate human prostate cancer cell proliferation by altering apoptosis in dividing cells, and this necrosis or apoptosis in confluent cells is not as effective.

Heritability of prostate-specific antigen and relationship with zonal prostate volumes in aging twins.

Both benign prostatic hyperplasia and prostate-specific antigen (PSA) have been shown to increase with age and with prostate volume in men, but the influence of heredity on these relationships is not completely understood. This study has two aims: 1) to investigate the inter-relationships of age, PSA, and various zonal measurements in the prostate; and 2) to assess the impact of heritable influences on total PSA. Eighty-four monozygotic twin pairs and 83 dizygotic twin pairs were studied, and serum total PSA, free PSA, and PSA-alpha1-antichymotrypsin were measured. Their prostate volumes [total (TV), transition zone (TZ), and peripheral zone) were quantitated using transrectal ultrasound. Total PSA is significantly correlated with all zonal prostate measurements (TZ, peripheral zone, TV, and TZ/TV) and with age. When linear regression was applied, only age and TZ were retained in the final model. The proportion of variability in total PSA explained by these two factors, however, is below 24%. In contrast, estimates of heritability show that approximately 45% of the variability in total PSA can be explained by inherited factors. Whereas age and TZ are linearly related to total PSA, their influence is much less than that of familial and genetic factors. It is uncertain whether these factors predispose also to prostate cancer or if they are independent of those, whether they confound the accuracy of using total serum PSA level as a diagnostic tool.

Pharmacokinetics, efficacy, and safety of a permeation-enhanced testosterone transdermal system in comparison with bi-weekly injections of testosterone enanthate for the treatment of hypogonadal men.

The pharmacokinetics, efficacy, and safety of the Androderm testosterone (T) transdermal system (TTD) and intramuscular T enanthate injections (i.m.) 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 i.m. treatment for 4-6 weeks and then randomly assigned to treatment with TTD (two 2.5-mg systems applied nightly) or i.m. (200 mg injected every 2 weeks); there were 33 patients per group. Twenty-six patients in the TTD group and 32 in the i.m. 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. i.m. 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 i.m. 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 i.m. 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. i.m. 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 i.m. 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 i.m. in minimizing excessive stimulation of erythropoiesis, preventing/ameliorating gynecomastia, and not over-suppressing gonadotropins.

Transforming growth factor beta-1 and beta-2 and type II receptor functional regulation of ALVA-101 human prostate cancer cells.

Transforming growth factor beta-1 (TGFbeta-1) causes apoptosis of many epithelial cells, including the prostate, but other secondary effects of TGFbeta-1 may be important in carcinogenesis. In a human prostate cancer cell line (ALVA-101), we determined the effects of TGFbeta-1 and TGFbeta type I and II receptor antibody on cell proliferation and TGFbeta-1 receptor binding. TGFbeta-1 and -2 and TGFbeta type II receptor mRNA expression levels were determined by polymerase chain reaction (PCR) and Northern blot analysis. A dose-responsive suppression (0.03 to 10 ng/mL) was observed for cells treated with TGFbeta-1 from 3 to 7 days (P < .01). Untreated cells had 1.1 x 10(3) (n = 3) TGFbeta receptors per cell, with a Kd of 0.20 nmol/L (n = 3) as determined by Scatchard analysis; treatment for 3 days with TGFbeta-1 (1 ng/mL) reduced the receptor number (0.9 x 10(3)) and the Kd (0.12 nmol/L). Antibodies to TGFbeta type I and II receptor stimulated proliferation with or without added TGFbeta-1 (50% +/- 5% above control, P < .01, n = 6). TGFbeta-1 and -2 and TGFbeta type II receptor mRNA expression was observed in untreated cells. In cells treated with TGFbeta-1, TGFbeta-1 mRNA was not affected by treatment, but expression levels of the TGFbeta type II receptor and TGFbeta-2 mRNA were moderately suppressed after 72 hours of treatment. Control cells actively produced TGFbeta-1 as measured by radioimmunoassay. The active and inactive forms of TGFbeta-1 were approximately equal, but TGFbeta-2 was secreted in smaller quantities than TGFbeta-1 and the inactive form of TGFbeta-2 predominated, with very small amounts of the active form. Our results suggest that the human prostate cancer cell line ALVA-101 retains negative control of proliferation in response to TGFbeta-1. Inhibition of endogenous TGFbeta action by antibodies to its receptor enhances the growth of ALVA-101 human prostate cancer cells, suggesting that endogenous TGFbeta exerts an inhibitory control on their growth and cellular function.

Heritability of the symptoms of benign prostatic hyperplasia and the roles of age and zonal prostate volumes in twins.

OBJECTIVES: Both benign prostatic hyperplasia and lower urinary tract symptoms (LUTS) have been shown to increase with age in men, but a causal relationship between prostate volume and symptoms has not been established. This study had two aims, to investigate the inter-relationships of age, symptoms, and various zonal measurements in the prostate and to assess the impact of heritable influences on symptom score. METHODS: Eighty-three monozygotic twin pairs and 83 dizygotic twin pairs were studied to determine age and LUTS as assessed by the American Urological Association symptom score. Their prostate volumes (total, transition zone, and peripheral zone) were measured by transrectal ultrasound. RESULTS: There was significant evidence of pairwise correlation between transition zone and symptom score (P = 0.04) and between age and symptom score (P = 0.03). Age also showed significant correlation with all volume measurements. Heritability appears to account for 82.6% of the variability in symptom score in men older than 50 years. CONCLUSIONS: This study provides evidence that age and transition zone volume play a role in LUTS, but also that their influence is not strong. Estimates of heritability suggest that hereditary factors contribute substantially to LUTS.

Bioequivalence assessment of a single 5 mg/day testosterone transdermal system versus two 2.5 mg/day systems in hypogonadal men.

A novel, nonscrotal, transdermal delivery system for testosterone therapy has been marketed for treatment of hypogonadal men. The usual dose of this system is two 2.5 mg/day systems applied daily. A new system has been developed that administers a dose of 5 mg/day using a single patch rather than two patches. A randomized, steady-state, four-period, replicate-design, open-label, crossover study was conducted to assess the bioequivalence of the two testosterone transdermal delivery systems in postpubertal, hypogonadal men: two 2.5 mg/day patches as the reference regimen (R) and one 5 mg/day patch as the test regimen (T). 21 men were enrolled, and 20 completed the study. Each subject was randomly assigned to one of four sequences (R1-R2-T1-T2, T1-T2-R1-R2, R1-T1-T2-R2, T1-R1-R2-T2), such that each subject received each regimen during two study sessions. Two subjects were inadvertently treated according to the sequence T1-R1-T2-R2. Patches were applied to the upper arm, thigh, and back in the evening on days 1, 2, and 3, respectively, of each study session. Serial blood samples were obtained for pharmacokinetic analysis of testosterone for 24 hours after patch application on day 3 of each study session. The two formulations would be considered bioequivalent if the 90% confidence intervals (CI) for the ratios of the adjusted geometric means for T:R for both area under the concentration--time curve from 0 to 24 hours (AUC0-24) and maximum concentration (Cmax) were completely contained in the interval (0.80, 1.25). Mean values for AUC0-24 and Cmax were similar for the two formulations. The T and R formulations were found to be bioequivalent based on both AUC0-24 (90% CI 0.96, 1.08) and Cmax (90% CI 0.92, 1.07). The median time to Cmax was also similar, indicating comparable rates of testosterone absorption for both formulations. Based on this analysis, the testosterone transdermal system 5 mg/day patch is bioequivalent to two of the 2.5 mg/day patches. Both systems were safe and well tolerated in hypogonadal men.

Androgen replacement in the treatment of Klinefelter's syndrome: efficacy and safety of a nonscrotal permeation-enhanced testosterone transdermal system.

OBJECTIVE: To report the efficacy and safety of a permeation-enhanced nonscrotal testosterone transdermal (TTD) system for the treatment of Klinefelter's syndrome. METHODS: Fifteen male patients with Klinefelter's syndrome, including 12 patients who received previous intramuscular (IM) treatment with testosterone esters, were part of the study population from three phase III clinical studies; 13 completed the studies. Patients applied two TTD systems nightly for 6 months or more. Nocturnal erections were assessed by RigiScan monitoring; sexual function was evaluated by using the Watts and Davidson questionnaires. Hypogonadal symptoms were determined by direct patient questioning. RESULTS: Mean morning serum testosterone levels increased to within normal range in all 13 patients (from 5.9 +/- 3.2 nmol/L at hypogonadal baseline to 22.3 +/- 5.6 nmol/L at 6 months). Luteinizing hormone levels decreased to within normal range in six patients and showed clinically significant decreases in four of the other seven patients (from 25 +/- 12 IU/L at hypogonadal baseline to 17 +/- 11 IU/L at 6 months). Nocturnal erections improved significantly during TTD system therapy in comparison with the hypogonadal state. Patient self-reported measures of sexual functioning were comparable to those during prior IM testosterone treatment and better than during the hypogonadal state. Hypogonadal symptoms decreased during TTD therapy in comparison with hypogonadal baseline. No clinically significant changes were noted in prostate volume, prostate-specific antigen, or lipid values. Three patients experienced anxiety or depression during TTD treatment, requiring discontinuation of therapy in one case and use of antidepressants in the other two. CONCLUSION: The testosterone patches were generally well tolerated in all patients. The nonscrotal TTD system for testosterone replacement is a safe and effective treatment for patients with Klinefelter's syndrome.

Age, genetic, and nongenetic factors influencing variation in serum sex steroids and zonal volumes of the prostate and benign prostatic hyperplasia in twins.

BACKGROUND: We have observed that hereditary and environmental factors have a substantial influence on the plasma content of sex steroids in normal male twins and in men of families with prostatic disease. METHODS: The contribution of genetic and nongenetic familial factors on the variation of plasma sex steroid concentrations and of the volume of zones of the prostate measured by transrectal ultrasound (TRUS) has now been investigated in pairs of male monozygotic (MZ) and dizygotic (DZ) twin pairs between age 25-75 years. Bioelectric impedance permitted quantitation of body fat, lean body mass, and water. Morphometrics and testicular volume were also determined. RESULTS: The intraclass correlation (rI) was > 0.40 for the variation of the total volume (TV), the transition zone (TZ), the peripheral zone (PZ), and the ratio of TZ/PZ in both MZ and DZ twins, and heredity affected 22% of the variation of the PZ and TZ and 30% of the ratio of TZ/PZ. None of the TV and environmental factors influenced the remainder of the variation. Heredity accounted for 25% or more of the variation of dihydrotestosterone (DHT), and the ratios of DHT/testosterone (T), estradiol (E2)/T, androstanediol glucuronide, sex hormone-binding globulin (SHBG)-bound T, T/SHBG, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and dehydroepiandrosterone sulfate (DHEA-S). In MZ twin pairs the variation of the volumes of the prostate became greater with age. In contrast, the variation of the sex hormone concentrations did not show greater variation with age. Heredity also affected > 30% of the variation for waist measurement, weight, body fat, body mass, water and lean body mass, body mass/fat, and testicular size. CONCLUSIONS: Our results indicated that both MZ and DZ twin pairs had zonal prostate volumes more like their twin pair than like unrelated twins. However, nongenetic factors exerted stronger influences than genetic factors on zonal volumes of the prostate. In contrast, hereditary factors had stronger influences on determining the variation of many sex hormones and morphometric characteristics than did nongenetic factors.

Prostate size in hypogonadal men treated with a nonscrotal permeation-enhanced testosterone transdermal system.

OBJECTIVES: This study examined the effects of testosterone replacement using a nonscrotal testosterone transdermal (TTD) system on prostate size and prostate-specific antigen (PSA) levels in hypogonadal men. METHODS: As part of an open-label, multicenter study, prostate volume as measured by transrectal ultrasound and PSA were assessed in 29 hypogonadal men during treatment with intramuscular testosterone enanthate (+TE), followed by 8 weeks of androgen withdrawal (-T), and then during 1 year of therapy with Androderm Testosterone Transdermal System, a nonscrotal permeation-enhanced TTD system (+TTD). RESULTS: Mean prostate volume decreased significantly from the +TE period (17 g) compared with the -T period (14 g) (P < 0.001). Prostate volume increased significantly from the -T period compared with the +TTD period (18 g) (P < 0.001). Maximum prostate size, comparable to that measured during +TE (P = 0.125), was reached by month 3 of +TTD therapy; prostate volume did not increase further during the remaining 9 months of +TTD therapy. Prostate volume correlated with age (P < 0.01) during all three periods of observation (+TE: r = 0.69; -T: r = 0.64; and +TTD: r = 0.55). No patient developed symptomatic benign prostatic hyperplasia during the treatment period. PSA levels decreased during androgen withdrawal compared with levels measured during +TE treatment (P < 0.001) and rose with resumption of androgen therapy with TTD (P < 0.006). However, PSA levels during +TTD replacement remained significantly lower (P < 0.001) than during +TE replacement. CONCLUSIONS: Physiologic testosterone replacement in hypogonadal men was achieved using the TTD system. Prostate size during therapy with TTD was comparable to that reported for normal men. In these men treated with TTD, PSA levels were also within the normal range.

Effects of age and sex hormones on transition and peripheral zone volumes of prostate and benign prostatic hyperplasia in twins.

Benign prostatic hyperplasia has been shown to increase with age and be influenced by sex hormones. The relationship between aging and hormonal influences on growth of zones of the prostate is unresolved. We studied the relationship of age and sex hormones on volume of prostate zones in 214 male twins between 25 and 75 yr old. Volumes of the total prostate (TV), transition zone (TZ), and peripheral zones (PZ) were measured using transrectal ultrasound, and sex steroid concentrations were measured using RIA. Using transformed data corrected for age, TV (r = 0.54, P < 0.00001), TZ (r = 0.58, P < 0.00001), and PZ (r = 0.39, P < 0.00001) volumes increased with age. However, the PZ volume rose more rapidly than the TZ before age 50, and TZ showed a steeper increase after age 50 yr than the PZ volume. The TZ, PZ, and ratio TZ/PZ correlated significantly (r = 0.87, 0.90, and 0.52, respectively; P < 0.00001). After a TV exceeded 30 g, the rise of the PZ became attenuated, and the slope of the TZ became steeper. Age-adjusted sex hormone concentration was not evaluated in men with larger prostate volumes. Men with American Urological Association symptom scores above 10 had significantly (P < 0.001) larger total prostate volume (TV) and TZ volume, but not PZ volumes, than men with scores below 10. Prostate volumes correlated inversely with age-adjusted serum testosterone (T), dihydrotestosterone, sex hormone binding globulin, and sex hormone binding globulin-bound T concentrations. These results demonstrate that before age 50 yr or before a prostate weight exceeds 30 g, prostate growth may be mainly from enlargement of the PZ and after age 50, the TZ. In addition, elevated T and dihydrotestosterone concentrations do not predispose men to prostate enlargement or symptoms of benign prostatic hyperplasia.

Evidence for sex steroid inhibition of lipoprotein lipase in men: comparison of abdominal and femoral adipose tissue.

Plasma estradiol has been suggested to suppress adipose tissue lipoprotein lipase (LPL) activity in women. The present study explores the regulation of LPL by sex steroids in sedentary obese men (N = 24) at their usual weight. Femoral adipose tissue LPL activity, eluted with serum and heparin or extracted with detergent, showed significant inverse correlations with plasma levels of testosterone, bioavailable testosterone, dihydrotestosterone, and estradiol. Both measures of femoral LPL activity were also correlated with the weight change occurring despite efforts to maintain a constant weight. Abdominal LPL activity showed significant but weaker inverse correlations with bioavailable testosterone only. Multivariate analysis of potential predictors for eluted femoral LPL activity showed that plasma testosterone, dihydrotestosterone, and estradiol were interdependent, whereas the rate of weight change was an independent variable. In the regression equation, only bioavailable testosterone and weight change were retained, explaining 63% of the variability (R = .79, P = .0002). These results suggest that sex steroids suppress adipose tissue LPL activity in men, and more so in the thigh than in the abdomen, thereby possibly contributing to a central fat accumulation. The data are compatible with a model from male animals suggesting that testosterone effects on adipose tissue LPL are mediated by estradiol formed locally.

Long-term efficacy and safety of a permeation-enhanced testosterone transdermal system in hypogonadal men.

OBJECTIVE: An important aim in treating male hypogonadism is restoration of physiological concentrations of testosterone and its metabolites. We have assessed hormone levels, pharmacokinetics and clinical response, including safety, of a permeation-enhanced testosterone transdermal system (TTD) in the treatment of hypogonadal men for a 12-month period. DESIGN: Open-label, multicentre study with four consecutive periods: Period I (3 weeks)--evaluation of patients' current androgen therapy, which consisted primarily of testosterone enanthate injections (mean dose 229 mg; mean interval 26d); Period II (8 weeks)--androgen washout; Period III (3-4 weeks)--single-dose pharmacokinetic studies of TTD systems; Period IV (12 months)--efficacy, safety, and steady-state pharmacokinetic evaluation of TTD systems (5 mg/day nominal delivery rate of testosterone). Results from Periods I, II, and IV were compared. PATIENTS: Thirty-seven hypogonadal men 21-65 years old enrolled; 34 entered Periods III and IV; 29 (9 primary, 20 secondary hypogonadism) completed the study. Four patients withdrew because of adverse events (Period II, one; Period IV, three). MEASUREMENTS: Morning serum levels of total testosterone (T), bioavailable testosterone (BT), dihydrotestosterone (DHT), and oestradiol (E2) levels. Circadian pattern of T profiles and 24-hour time-average T level. LH levels in patients with primary hypogonadism. Reduction of hypogonadal symptoms. Safety assessments including skin tolerability, prostate parameters, lipid profile, and systemic parameters. RESULTS: Twelve months of TTD therapy normalized morning serum T levels in 93% of patients, and produced greater than 80% normalization of BT, DHT and E2 levels. The TTD system mimicked the circadian variation in T levels seen in healthy young men and normalized 24-hour time-average T levels in 86% of patients. Luteinizing hormone was suppressed in 8 of 9 men with primary hypogonadism, and normalized in 5 of these. Subjective symptoms of hypogonadism, including decreased libido and fatigue, showed improvement after 2-4 weeks of TTD treatment in most patients. The majority of adverse events were local skin reactions, and 3 patients (9%) discontinued the study for this reason. Prostate assessments showed a lower prostate-specific antigen level during TTD therapy compared to IM injections (0.66 vs 1.00 microgram/l P < 0.001), while prostate size did not differ significantly between the two treatment regimens. CONCLUSIONS: The permeation-enhanced testosterone transdermal system produces physiological levels and circadian patterns of testosterone, and its metabolites, in hypogonadal men. Although transient erythema and itching is commonly reported, the TTD is generally well tolerated by most patients. This system offers a new treatment option for testosterone replacement therapy that results in physiological serum levels of sex hormones in hypogonadal men.

Pharmacokinetics of testosterone in hypogonadal men after transdermal delivery: influence of dose.

To assess the pharmacokinetics of testosterone after application of one, two, or three testosterone transdermal delivery systems to hypogonadal patients, 12 hypogonadal men (mean age 46.6 +/- 10.5 years) were enrolled in an open-label, randomized, crossover study. Each application period comprised 4 days: a 2-day washout period with no exogenous testosterone therapy followed by 2 days of therapy with one, two, or three transdermal systems applied daily to the patient's back. On day 4 of each period, serial blood samples were collected for determination of total and non-sex hormone binding globulin (non-SHBG) bound serum testosterone concentrations. Serum concentrations of testosterone were determined using validated radioimmunoassay methods. Residual testosterone analysis of used transdermal systems was used to estimate testosterone delivery through the skin. In general, serum concentrations of testosterone rose in accordance with an increase in dose. Using a strict bioequivalence approach to dose proportionality, the increases in area under the concentration-time curve (AUC) and morning concentrations were proportional to the increase in dose from two to three transdermal systems, but somewhat less than proportional with an increase from one to two transdermal systems. Results from the non-SHBG bound serum testosterone concentrations closely paralleled those of total serum testosterone. Use of three transdermal systems yielded serum concentrations of testosterone that tended to be above the upper limit of the normal range. The AUC and cumulative release of testosterone were linearly related to the number of applied systems. If necessary, the standard recommended dose of two testosterone transdermal delivery systems can be modified to accommodate interindividual differences in testosterone requirements of hypogonadal men.