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PubMed2006

Vaginal application of testosterone: A study on pharmacokinetics and the sexual response in healthy volunteers.

INTRODUCTION: Androgen substitution is advocated to improve sexual functioning in women with androgen insufficiency. Nevertheless, the role of androgens in female sexual functioning is not yet unraveled. Even less is known about changes in androgens and the female sexual response. AIM: The aim of the study is to describe the pharmacokinetics of a single dose of vaginally applied testosterone. In addition, the study aims to gain more insight into the relation between acute changes in testosterone levels and the sexual response in women. METHODS: A randomized, double-blind, crossover study design was used to compare a single vaginal dose of testosterone propionate (2 mg) with placebo. Ten healthy premenopausal women participated. Serum levels of testosterone, free testosterone, and estradiol were measured. The sexual response was measured before application of medication and 4 and 8 hours after application. Erotic video fragments and erotic fantasies were used as stimuli. The genital sexual response was measured using vaginal plethysmography. The subjective sexual response was measured using a visual analog scale. RESULTS: Vaginal administration of testosterone propionate induced a significant rise in serum testosterone levels and free testosterone levels, but not in serum estradiol levels. Peak levels were reached after 5.5 hours (range 2-12 hours). Mean peak levels of testosterone were 7.71 nmol/L after testosterone propionate and 2.99 nmol/L after placebo (P < 0.005). Mean peak levels of free testosterone were 0.12 nmol/L after testosterone propionate and 0.04 nmol/L after placebo (P < 0.005). Despite marked elevated levels of androgens this study was unable to detect a direct effect on the genital or subjective sexual response. CONCLUSIONS: A single dose of vaginally applied testosterone propionate elevates serum levels of testosterone and free testosterone within 6 hours. Nevertheless, this acute rise in androgens has no effects on the female sexual response.

Administration, Intravaginal↗

PubMed2006

Wide variability in laboratory reference values for serum testosterone.

INTRODUCTION: The laboratory determination of testosterone levels consistent with a diagnosis of hypogonadism is complicated by the availability of multiple testosterone assays and varying reference ranges. AIM: To assess current laboratory practices regarding availability of testosterone assays and use of reference values. METHODS: A telephone survey of 12 academic, 12 community medical laboratories, and one national laboratory. MAIN OUTCOME MEASURES: Types of androgen assays offered and determination of reference values. RESULTS: All of the academic and eight of the community centers performed total testosterone testing. Free testosterone was performed in-house by six of the 12 academic and one community center. Testing for bioavailable testosterone, free androgen index, and percent free testosterone was performed in-house by no more than two centers. There were eight and four different assays used for total and free testosterone, respectively. One national laboratory offered equilibrium dialysis measurement of free testosterone. Of the 25 labs, there were 17 and 13 different sets of reference values for total and free testosterone, respectively. The low reference value for total testosterone ranged from 130 to 450 ng/dL (350% difference), and the upper value ranged from 486 to 1,593 ng/dL (325% difference). Age-adjusted reference values were applied in four centers for total testosterone and in seven labs for free testosterone. All reference values were based on a standard statistical model without regard for clinical aspects of hypogonadism. Twenty-three of the 25 lab directors responded that clinically relevant testosterone reference ranges would be preferable to current standards. CONCLUSIONS: Laboratory reference values for testosterone vary widely, and are established without clinical considerations.

Androgens↗

PubMed2001

Testosterone dose-response relationships in healthy young men.

Testosterone increases muscle mass and strength and regulates other physiological processes, but we do not know whether testosterone effects are dose dependent and whether dose requirements for maintaining various androgen-dependent processes are similar. To determine the effects of graded doses of testosterone on body composition, muscle size, strength, power, sexual and cognitive functions, prostate-specific antigen (PSA), plasma lipids, hemoglobin, and insulin-like growth factor I (IGF-I) levels, 61 eugonadal men, 18-35 yr, were randomized to one of five groups to receive monthly injections of a long-acting gonadotropin-releasing hormone (GnRH) agonist, to suppress endogenous testosterone secretion, and weekly injections of 25, 50, 125, 300, or 600 mg of testosterone enanthate for 20 wk. Energy and protein intakes were standardized. The administration of the GnRH agonist plus graded doses of testosterone resulted in mean nadir testosterone concentrations of 253, 306, 542, 1,345, and 2,370 ng/dl at the 25-, 50-, 125-, 300-, and 600-mg doses, respectively. Fat-free mass increased dose dependently in men receiving 125, 300, or 600 mg of testosterone weekly (change +3.4, 5.2, and 7.9 kg, respectively). The changes in fat-free mass were highly dependent on testosterone dose (P = 0.0001) and correlated with log testosterone concentrations (r = 0.73, P = 0.0001). Changes in leg press strength, leg power, thigh and quadriceps muscle volumes, hemoglobin, and IGF-I were positively correlated with testosterone concentrations, whereas changes in fat mass and plasma high-density lipoprotein (HDL) cholesterol were negatively correlated. Sexual function, visual-spatial cognition and mood, and PSA levels did not change significantly at any dose. We conclude that changes in circulating testosterone concentrations, induced by GnRH agonist and testosterone administration, are associated with testosterone dose- and concentration-dependent changes in fat-free mass, muscle size, strength and power, fat mass, hemoglobin, HDL cholesterol, and IGF-I levels, in conformity with a single linear dose-response relationship. However, different androgen-dependent processes have different testosterone dose-response relationships.

Adult↗

PubMed1990

Testosterone at high concentrations interacts with the human androgen receptor similarly to dihydrotestosterone.

Testosterone and dihydrotestosterone are believed to exert their androgenic effects by interacting with a single intracellular receptor protein in androgen target tissues. During fetal life, however, testosterone mediates the virilization of the Wolffian ducts into the epididymis, vas deferens, and seminal vesicles, whereas the urogenital sinus and external genitalia require the in situ conversion of testosterone to dihydrotestosterone to undergo male development. The reason why the signal provided by testosterone needs to be amplified in some androgen target tissues but not in others remains an enigma. To provide insight into the different actions of these androgens we studied their interaction with the human androgen receptor in fibroblasts cultured from the genital skin of a patient with 5 alpha-reductase deficiency. Dihydrotestosterone was formed in negligible amounts in these cells, and in some experiments the residual 5 alpha-reductase activity was further blocked with the 5 alpha-reductase inhibitor finasteride. Saturation analysis in fibroblast monolayers disclosed similar amounts of binding with testosterone and dihydrotestosterone, and the affinity of binding of dihydrotestosterone was, on the average, about 2-fold greater than that of testosterone. [3H]Testosterone also exhibited a 5-fold faster dissociation rate from the receptor than [3H]dihydrotestosterone. In thermolability experiments the [3H]testosterone-receptor complex displayed marked instability at 42 C with 2 nM [3H] testosterone, whereas with 20 nM [3H]testosterone, receptor stability was similar to that seen with [3H]dihydrotestosterone. In up-regulation experiments, 2 nM [3H]testosterone produced a 34% increase in specific androgen receptor binding after 24 h, whereas 20 nM [3H]testosterone produced an average increase of 64%. Our results suggest that the weaker androgenic potency of testosterone compared to that of dihydrotestosterone resides in its weaker interaction with the androgen receptor, most clearly demonstrable as an increase in the dissociation rate of testosterone from the receptor. When present in relatively high concentrations, however, testosterone overcomes this defect by mass action.(ABSTRACT TRUNCATED AT 400 WORDS)

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed2003

Middle-aged men secrete less testosterone at night than young healthy men.

Aging men largely maintain their testicular androgen production. Cross-sectional studies have demonstrated that after the age of 40 yr a 0.2-2% annual decline is observed in morning total testosterone. In elderly males, the coordinate release of LH and testosterone became asynchronous despite normal serum levels of these hormones. The aim of this study was to test the reproductive hormone rhythm at night in middle-aged men. We studied seven healthy middle-aged (46.6 +/- 6.7 yr) and six healthy young (23.9 +/- 2.4 yr) men by determining their serum levels of LH and testosterone levels every 15 min from 1900-0700 h with simultaneous sleep recordings. The nocturnal rise in testosterone occurred earlier in young men (2235 +/- 0022 h) and at 2331 +/- 0057 h in middle-aged men (P < 0.04). In young men, the mean testosterone level at night (5.0 +/- 1.3 ng/ml; 17.4 +/- 4.4 nmol/liter) and the integrated nocturnal secretion [area under the curve (AUC); 60.6 +/- 8.9 ng/ml.h; 210 +/- 31 nmol/liter.h] were significantly higher compared with the values (3.6 +/- 1.1 and 31.1 +/- 7.2 ng/ml.h; 12.6 +/- 3.8 and 108 +/- 24.8 nmol/liter.h, respectively) observed in middle-aged men (P < 0.04 and P < 0.01, respectively). The mean (3.5 +/- 0.3 mIU/ml; 3.5 +/- 0.3 IU/liter) and AUC (43.4 +/- 8.3 mIU/ml.h; 43.4 +/- 8.3 IU/liter.h) LH values in middle-aged men were significantly higher than the values observed in young men (2.0 +/- 0.7 and 30.8 +/- 6.1 mIU/ml.h; 2.0 +/- 0.7 and 30.8 +/- 6.1 IU/liter.h; P < 0.05 and P < 0.01, respectively). Young men had significantly more testosterone pulses at night (6.7 +/- 1.6/12 vs. 3.8 +/- 1.1/12 h in middle-aged men; P < 0.005) of shorter interpulse interval (88.5 +/- 23.6 vs. 137.4 +/- 46.4 min; P < 0.02). LH pulse characteristics and sleep quality were similar in both groups. However, the first rapid eye movement (REM) sleep episode occurred earlier in middle-aged men (2303 +/- 0034 h) vs. young men (0010 +/- 0054 h; P < 0.04). As a consequence, the testosterone rise antedated the first REM episode by 90 min in young men. The link between testosterone rise and REM sleep episode was not observed in middle-aged men. Linear regression analysis revealed that the LH AUC was significantly related to age (P < 0.02). Analysis of covariance revealed that the two groups differed significantly in testosterone AUC (P < 0.04). Comparison of LH and testosterone concentrations showed significant and positive cross-correlations between LH and testosterone only in young men, with the testosterone rise lagging 60 min after the rise in LH. Our findings suggest that in middle-aged men, less pulsatile testosterone and more LH are secreted at night than in young men, with disruption of the association between testosterone rhythm and REM sleep. The decline in nocturnal testosterone secretion appears to involve a combination of testicular and pituitary hypogonadism.

Adult↗

PubMed1998

The use of a sensitive equilibrium dialysis method for the measurement of free testosterone levels in healthy, cycling women and in human immunodeficiency virus-infected women.

Measurements of total and free testosterone levels in women have lacked precision and accuracy because of limited assay sensitivity. The paucity of normative data on total and free testosterone levels in healthy women has confounded interpretation of androgen levels in women with human immunodeficiency virus (HIV) infection and other disease states. Therefore, the objectives of this study were to develop sensitive assays for the measurement of the low total and free testosterone levels in women to define the range for these hormones during the normal menstrual cycle and assess the total and free testosterone levels in HIV-infected women. By using a larger volume of serum, increasing the incubation time, and reducing the antibody concentration, the sensitivity of the total testosterone assay was increased to 0.008 nmol/L, and that of the free testosterone assay was increased to 2 pmol/L. The mean percent free testosterone was 1.0 +/- 0.1% of the total testosterone. Serum total and free testosterone levels in the follicular and luteal phases were not significantly different, but both demonstrated a modest preovulatory increase, 3 days before the LH peak. Serum total [0.50 +/- 0.32 (14.60 +/- 9.22) vs. 1.2 +/- 0.7 nmol/L (34.3 +/- 21.0 ng/dL); P < 0.0001] and free testosterone levels (5.56 +/- 2.70 (1.58 +/- 0.80) vs. 12.8 +/- 5.5 pmol/L (3.4 +/- 1.7 pg/mL); P < 0.0001) were significantly lower in HIV-infected women (n = 37) than in healthy women (n = 34). Serum total and free testosterone levels were also significantly lower in HIV-infected women who were menstruating normally. There were no significant differences in serum total and free testosterone levels between those who had lost weight and those who had not. Testosterone levels correlated inversely with plasma HIV ribonucleic acid copy number. Serum FSH, but not LH, levels were significantly higher in HIV-infected women than in controls. Using assays with sufficient sensitivity, we defined the range for total and free testosterone levels during the normal menstrual cycle. Serum total and free testosterone levels are lower in HIV-infected women and correlate inversely with plasma HIV ribonucleic acid levels. The hypothesis that androgen deficiency contributes to wasting in HIV-infected women remains to be tested.

Adult↗

PubMed2002

Pharmacokinetics of a new transdermal testosterone gel in gonadotrophin-suppressed normal men.

OBJECTIVE: In a phase I single-centre, open, randomized study, the pharmacokinetics of two doses of a transdermal testosterone gel containing 2.5% testosterone were evaluated in 26 healthy male volunteers. DESIGN: To eliminate the influence of endogenous serum testosterone, gonadotrophins and endogenous testosterone secretion were suppressed by a single intramuscular injection of 400 mg norethisterone enanthate. Fourteen men applied 5.0 g and 12 men applied 2.5 g testosterone gel daily for 10 days. Half the men in each group washed the gel off 10 min after it had been applied. RESULTS: In all the men, a marked suppression of LH, FSH, testosterone, dihydrotestosterone (DHT) and oestradiol was observed after norethisterone treatment. Physiological serum concentrations of testosterone were restored during the 10-day treatment period in the group of men applying 5.0 g testosterone gel. Increasing serum concentrations of testosterone from day 1 to day 10 were observed. Oestradiol and DHT concentrations did not exceed normal values. Washing 10 min after gel application did not influence the resorption of testosterone. A dose of 2.5 g testosterone gel was insufficient to achieve physiological serum concentrations of testosterone. CONCLUSION: Testosterone replacement treatment with 5.0 g of this 2.5% testosterone gel is able to achieve constant physiological testosterone concentrations in gonadotrophin-suppressed men. Washing the skin after 10 min does not influence the pharmacokinetic profile and thus significantly reduces the risk of contamination of female partners or infants.

Adult↗

PubMed2006

Testosterone and cognitive function: current clinical evidence of a relationship.

BACKGROUND: Testosterone levels decline as men age, as does cognitive function. Whether there is more than a temporal relationship between testosterone and cognitive function is unclear. Chemical castration studies in men with prostate cancer suggest that low serum testosterone may be associated with cognitive dysfunction. Low testosterone levels have also been observed in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI). This paper reviews the current clinical evidence of the relationship between serum testosterone levels and cognitive function in older men. METHODS: A systematic literature search was conducted using PubMed and EMBASE to identify clinical studies and relevant reviews that evaluated cognitive function and endogenous testosterone levels or the effects of testosterone substitution in older men. RESULTS: Low levels of endogenous testosterone in healthy older men may be associated with poor performance on at least some cognitive tests. The results of randomized, placebo-controlled studies have been mixed, but generally indicate that testosterone substitution may have moderate positive effects on selective cognitive domains (e.g. spatial ability) in older men with and without hypogonadism. Similar results have been found in studies in patients with existing AD or MCI. CONCLUSIONS: Low endogenous levels of testosterone may be related to reduced cognitive ability, and testosterone substitution may improve some aspects of cognitive ability. Measurement of serum testosterone should be considered in older men with cognitive dysfunction. For men with both cognitive impairment and low testosterone, testosterone substitution may be considered. Large, long-term studies evaluating the effects of testosterone substitution on cognitive function in older men are warranted.

Androgens↗

PubMed1991

Metabolic clearance rate of testosterone in male epileptic patients on anti-convulsant therapy.

There are several reports which state that male epileptics on anti-convulsant therapy have reduced sexual activity. We and others have shown that, although total testosterone is raised, the free testosterone concentration is reduced in this patient population. This could be a result of an increased metabolic clearance rate (MCR) of testosterone, inadequate secretion of LH to stimulate testosterone synthesis or inappropriately low testosterone production by the Leydig cells. We have examined these possibilities by measuring the MCR of testosterone in 15 male epileptics on anti-convulsant therapy. In this group of patients, the mean LH (9.3 +/- 5.9 IU/l) and sex-hormone binding globulin (SHBG) (54.5 +/- 22.9 nmol/l) concentrations were significantly greater than those of five normal control subjects (4.7 +/- 1.11 IU/l and 26.0 +/- 7.0 nmol/l respectively). Mean total testosterone concentrations of the two groups were not significantly different but the mean percentage of free testosterone and free testosterone concentration were significantly lower in the patient population (2.06 +/- 0.43 vs 2.98 +/- 0.27 and 0.56 +/- 1.1 vs 0.79 +/- 0.07 pmol/l). The MCR of testosterone was significantly lower in the patients (773 +/- 322 vs 1354 +/- 443 l/day) and showed a positive correlation with the percentage of free testosterone. Therefore, our results suggest that the lowered free testosterone in male epileptics on anti-convulsant therapy is not due to an increased MCR of testosterone. The increased LH concentration suggests primary hypogonadism. This, in turn, could be responsible for low free testosterone levels in the presence of normal testosterone.

Adult↗

PubMed1999

[Testosterone and atherosclerosis in males during andropause].

Nowadays besides the commonly accepted atherogenic risk factors a special emphasis is laid on the significance of testosterone in atherogenesis in men which physiologic deficit during "andropause" is able to promote this pathology. An elevated estradiol:testosterone ratio seems to be an independent risk factor of atheromatous heart complications. There is a proved positive correlation between free testosterone, total testosterone, dihydrotestosterone and HDL-cholesterol, apoA1 apolipoprotein. The relationship between LDL-cholesterol, VLDL-cholesterol, total cholesterol and total and free testosterone seems to be unanimous, but in certain studies the beneficial influence of testosterone on the mentioned lipids has been observed. The discussed hormone is also functionally connected with coagulation and fibrynolisis; a positive correlation was found between endogenous testosterone and tPA-Fx and a negative correlation between testosterone and PAI-1, fibrinogen, D-dimers, alpha 2-antiplasmin. Testosterone is a functional regulator of the vascular tonus and influences on reological properties of microcirculation (the application of testosterone infusion into canine coronary arteries causes the dilatation of main and the small vessels, through NO syntetase induction and ATP-dependent K(+)- channel activation). A statistically significant positive correlation between testosterone and insulin has been stated (an elevated oestradiol:testosterone ratio is connected with the insulin resistance). Additionally a negative relationship between testosterone and android obesity has been observed. Although nowadays there are more and more facts proving the benefits of the retaining the proper testosterone levels in aging men, the final influence of the testosterone supplementary therapy on atherogenesis is not solved.

Adult↗

PubMed1997

Testosterone implants increase song but not aggression in male Lapland longspurs

Lapland longspurs, Calcarius lapponicusare tundra-nesting arctic birds with an extremely short breeding season. Males show a pronounced brief peak of plasma testosterone early in the season. We studied the effect of exogenous testosterone on song and aggression in free-living male Lapland longspurs. We gave high-testosterone implants to 16 birds, low-testosterone implants to seven birds, and empty or no implants to 33 birds. The implants resulted in significantly different plasma testosterone levels during incubation (high-testosterone mean=20.79±3.4 ng/ml, low-testosterone mean=2.54±0.5 ng/ml, control mean=0.53±0.1 ng/ml). High-testosterone birds had larger cloacal protuberances than controls, but low-testosterone birds did not. We measured aggression and song with simulated territorial intrusions during incubation, a mean of 12.03±1.45 days after the insertion of implants. High-testosterone birds and low-testosterone birds were no more aggressive than controls. However, high-testosterone birds, but not low-testosterone birds, were significantly more likely than controls to sing. These results suggest that the high, brief testosterone peak of Lapland longspurs may be related more to song than to territorial aggression. Alternatively, both aggression and song may be testosterone-influenced, but aggression may be more readily suppressed during incubation. The hormone-behaviour patterns demonstrated in this study may be adaptations for breeding in the short arctic summer.Copyright 1997 The Association for the Study of Animal Behaviour1997The Association for the Study of Animal Behaviour

Journal Article↗

PubMed2001

17alpha-methyl testosterone is a competitive inhibitor of aromatase activity in Jar choriocarcinoma cells and macrophage-like THP-1 cells in culture.

17alpha-methyl testosterone is a synthetic androgen with affinity for the androgen receptor. 17alpha-methyl testosterone is used widely as a component of hormone replacement therapy. Previous reports have indicated that contrary to testosterone, 17alpha-methyl testosterone is not aromatized. However, 17alpha-methyl testosterone still could affect local estrogen formation by regulating aromatase expression or by inhibiting aromatase action. Both possibilities have important clinical implications. To evaluate the effect of 17alpha-methyl testosterone on the expression and activity of aromatase, we tested the choriocarcinoma Jar cell line, a cell line that express high levels of P450 aromatase, and the macrophage-like THP-1 cells, which express aromatase only after undergoing differentiation. We found that in both cell lines, 17alpha-methyl testosterone inhibits aromatase activity in a dose-related manner. The curve of inhibition parallels that of letrozole and gives complete inhibition at 10(-4) M 17alpha-methyl testosterone, determined by the tritium release assay. 17alpha-methyl testosterone does not have detectable effects on aromatase RNA and protein expression by Jar cells. Undifferentiated THP-1 cells had no aromatase activity and showed no effect of 17alpha-methyl testosterone, but differentiated THP-1 (macrophage-like) cells had a similar inhibition of aromatase activity by 17alpha-methyl testosterone to that seen in Jar cells. The Lineweaver-Burke plot shows 17alpha-methyl testosterone to be a competitive aromatase inhibitor. Our results show for the first time that 17alpha-methyl testosterone acts as an aromatase inhibitor. These findings are relevant for understanding the effects of 17alpha-methyl testosterone as a component of hormone replacement therapy. 17alpha-methyl testosterone may, as a functional androgen and orally active steroidal inhibitor of endogenous estrogen production, also offer special possibilities for the prevention/treatment of hormone-sensitive cancers.

Aromatase↗

PubMed1980

Effects of diethylstilbestrol and estramustine phosphate on serum sex hormone binding globulin and testosterone levels in prostate cancer patients.

Serum testosterone-estradiol binding globulin and total testosterone were measured in 2 groups of male controls (less than 50 and more than 65 years old) and in 7 groups of prostatic cancer patients treated with various endocrine manipulation procedures, including orchiectomy, and estramustine phosphate and diethylstibestrol therapy. There were 133 individuals studied. Total serum testosterone levels were significantly higher in the younger versus the older control group and testosterone-estradiol binding globulin levels were significantly higher in the older men. Whereas orchiectomy reduced serum testosterone to low concentrations (72 plus or minus 11 ng. per 100 ml.) testosterone-estradiol binding globulin levels were not altered. In contrast, estramustine phosphate and diethylstilbestrol therapy, when administered to intact or castrated patients, resulted in depressed testosterone and markedly elevated testosterone-estradiol binding globulin serum levels, particularly in those patients receiving estramustine phosphate (less than 35 ng. per 100 ml. and more than 6 micrograms per 100 ml., respectively). These studies led to the conclusion that diethylstilbestrol or estramustine phosphate therapy is significantly more effective than orchiectomy in eliciting a concomitant elevation of testosterone-estradiol binding globulin and a depression of total testosterone. Even though free serum testosterone was not measured in the present study the law of mass action would indicate that in those patients with high testosterone-estradiol binding globulin (more than 5 microgram. per 100 ml.) and low total testosterone levels (less than 80 ng. per 100 ml.) the availability of biologically active (unbound steroid) testosterone would be negligible.

Adult↗

PubMed1996

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.

Administration, Cutaneous↗

PubMed2006

Does testosterone have a role in erectile function?

PURPOSE: Despite the well-established role of testosterone in enhancing libido, its exact contribution to erections in men remains unclear. The main objectives of this review are to clarify the role of testosterone in erectile function and evaluate its therapeutic value in men with erectile dysfunction (ED). METHODS: Review of the relevant literature (English, French, and Spanish) from 1939 to June 2005 was conducted using data sources from MEDLINE, endocrinology text books, and hand searching of cross-references from original articles and reviews. Clinical trials, animal studies, case reports, reviews, and guidelines of major associations were included. RESULTS: Animal and preliminary human studies suggest that testosterone may facilitate erection by acting as vasodilator of the penile arterioles and cavernous sinusoids. Following castration, most, but not all, men had partial or complete loss of erection. Hypogonadism is not a common finding in ED, occurring in about 5% of cases, and in general, there is lack of association between serum testosterone levels, when present in normal or moderately low levels, and erectile function. Most trials using testosterone for treatment of ED in hypogonadal men suffer from methodological problems and report inconsistent results, but overall, suggest that testosterone may be superior to placebo. Erectile function is more likely to improve with testosterone therapy in patients with severe degrees of hypogonadism. Testosterone treatment may ameliorate the response to the phosphodiesterase 5 (PDE5) inhibitors in hypogonadal men and men with low-normal serum testosterone. Repeated measurement of morning serum total testosterone is a fairly accurate and easy method to evaluate androgenecity, but measurement of free or bioavailable testosterone is recommended in conditions that alter the levels of sex-hormone-binding globulin (SHBG), such as in the elderly and in obesity. CONCLUSIONS: Available data suggest that in most men circulating levels of testosterone, well below the normal range, are essential for normal erection and that higher levels of serum testosterone may not have major impact on erectile function. Screening for hypogonadism in all men with ED is necessary to identify cases of severe hypogonadism and some cases of mild to moderate hypogonadism, who may benefit from testosterone treatment.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2006

Monitoring testicular activity of male Eurasian (Lynx lynx) and Iberian (Lynx pardinus) lynx by fecal testosterone metabolite measurement.

The aim of the present study was to identify relevant fecal testosterone metabolites in the Eurasian lynx (Lynx lynx) using HPLC analysis and to evaluate the specificity of two testosterone immunoassays against these fecal metabolites. Finally, fecal hormone analysis was used to characterize seasonal reproductive activity of captive male Eurasian and Iberian (Lynx pardinus) lynx. Fecal samples from a male Eurasian lynx who received an i.v. injection of [3H]testosterone were subjected to HPLC analysis. All HPLC fractions were analyzed for radioactivity and androgen content by two testosterone immune assays (EIA and Testosterone-Immulite kits, DPC Biermann, Germany). Furthermore, fecal samples from four Eurasian lynx males (n=174) and three Iberian lynx (n=52) were collected throughout the year and fecal testosterone metabolites were determined with Testosterone-Immulite assay. HPLC separation of radiolabeled Eurasian lynx fecal extract indicated that the majority of testosterone metabolites are substances with a higher polarity than testosterone. Only minor proportion of radioactivity co-eluted with authentic testosterone and dihydrotestosterone. Enzymatic hydrolysis and solvolysis of the fecal extract were insufficient to liberate testosterone. After solvolysis relatively more activity was eluated the position of DHT, but the majority of metabolites remained unaffected. The EIA measured substantial amount of immunoreactivity, which corresponded with two radioactive peaks. Additionally, both immunoassays recognized two metabolites, which were only minor components according to their radioactivity. The Immulite assay was able to recognize a metabolite at the position of dihydrotestosterone. HPLC separation of Iberian lynx feces extracts revealed a similar metabolite pattern determined by EIA that were typical for Eurasian lynx fecal extracts. Simultaneous analyses of fecal samples with both testosterone assays provided comparative results for both lynx species (Eurasian lynx, r2=0.488; p<0.001; Iberian lynx, r2=0.85, p<0.0001). Thus, seasonal reproductive activity of male Eurasian lynx was demonstrated also by Immulite -assay, confirming high testosterone levels during breeding season in March/April as previously documented with EIA. Preliminary results on testosterone measurements in Iberian lynx feces confirmed the suitability of the applied Immulite test in this highly endangered species.

Animals↗

PubMed2001

Pharmacokinetics of testosterone after percutaneous gel or buccal administration.

OBJECTIVE: To determine the pharmacokinetics of testosterone following its administration using transdermal gel or buccal lozenges. DESIGN: Pilot study. SETTING: University-based hospital. PATIENT(S): Ten bilaterally oophorectomized women. INTERVENTION(S): Daily micronized testosterone gel (1 mg) and testosterone propionate lozenge (1 mg). MAIN OUTCOME MEASURE(S): Total testosterone, androstenedione, dihydrotestosterone, 3alpha-androstanediol glucuronide, and sex hormone-binding globulin were measured in serum by specific radioimmunoassays; free testosterone levels were also calculated. RESULT(S): Before treatment, serum testosterone levels in the groups using the lozenge and gel were 16 +/- 4.0 and 20 +/- 6.0 ng/dL, respectively. Mean maximum testosterone levels obtained with the lozenge occurred 1 hour after administration on days 1 (692 +/- 236 ng/dL) and 14 (836 +/- 309 ng/dL) of treatment and fell precipitously thereafter. In contrast, testosterone levels obtained with the gel showed a prolonged rise reaching maximal levels of 97 +/- 78 and 100 +/- 60 ng/dL after 18 hours. The serum level patterns of free testosterone, dihydrotestosterone, and 3alpha-androstanediol glucuronide were similar to the corresponding total testosterone levels. CONCLUSION(S): Administration of testosterone lozenge by buccal absorption produced a rapid and brief elevation of testosterone levels, with levels reaching upper limits of the male range. In contrast, transdermal testosterone gel absorption resulted in a prolonged elevation of testosterone levels, which were in the hyperandrogenic female range but resembled steady state pharmacokinetics.

Absorption↗

PubMed2002

Developmental toxicity of testosterone in the crustacean Daphnia magna involves anti-ecdysteroidal activity.

Testosterone has been shown to cause developmental arrest of embryonic daphnids (Daphnia magna). The present study was undertaken to determine whether this toxicity might be due to anti-ecdysteroidal activity associated with testosterone. The effect of testosterone on molt frequency of early instar daphnids was first evaluated to determine whether testosterone interfered with this ecdysteroid-regulated process. Molt frequency was delayed by exposure to testosterone and this effect was mitigated by co-exposure to the ecdysteroid 20-hydroxyecdysone. Testosterone exposure concentrations that interfered with molting also elicited developmental abnormalities among neonatal organisms produced by maternal organisms that were continuously exposed to testosterone or among embryos that were removed from unexposed mothers and exposed directly to the hormone. Embryos were significantly protected against the developmental toxicity of testosterone by co-exposure to 20-hydroxyecdysone. Taken together, these results demonstrated that the embryo toxicity of testosterone to daphnids is due largely to its ability to interfere with ecdysteroid control of development. Experiments next were conducted to determine whether testosterone interfered with ecdysteroidal activity by acting as an ecdysone receptor antagonist or by reducing endogenous ecdysone levels. Testosterone significantly antagonized the action of 20-hydroxyecdysone in an ecdysone-responsive cell line. Testosterone had no discernable effect on endogenous ecdysone levels in daphnids. These results demonstrated that (1). ecdysteroids regulate critical processes in daphnid embryo development, (2). testosterone elicits embryo toxicity to daphnids by interfering with ecdysteroid activity, and (3). ecdysteroid receptor antagonism could be one mechanism by which testosterone elicits these effects.

Animals↗