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PubMed2002

Interrelationships of serum testosterone and free testosterone index with FFM and strength in aging men.

Muscle mass and strength losses during aging may be associated with declining levels of serum testosterone (T) in men. Few studies have shown a direct relationship between T and muscle mass and strength. Subjects were 262 men, aged 24-90 yr, from the Baltimore Longitudinal Study of Aging, who had T and sex hormone-binding globulin sex hormone-binding globulin (SHBG) measurements, from which the free T index (FTI) was calculated (T/SHBG) from serum samples collected longitudinally since 1963, total body fat mass and arm and leg fat-free mass (FFM) by dual-energy X-ray absorptiometry and arm and leg strength by dynanomometry. Mixed-effects models estimated T and FTI at the time of mass and strength measurements. Age, total body fat, arm and leg FFM, T, and FTI were significantly associated with concentric and eccentric strength. FTI, not T, was modestly, but directly, related to arm and leg strength after fat, arm and leg FFM, height, and age were accounted for and indirectly through body mass. FTI is a better predictor of arm and leg strength than T in aging men.

Adult↗

PubMed1991

Salivary testosterone concentrations in prepubertal and pubertal males: comparison with total and free plasma testosterone.

Salivary testosterone (T) levels in male children and adolescents were measured and compared with plasma T. Salivary concentrations correlated well with plasma total T (r = 0.72) and even better with free plasma T (r = 0.89) in subjects with plasma T levels of pubertal or adult levels (greater than 1.0 nmol/l). In subjects with prepubertal or low plasma T (less than 1.0 nmol/l), there was neither a correlation with plasma total, nor with free T. In hCG tests (responder and nonresponder), salivary T reflected plasma levels faithfully. The results suggest that salivary T, which is suitable for repeated sampling, is a good marker of T secretion in pubertal males.

Adolescent↗

PubMed1984

Does prolactin modify testosterone feedback in the hamster? Suppression of plasma prolactin inhibits photoperiod-induced decreases in testosterone feedback sensitivity.

The hormonal changes during the photoperiodically driven annual reproductive cycle of the male golden hamster can be explained partially by a change in the sensitivity of the hypothalamo-pituitary axis to negative feedback by testosterone (T). The present studies test the hypothesis that the increases in plasma levels of LH and FSH that follow photo-stimulation are due to decreasing feedback sensitivity and examine if this change in sensitivity is dependent upon increasing PRL levels. Adult males were exposed to a lighting schedule of 5 h of light, 19 h of darkness (5:19) for 12 weeks to induce gonadal regression. The animals were castrated; treated with an inhibitor of PRL release, bromocriptine (CB-154), or oil; and received a Silastic capsule that was empty or filled with T. Subsequently, the animals were transferred to 14:10 and killed 9 or 31 days later. There were no significant changes in FSH and LH in animals receiving oil injections and empty implants between days 9 and 31, suggesting no steroid-independent changes in gonadotropin secretion during this time period. However, 4-mm T implants were more effective in suppressing LH and FSH levels on day 9 than on day 31. This suggests that there is a gradual decrease in feedback sensitivity to T following photostimulation. T was more effective in inhibiting LH and FSH levels in CB-154-treated than in oil-treated animals on both day 9 and day 31. Thus, increases in PRL release are instrumental in causing decreases in feedback sensitivity following photostimulation.

Animals↗

PubMed1991

The effects of a brain-enhanced estradiol delivery system on testosterone and androgen-dependent tissues. II. The role of testosterone.

The present study was undertaken to evaluate the efficacy of an estradiol-chemical delivery system (E2-CDS) for the brain vs. estradiol benzoate (E2-BNZ) in suppressing serum testosterone (T) and weights of the ventral prostate and seminal vesicle in male rats. Also, the role of serum T in the weight reduction of androgen-dependent tissues observed after E2-CDS treatment was further evaluated in these studies. Intact male rats received a single iv injection of either E2-CDS at a dose of 1.0 mg/kg or an equimolar dose of E2-BNZ (0.95 mg/kg). Sera and tissue samples were collected 1, 7, 14, or 21 days after injection for determination of hormones and tissue weights. A single injection of E2-CDS suppressed serum T levels by 96%, 83%, 46%, or 63% 1, 7, 14, or 21 days after treatment, respectively. In contrast, an equimolar dose of E2-BNZ had no significant effect on serum T at any sampling time examined. Prostate weight was maximally reduced by 53% at 7 days and remained significantly suppressed by more than 31% throughout the 21-day time course. Similarly, seminal vesicle weight was reduced by 14% on day 1, maximally reduced by 41% on day 7 and remained significantly suppressed through day 21. In contrast, E2-BNZ was ineffective in inducing weight changes in either of these tissues. Serum PRL was significantly elevated through day 14, while E2 was elevated through day 7 by E2-CDS. Both the anterior pituitary and adrenal gland weights were stimulated by E2-CDS treatment. Testis weight was moderately reduced by both esters. In a subsequent study serum T was reduced by 98% and 97% 1 and 7 days, respectively, after E2-CDS treatment, and weights of the ventral prostate and seminal vesicle were reduced by 47% and 40%, respectively, at 7 days. In contrast, in rats treated with Silastic capsules containing T, the expected E2-CDS-induced weight regression was prevented in both prostate and seminal vesicles. These data indicate that the prolonged effects of E2-CDS on weights of androgen-dependent tissues are caused by its ability to produce profound suppression of the serum T concentration.

Adrenal Glands↗

PubMed1976

Testosterone metabolism in rabbits actively immunized with testosterone.

Active immunization of male rabbits results in a marked increase in plasma testosterone (T) and in the fraction of T bound to circulating proteins. In order to identify the cause of the increased T levels, the half-life of T after castration, and the metabolic clearance rate (MCR) and production rate (PR) after a single injection of tritiated T were determined in normal and immunized rabbits. In the immunized animals the half-life of T was significantly longer, the MCR showed a 10-fold decrease (10.2 +/- 3.2 1/day compared to 108 +/- 43 1/day) and the PR was increased from 0.44 +/- 0.34 mg/day to 1.20 +/- 0.36 mg/day compared with the control group. The binding of T to circulating antibodies is considered to be the direct cause of the decreased MCR and, via the diminished negative feedback at the hypothalamic-pituitary levels, the indirect cause of the increased PR in the immunized animals.

Animals↗

PubMed2003

The male contraceptive regimen of testosterone and levonorgestrel significantly increases lean mass in healthy young men in 4 weeks, but attenuates a decrease in fat mass induced by testosterone alone.

In hypogonadal men, testosterone (T) in replacement dosages is known to increase fat-free mass (lean mass) and decrease fat mass. In young eugonadal men, similar dosages of T increase lean mass, but much higher dosages of T are required to decrease total body fat mass. Current T-based male hormonal contraceptive regimens include a second agent, such as a progestin, to maximize inhibition of pituitary gonadotropins and improve efficacy. To study the effect of such combinations on body composition, we randomized healthy, young, eugonadal men into four combinations of exogenous T and the progestin, levonorgestrel (LNG): 1) 100 mg T enanthate, im, weekly plus 125 micro g LNG, orally, daily (T+LNG); 2) T plus placebo LNG (T alone); 3) placebo T plus LNG (LNG alone); and 4) placebo T plus placebo LNG (placebo). We then analyzed body composition by dual energy x-ray absorptiometry after 4 and 8 wk of treatment. T+LNG significantly increased total lean mass after 4 and 8 wk of treatment (3.5 +/- 0.9% and 4.2 +/- 1.2%, respectively; P < 0.05) and truncal lean mass after 4 and 8 wk of treatment (4.7 +/- 0.9% and 5.0 +/- 0.9%, respectively; P < 0.05) compared with baseline and placebo. T alone also increased total and truncal lean mass significantly compared with placebo after 4 wk of treatment, but not compared with baseline (3.3 +/- 1.4% and 3.2 +/- 2.3%, respectively; P < 0.05 vs. placebo), suggesting an additive effect of T and LNG to increase lean mass. Fat mass significantly decreased in the abdomen in men administered T alone compared with LNG alone (-4.9 +/- 2.8%; P < 0.05). Fat mass significantly increased in the abdomen with LNG alone (4.1 +/- 1.0%; P < 0.05) compared with baseline and was unchanged with the combination of T+LNG, suggesting that LNG attenuates the decrease in fat mass seen with T alone. There was no change in weight or body mass index in any group during the study. This study shows that in young eugonadal men 1) T alone rapidly increases lean mass and decreases fat mass in 4-8 wk; 2) T+LNG rapidly increases lean mass, but has no effect on fat mass; and 3) LNG alone increases fat mass. The favorable profile on body composition by T is, therefore, partially attenuated by the progestin, LNG. These findings suggest that androgen-based male hormonal contraceptives might have favorable effects on body composition. The impact of these changes on cardiovascular risk in normal men needs further study.

Adipose Tissue↗

PubMed2003

Testosterone undecanoate maintains spermatogenic suppression induced by cyproterone acetate plus testosterone undecanoate in normal men.

In this study we evaluated whether testosterone undecanoate (TU), alone or combined with low dose cyproterone acetate (CPA), can maintain spermatogenic suppression induced by higher doses of CPA plus TU. Twenty-four men received for 12 wk 20 mg/d CPA plus 1000 mg/6 wk TU and then 1000 mg/8 wk TU plus 20 mg/d CPA (n = 8), 2 mg/d CPA (n = 8), or plus placebo (n = 8) for 32 wk. Blood samples, physical examinations, hormones, chemistry, hematology, semen analysis, and sexual/behavioral assessments were performed throughout the study. Sperm counts decreased to less than 1 million/ml in all subjects by wk 12, and 54% of them achieved azoospermia. Suppression of sperm counts was maintained until wk 44. Serum LH and FSH levels were suppressed by wk 12 of hormone administration and remained suppressed until wk 44. No significant changes in any biochemical parameters were detected at wk 44 in any group. There was a slight increase in total prostate volume to within the normal range at wk 44 that returned to baseline 1 yr after stopping hormone administration. In conclusion, TU alone or combined with lower doses of CPA maintains sperm suppression induced by higher dose CPA plus TU for 32 wk. This prototype regimen represents a promising male contraceptive regimen.

Adult↗

PubMed1978

Depressed plasma testosterone and fractional binding of testosterone in obese males.

Plasma testosterone (T), fractional binding of T to T-binding globulin (TeBG), LH, and FSH were evaluated in 22 obese men. Only 1 of 12 men weighing from 176-200% of ideal body weight (group I) had a low T concentration, while 9 of 10 men greater than 200% of ideal weight (group II) had plasma T concentrations 2 SD below the normal mean. The fractional binding of T to TeBG was equally and significantly decreased in both groups. As a result, the mean and individually calculated free T concentrations (free T index) were normal in group I. In contrast, the mean free T index in group II was significantly less than normal males and group I. Individually, 1 of 7 group II men had a free T index 2 SD below the normal mean. LH and FSH were normal in both groups. These studies indicate that in most obese males a low or low normal T is offset by decreased binding to TeBG, resulting in a normal free T index. However, some morbidly obese males are unable to alter their hypothalamic-hypophyseal-gonadal axis to maintain a normal free T index.

Adult↗

PubMed1981

Salivary testosterone in men: further evidence of a direct correlation with free serum testosterone.

An excellent correlation was found between salivary testosterone (T) and serum T concentrations, as measured by RIA. Using polyacrylamide gel electrophoresis, we have demonstrated that sex steroid-binding globulin could not be identified in the saliva of men with serum sex steroid-binding globulin. After exogenous T administration, saliva and serum T rose abruptly and in parallel. Salivary T concentrations in male patients with thyrotoxicosis were similar to those in normal males, whereas the serum T and sex steroid-binding globulin values were significantly higher in the hyperthyroid patients. This study demonstrates that salivary T levels may be used as an index of free serum T.

Adult↗

PubMed1991

Metabolic clearance rate of dehydroepiandrosterone sulfate, its metabolism to testosterone, and its intrafollicular metabolism to dehydroepiandrosterone, androstenedione, testosterone, and dihydrotestosterone in vivo.

At the time of surgery, women were infused with [3H]dehydroepiandrosterone sulfate ([3H]DS)/[14C]testosterone ([14C]T) for 6 h; blood samples were obtained from an artery the ovarian veins, and a peripheral vein; and fluid was obtained from ovarian follicles. Both blood and follicular fluid samples were analyzed for radioactivity as DS, dehydroepiandrosterone (D), androstenedione (delta 4A). T, and dihydrotestosterone (DHT), and the blood was also analyzed for the concentration of nonisotopic DS by RIA. In other subjects the concentrations of D and DS were measured in paired samples of blood and follicular fluid. From these data, values of 13.6 +/- 0.69 L/day four (mean +/- SE; n = 4) for MCRDS, 607 +/- 90 L/day (n = 3) for MCRT, and 0.0190 +/- 0.0089 (n = 3) for [p]DS-T (fraction of plasma DS metabolized to plasma T) were obtained. The ratio of the concentration of the tracer-labeled steroid in the follicular fluid to the concentration in the arterial plasma sample was elevated significantly above 1 for three 3H-labeled and three [14C-labeled metabolites: [3H]D (21-fold; P less than 0.001), [3H]T (81-fold; P less than 0.001), [3H]DHT (19-fold; P less than 0.001), [14C]T (4-fold; P less than 0.025), [14C]DHT (21-fold; P less than 0.01), and [14C]delta 4A (50-fold; P less than 0.001). The estimated concentrations of steroids in follicular fluid derived from DS based on specific activity calculations were as follows: [geometric mean (95% confidence limits; n)]: DS, 5600 (4800-6500 nmol/L; 12); D, 370 (88-1500 nmol/L; 10); delta 4 A, 120 (67-220 nmol/L; 12); T, 130 (39-450 nmol/L; 10); and DHT, 64 (35-120 nmol/L; 8). Comparison of these data to known follicular fluid steroid concentrations shows that DS from the intravascular pool can be used as an ovarian prehormone.

Adult↗

PubMed1992

Enhanced transdermal delivery of testosterone across nonscrotal skin produces physiological concentrations of testosterone and its metabolites in hypogonadal men.

None of the current or experimental androgen treatment modalities for male hypogonadism has been reported to produce physiological concentrations or circadian variations in testosterone (T) and its metabolites, dihydrotestosterone (DHT) and estradiol (E2). This investigation describes a novel transdermal dosage form designed to enhance the delivery of native T across nonscrotal skin. The main objective was to determine whether the nightly application of two experimental transdermal patches to different sites on the body (e.g. back, chest, arms, etc.) would result in normal plasma levels of T, DHT, and E2 for men and mimic the normal circadian variation. Six hypogonadal males (aged 24-66 yr) were studied 4 weeks after stopping T ester treatment. After single application of two patches, T levels increased from a pretreatment baseline of 5.8 +/- 0.94 nmol/L (mean +/- SE; 167 +/- 27 ng/dL) to an average peak concentration of 44.1 +/- 4.8 nmol/L (1273 +/- 138 ng/dL) 5.7 +/- 0.6 h after application and reached a 24-h level of 16.9 +/- 2.9 nmol/L (488 +/- 85 ng/dL). DHT and E2 levels exhibited parallel variations within the normal reference ranges. During 4 weeks of daily evening application to various sites on the torso, the mean delivery of T from two patches was 5.2 +/- 0.1 mg/day (approximately 20% of the patch content), and morning T levels were within the normal limits. On day 28 of treatment, the 24-h plasma profiles of T, DHT, and E2 (obtained with two patches on the back) approximately mimicked the normal circadian variations reported in healthy young men. The time-averaged T level was 21.8 +/- 2.9 nmol/L (629 +/- 84 ng/dL), and the plasma concentration ratios of DHT/T (0.07 +/- 0.01) and E2/T (0.005 +/- 0.001) were within the normal range. SHBG concentrations were not significantly altered over the 4 weeks of treatment. The patches were well tolerated, except for one patient who developed a local reaction to an excipient during the third week of treatment. Two of the patients (one with Klinefelter's syndrome) completed several months of continuous therapy. T, DHT, and E2 have remained in the range of normal, and plasma LH levels in the patient with Klinefelter's syndrome became normal. Subjective improvement in symptoms has continued, and tolerability has been good in both patients. These results indicate that the enhanced transdermal delivery of T across nonscrotal skin is a patient-friendly androgen replacement modality and produces physiological concentrations of T and its metabolites, which are unattainable with other treatment modalities.

Administration, Cutaneous↗

PubMed1996

Comparison between testosterone enanthate-induced azoospermia and oligozoospermia in a male contraceptive study. II. Pharmacokinetics and pharmacodynamics of once weekly administration of testosterone enanthate.

Hormonal suppression of spermatogenesis is currently being investigated as a method of reversible male contraception. However, administration of exogenous testosterone (T) induces azoospermia in only 40-70% of Caucasian men, whereas the remainder suppresses to severe oligozoospermia (< 5 x 10(5)/mL). The reason(s) for the heterogeneity in the spermatogenic response is not clear. We have prospectively investigated the possibilities that higher plasma concentrations of T and/or differences in the extent and rate of gonadotropin suppression could maintain a low level of spermatogenesis in subjects taking part in a clinical efficacy trial of hormonal male contraception. Thirty-three healthy adult men, aged 21-41 yr, were given 200 mg T enanthate (TE), im, weekly for up to 18 months. Azoospermia was achieved in 18 men (55%) after 20 weeks of treatment, at which time the remaining 15 (45%) stabilized at a mean sperm density of 2.0 +/- 0.8 (+/- SD) x 10(6)/mL. These 15 subjects remained oligozoospermic for the rest of the efficacy study. To compare the pharmacokinetics and pharmacodynamics of TE between the azoospermic and oligozoospermic responders, plasma samples were obtained immediately before and 1, 2, 4, and 7 days after the 1st and 16th TE injections. Further samples were taken after 2, 4, 8, and 12 weeks of treatment. Plasma concentrations of total, free, and non-sex hormone-binding globulin (non-SHBG)-bound T, estradiol, LH, and FSH were measured. Compared to baseline, preinjection levels of total T increased 2.5-fold, reaching a steady state around 12 weeks of treatment. Peak concentrations of total T increased by 5-fold, but free and non-SHBG-bound T levels were increased by 10-fold after 16 weeks. The plasma levels of estradiol showed similar changes as T. However, neither T (bound or free) nor estradiol was significantly different between azoospermic and oligozoospermic responders. Plasma SHBG was reduced to a similar degree in both groups of men after 16 weeks of TE treatment. Plasma concentrations of both LH and FSH decreased rapidly after the first TE injection; a significant decline in LH was detectable after 24 h. Mean levels of both gonadotropins decreased to less than 0.5 U/L by the end of 4 weeks and to below the limit of sensitivity of the assays (0.05 IU/L) by 12 weeks. There were no significant differences in plasma concentrations of LH or FSH or in the rates of suppression between azoospermic and oligozoospermic responders. We conclude that the polymorphism of spermatogenic suppression in response to exogenous T is unlikely to be due to differences in the pharmacokinetics or pharmacodynamics of TE or in the sensitivity of the hypothalamo-pituitary-testicular axis to sex steroid inhibition. Measurements of total plasma T considerably underestimate the increase in bioavailable T during the weekly TE regimen.

Adult↗

PubMed1996

Comparison between testosterone enanthate-induced azoospermia and oligozoospermia in a male contraceptive study. III. Higher 5 alpha-reductase activity in oligozoospermic men administered supraphysiological doses of testosterone.

The administration of exogenous testosterone (T) to eugonadal men causes suppression of gonadotropin secretion and thus of spermatogenesis. This is currently being investigated as a possible method of hormonal male contraceptive, but complete suppression of spermatogenesis to azoospermia is induced in only 50-70% of Caucasian men; the remainder maintain a low rate of spermatogenesis. The basis for this polymorphism in response is unclear. The enzyme 5 alpha-reductase (5 alpha R) converts T to dihydrotestosterone (DHT) and is important in determining the magnitude of the androgen stimulus in some tissues. We investigated whether the maintenance of spermatogenesis in men remaining oligozoospermic while receiving suppressive doses of T is associated with evidence of increased 5 alpha R activity. Thirty-three normal men were given 200 mg T enanthate (TE), im, weekly in a clinical trial of hormonal male contraception. The MCR of T (MCRT) and the conversion ratio of T to DHT (CRT-DHT) were measured by infusion of [3H]T, plasma levels of DHT and androstanediol glucuronide (AdiolG) were measured by RIA, and 24-h urinary steroid metabolites were measured by capillary column gas chromatography. Sperm density decreased in all men; 18 achieved azoospermia by 20 weeks of treatment, and the remainder had a mean sperm density of 2.0 +/- 0.8 x 10(5)/mL at that time. This treatment caused increases in plasma T levels and MCRT, but with no differences between azoospermic and oligozoospermic responders. There were no differences in CRT-DHT plasma DHT, or AdiolG before treatment, but after 16 weeks, CRT-DHT had increased in the oligozoospermic responders, but not in the azoospermic responders. TE treatment increased plasma DHT and AdiolG levels in both groups, but the increases in both 5 alpha R metabolites were significantly greater in the oligozoospermic responders. Urinary excretion of etiocholanolone and androsterone was increased after 16 weeks of TE treatment, but did not differ between the two groups, andetiocholanolone/androsterone ratios did not differ greatly from unity. There was no change in urinary excretion of tetrahydrocortisol, allo-tetrahydrocortisol, or cortisone after 16 weeks of TE treatment in either group. These results suggest that after TE administration there is a selective increase in 5 alpha R activity in those men who remain oligozoospermic, but not in those becoming azoospermic. This difference in the androgenic milieu may underlie the incomplete suppression in the oligozoospermic responders, in whom a low rate of spermatogenesis is maintained despite the apparent absence of gonadotropins.

Adult↗

PubMed1999

Oral progestogen combined with testosterone as a potential male contraceptive: additive effects between desogestrel and testosterone enanthate in suppression of spermatogenesis, pituitary-testicular axis, and lipid metabolism.

The effects of a synthetic oral progestogen, desogestrel (DSG), administered with low dose testosterone (T) were investigated to determine the optimal combination for suppression of gonadotropins and spermatogenesis to targets compatible with effective male contraception. Twenty-four healthy male volunteers (33.2 +/- 0.9 yr) were randomly assigned to 3 groups (n = 8) to receive: 1) 300 microg DSG orally daily and 100 mg T enanthate, i.m., weekly; 2) 300 microg DSG and 50 mg T enanthate; or 3) 150 microg DSG and 100 mg T enanthate for 24 weeks. To investigate the individual contribution to the combined action, DSG was administered alone for the first 3 weeks, and T enanthate was added on day 22. After 24-week treatment, sperm density in 78% (18 of 23) of the subjects became azoospermic, whereas 91.7% (22 of 24) and 95.8% (23 of 24) suppressed to less than 1 million/mL and less than 3 million/mL, respectively. The 300 microg DSG with 50 mg T enanthate combination induced azoospermia in 8 of 8 subjects, and the suppression of sperm density was significantly greater than that in the 300 microg DSG/100 mg T enanthate group, but was not different from that in the 150 microg DSG/100 mg T enanthate group. DSG (300 or 150 microg daily) alone in the first 3 weeks suppressed LH, FSH, and T to 60.6%, 48.0%, and 35.4%, respectively, of the baseline. Addition of T enanthate (50 and 100 mg weekly) raised plasma T to the physiological range and induced a further fall in LH and FSH to the limits of assay detection. There was no consistent difference in mean LH and FSH levels among the three groups during treatment or recovery, except that FSH remained detectable in a higher proportion of samples from the group receiving 300 microg DSG with 50 mg T enanthate. Total cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol decreased by 9.3 +/- 1.7%, 10.3 +/- 2.6%, and 7.7 +/- 2.8%, respectively, during treatment with DSG alone with no difference between 300 and 150 microg. Addition of T enanthate (both 50 and 100 mg weekly) induced a further fall only in high density lipoprotein cholesterol to 22.6 +/- 3.7% from the baseline. In summary, the combined actions of oral DSG with low doses of T enanthate were highly effective in suppressing pituitary-testicular functions in adult men. The optimal regimen for inducing azoospermia was 300 microg DSG daily with 50 mg T enanthate weekly. Oral DSG exerted discernible effects on lipid metabolism. We conclude that the combination of oral progestogens with low dose T is a promising approach to achieve effective reversible male contraception.

Administration, Oral↗

PubMed1999

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.

Administration, Cutaneous↗

PubMed2001

Differential regulation of gonadotropin secretion by testosterone in the human male: absence of a negative feedback effect of testosterone on follicle-stimulating hormone secretion.

Studies of sex steroid regulation of gonadotropin secretion in the human male have focused primarily on the respective site(s) of negative feedback of testosterone (T) and estradiol (E(2)). The use of pharmacological doses of sex steroids in these studies has precluded conclusions about the relative roles of T and E(2) in gonadotropin feedback. Thus, the aims of the present study were to 1) determine the relative contributions of T vs. E(2) to the sex steroid component of gonadotropin regulation, and 2) distinguish the feedback effects of T that that are direct (i.e. mediated by the androgen receptor) vs. indirect (mediated by aromatization to E(2)). Two experimental interventions were used: 1) inhibition of aromatization by a selective aromatase inhibitor to examine the impact of selective E(2) withdrawal; and 2) acute medical castration to examine the effect of ablating both T and E(2). Sixteen normal (NL) men (mean age, 30.5 +/- 2.2 yr) were studied. Nine NL subjects were treated with the aromatase inhibitor, anastrozole (10 mg, orally, daily, for 5 days). Twelve NL men underwent medical castration with ketoconazole (1-g loading dose followed by 400 mg, orally, four times a day for 5 days). Ketoconazole-treated subjects received concomitant treatment with dexamethasone (0.5 mg twice daily) to prevent the development of adrenal insufficiency. Single blood samples were drawn daily between 0800-1000 h. To ensure that dexamethasone was not altering the gonadotropin response to sex steroid ablation by a direct pituitary effect, five GnRH-deficient men (mean age, 37.6 +/- 3.9 yr) underwent GnRH dose-response studies at baseline and after treatment with dexamethasone (0.5 mg twice daily). Aromatase blockade caused significant lowering of E(2) (33 +/- 3 to 14 +/- 1 pg/mL; P: < 0.0005) with a corresponding increase in T levels (563 +/- 42 to 817 +/- 81 ng/dL; P: < 0.05). Treatment with ketoconazole resulted in equivalent suppression of E(2) (41 +/- 4 to 14 +/- 1 pg/mL; P: < 0.0005), but also induced castrate levels of T (491 +/- 28 to 40 +/- 3 ng/dL; P: < 0.0005). Both treatment regimens were associated with a significant increase in gonadotropin levels. For LH, the percent increase in serum levels after castration was almost 3-fold greater than that seen after selective E(2) withdrawal (275 +/- 23% with ketoconazole vs. 95.6 +/- 21% with anastrozole; P: < 0.005). Despite the divergent changes in T levels with these two maneuvers (a marked decrease after ketoconazole and a significant increase with anastrozole), the percent rise in FSH levels was similar in the two protocols (91 +/- 6% vs. 71 +/- 7%, respectively; P: = NS). Inhibin B levels were unchanged after selective E(2) withdrawal (156 +/- 23 vs. 176 +/- 19 pg/mL), but decreased slightly with ketoconazole (156 +/- 15 to 131 +/- 11 pg/mL; P: < 0.05). In contrast to the effects of glucocorticoid administration on gonadotropin secretion in women, no significant changes were observed in the GnRH-deficient men treated with dexamethasone in terms of mean LH levels (19.8 +/- 3.2 vs. 23.3 +/- 5.4 IU/L), mean LH pulse amplitude after GnRH (16.0 +/- 2.5 vs. 19.0 +/- 5.1 IU/L), or mean FSH levels (8.0 +/- 1.9 vs. 9.2 +/- 2.4 IU/L, pre vs. post). These studies provide evidence of differential regulation of gonadotropin secretion by T in the human male. T exerts both direct and indirect feedback on LH secretion, whereas its effects on FSH appear to be mediated largely by aromatization to E(2). From these data we conclude that in terms of sex steroid feedback, E(2) is the predominant regulator of FSH secretion in the human male.

Adult↗

PubMed2000

Changes in plasma testosterone and testicular transferrin concentration, testicular histology and semen quality after treatment of testosterone-depot plus PMSG to 3 dogs with asthenozoospermia.

Three dogs diagnosed as having asthenozoospermia were given three intramuscular injections of 50 mg testosterone(T)-depot plus 250 IU pregnant mare serum gonadotropin (PMSG) at 2-week intervals, and their plasma T and testicular transferrin (Tf) concentrations, testicular histology, and semen quality were examined during the period of hormone therapy. Plasma T concentrations temporarily increased, and there was a slight improvement in spermatogenesis. Increased Tf concentrations suggested that Sertoli cell function in all three dogs was promoted by hormone treatment. The results showed that semen quality, especially the percentages of motile sperm and abnormal sperm, were improved between 1 and 5 weeks after the start of T-depot plus PMSG treatment.

Animals↗

PubMedDate not supplied

Interaction of testosterone and testosterone receptor complexes with nuclei of skeletal muscle from intact male mice and from mice bearing the testicular feminization (Tfm) mutant gene.

With the nuclear exchange assay and the nuclear retention assay it is shown that the androgen insensitivity of Tfm mice is probably due to a defect of the nuclear acceptor sites for the testosterone receptor complex. Further on the results obtained point strongly to the possibility that hormone free androgen receptor is localized in the nuclei and in the cytoplasma according to the "equilibrium model". A practicable method for separation of unbound steroids from nuclei is described.

Androgen-Insensitivity Syndrome↗