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PubMedDate not supplied

Testosterone release from a subcutaneous, biodegradable microcapsule formulation (Viatrel) in hypogonadal men.

Men with hypogonadism require testosterone replacement for optimal health. In the United States, testosterone is currently administered by daily transdermal patches, topical gels or intramuscular injections every 1-3 weeks. Biodegradable polylactide-co-glycolide microcapsules are currently used for long-term drug delivery in humans. Such microcapsules that contain testosterone could provide a better means of long-term testosterone therapy. We therefore studied the pharmacokinetics and pharmacodynamics of testosterone release from testosterone microcapsules in men with hypogonadism. Fourteen men who had been treated previously with testosterone were enrolled in an open-label, prospective study of testosterone microcapsule administration. Subjects were enrolled if 2 consecutive serum total testosterone levels were lower than 8.7 nmol/L after a 4-week washout from testosterone therapy. Subjects were injected with a single dose of either 267 mg (n = 7) or 534 mg (n = 7) of (Viatrel) testosterone microcapsule, and serum total testosterone, dihydrotestosterone, estradiol, sex-hormone binding globulin, luteinizing hormone, and follicle-stimulating hormone levels were determined at days -14, -7, and 0 before the injection; at days 1, 2, and 7 after the injection; and then weekly thereafter for 8-12 weeks. Mean serum total testosterone levels peaked immediately following injection on day 1 at 25.2 +/- 2.6 nmol/L in the 267 mg group and 34.7 +/- 2.4 nmol/L in the 534 mg group. Total serum testosterone levels declined gradually and fell below 8.7 nmol/L at 42 days after injection in the 267 mg group, and 70 days after injection in the 534 mg group. Estradiol and dihydrotestosterone levels followed a similar pattern. Mean serum free testosterone also peaked immediately following injection on day 1 at 0.51 +/- 0.05 nmol/L in the 267 mg group and 0.97 +/- 0.08 nmol/L in the 534 mg group. No significant adverse reactions were seen, although 2 subjects complained of transient tenderness and fullness at their injection sites. We conclude that a single injection of 534 mg of testosterone microcapsules to men with hypogonadism normalizes serum hormone levels for up to 10-11 weeks, albeit with a pronounced early peak and a relatively long period of low-normal serum total testosterone. Subcutaneously administered testosterone microcapsules may provide a safe and convenient method for the long-term treatment of male hypogonadism or testosterone replacement in male contraceptive regimens.

Affect↗

PubMed2003

The biocide tributyltin reduces the accumulation of testosterone as fatty acid esters in the mud snail (Ilyanassa obsoleta).

Imposex, the development of male sex characteristics by female gonochoristic snails, has been documented globally and is causally associated with exposure to the ubiquitous environmental contaminant tributyltin (TBT). Elevated testosterone levels in snails also are associated with TBT, and direct exposure to testosterone has been shown to cause imposex. We discovered previously that the mud snail (Ilyanassa obsoleta)biotransforms and retains excess testosterone primarily as fatty acid esters. The purpose of this study was to determine whether TBT interferes with the esterification of testosterone, resulting in the elevated free (unesterified) testosterone levels associated with imposex. Exposure of snails to environmentally relevant concentrations of TBT (> or = 1.0 ng/L as tin) significantly increased the incidence of imposex. Total (free + esterified) testosterone levels in snails were not altered by TBT; however, free testosterone levels increased with increasing exposure concentration of TBT. TBT-exposed snails were given [14C]]testosterone to measure the production of [14C]testosterone-fatty acid esters. The production of testosterone-fatty acid esters decreased with increasing exposure concentration of TBT. These results indicate that TBT elevates free testosterone levels in snails by decreasing the production or retention of testosterone-fatty acid esters. These findings were confirmed among field-sampled snails where individuals collected from a high-tin-affected site exhibited a greater incidence of imposex, higher free testosterone levels, and lower testosterone-fatty acid ester levels when compared with individuals sampled from a low-tin-affected site. Decreased testosterone-fatty acid esterification among TBT-treated snails was not caused by direct inhibition of the acyl coenzyme A:testosterone acyltransferase (ATAT) enzyme responsible for testosterone esterification, nor by suppressed ATAT protein expression. The target of TBT may be a co-contributor to the testosterone fatty esterification process or a factor in the enhanced hydrolysis of the testosterone-fatty acid pool.

Animals↗

PubMed2003

Testosterone supplementation: what and how to give.

Several epidemiological studies have demonstrated a gradual decrease of serum testosterone with aging in men. A considerable number of men will experience hypogonadal androgen levels, defined by the normal range for young men. Thus, in addition to the long-standing use of androgen replacement therapy in the classical forms of primary and secondary hypogonadism, age-associated testosterone deficiency has led to considerable developments in application modes for testosterone. Since oral preparations of testosterone are ineffective, due to the first-pass effect of the liver, or, in case of 17 alpha-alkylation, cause hepatotoxicity, intramuscular injection of long-acting esters, such as testosterone enanthate, have been the mainstay of testosterone therapy. However, the large fluctuations of serum testosterone levels cause unsatisfactory shifts of mood and sexual function in some men; combined with the frequent injections, this delivery mode is thus far from being ideal. In contrast, the transdermal testosterone patches are characterized by favorable pharmacokinetic behavior and have proven to be an effective mode of delivery. Safety data over 10 years indicate no negative effect on the prostate. Nevertheless, the scrotal testosterone patch system is hampered by the application site, which is not easily accepted by many subjects; the non-scrotal patch has a high rate of skin irritations. In view of the drawbacks of the currently available preparations, the most recent developments in testosterone supplementation appear to be highly promising agents. Androgen, which has been available in the United States since mid-2000, will be introduced this year in most European markets as Testogel, a hydroalcoholic gel containing 1% testosterone. Doses of 50-100 mg gel applied once daily on the skin deliver sufficient amounts of testosterone to restore normal hormonal values and to correct the signs and symptoms of hypogonadism. The gel has shown to be very effective and successful in American patients, who have benefited from its availability for almost 3 years. Furthermore, in phase II and III clinical studies, the intramuscular injection of 1000 mg testosterone undecanoate every 12-15 weeks has led to extremely stable serum testosterone levels for a prolonged period of time and has resulted in excellent efficacy. It is very likely in the future that these products will be the mainstay of testosterone supplementation. Whereas the indication for testosterone substitution for men with classical forms of hypogonadism is unequivocal, the use of testosterone in men with age-associated hypogonadism is less uniformly accepted. Yet, the few studies addressing this question indicate that men with testosterone serum levels below the lower normal limit for young adult men and with lack of energy, libido, depressed mood and osteoporosis may benefit from testosterone supplementation. However, it should be kept in mind that the experience documented in studies is limited. Nevertheless, serious side-effects, especially in regard to the prostate, did not occur, with the longest study extending over 3 years.

Drug Administration Routes↗

PubMed1984

Salivary and plasma bound and "free" testosterone in men and women.

Paired samples of blood and saliva from 37 men and nine women throughout the menstrual cycle were measured for testosterone by radioimmunoassay and free testosterone by equilibrium dialysis. There was a highly significant correlation between plasma and salivary testosterone, with a correlation coefficient r = 0.71 (p = less than 0.001). In men, free testosterone constituted 78% of salivary testosterone but only 4% of plasma testosterone; mean +/- SE salivary testosterone was 193.7 +/- 6.7 pg/ml compared to plasma testosterone of 5,140 +/- 298.0 pg/ml. Salivary testosterone decreased significantly from a morning (0800 hours) level of 208 +/- 7.5 to an evening (1800 hours) level of 174 +/- 8.4 pg/ml (p = less than 0.001) (n = 23). Similarly, plasma testosterone was significantly higher in the morning (6,584 +/- 472 pg/ml) than in the evening (5,571 +/- 357 pg/ml) (p = less than 0.005) (n = 25). Free testosterone in saliva and plasma also showed significantly higher morning than evening levels. The coefficients of variability for hourly changes (0900 to 1800 hours) in salivary testosterone and free testosterone were 13.6% and 16.7% compared to 12.7% and 20.9% for plasma testosterone and free testosterone, respectively. In women, salivary testosterone during the proliferative phase of the menstrual cycle was 108.3 +/- 5.8 pg/ml, and it increased significantly to 130.5 +/- 6.0 pg/ml in the secretory phase (p = less than 0.02). Our findings indicate that measurements of salivary testosterone reflect plasma testosterone and may be a useful noninvasive method of assessing levels of testosterone.

Adolescent↗

PubMed1998

The analog free testosterone assay: are the results in men clinically useful?

Men with low testosterone concentrations are usually hypogonadal. However, because variations in the testosterone transport protein, sex hormone-binding globulin (SHBG), directly influence the total testosterone concentration, confirmation of a low testosterone with a measurement of free testosterone or "bioavailable" testosterone (BAT) is recommended. In the present study, we examined the relationship of SHBG with free testosterone (Coat-A-Count assay, Diagnostic Products) and with BAT in men (n = 29) and women (n = 28) who participated in a study of the metabolic determinants of body composition. As expected, total testosterone was strongly positively correlated with SHBG among men (r = 0.68; P <0.01). Although the BAT was independent of SHBG in men (r = 0.02), SHBG was an important predictor of free testosterone (r = 0.62; P <0.01). In contrast, in women serum concentrations of total testosterone (r = -0.26; P = 0.17), free testosterone (r = -0.30; P = 0.17), and BAT (r = -0.46; P = 0.013) all tended to be lower with increasing SHBG. Free testosterone was nearly perfectly positively correlated with total testosterone (r = 0.97) in men, among whom free testosterone represented a relatively constant percentage of the total testosterone (0.5-0.65%), and the percentage of free testosterone was unrelated to SHBG. Thus the Coat-A-Count free testosterone concentration in men, like the total testosterone concentration, is determined in part by plasma SHBG. Accordingly, androgen deficiency may be misclassified with this assay in men with low SHBG. Moreover, the previous findings of reduced free testosterone concentrations with hypertension or hyperinsulinemia or as a risk factor for developing type 2 diabetes, conditions in which SHBG is reduced, may have been methodology-related.

Adult↗

PubMedDate not supplied

Low serum testosterone and mortality in male veterans.

BACKGROUND: Low serum testosterone is a common condition in aging associated with decreased muscle mass and insulin resistance. This study evaluated whether low testosterone levels are a risk factor for mortality in male veterans. METHODS: We used a clinical database to identify men older than 40 years with repeated testosterone levels obtained from October 1, 1994, to December 31, 1999, and without diagnosed prostate cancer. A low testosterone level was a total testosterone level of less than 250 ng/dL (<8.7 nmol/L) or a free testosterone level of less than 0.75 ng/dL (<0.03 nmol/L). Men were classified as having a low testosterone level (166 [19.3%]), an equivocal testosterone level (equal number of low and normal levels) (240 [28.0%]), or a normal testosterone level (452 [52.7%]). The risk for all-cause mortality was estimated using Cox proportional hazards regression models, adjusting for demographic and clinical covariates over a follow-up of up to 8 years. RESULTS: Mortality in men with normal testosterone levels was 20.1% (95% confidence interval [CI], 16.2%-24.1%) vs 24.6% (95% CI, 19.2%-30.0%) in men with equivocal testosterone levels and 34.9% (95% CI, 28.5%-41.4%) in men with low testosterone levels. After adjusting for age, medical morbidity, and other clinical covariates, low testosterone levels continued to be associated with increased mortality (hazard ratio, 1.88; 95% CI, 1.34-2.63; P<.001) while equivocal testosterone levels were not significantly different from normal testosterone levels (hazard ratio, 1.38; 95% CI, 0.99%-1.92%; P=.06). In a sensitivity analysis, men who died within the first year (50 [5.8%]) were excluded to minimize the effect of acute illness, and low testosterone levels continued to be associated with elevated mortality. CONCLUSIONS: Low testosterone levels were associated with increased mortality in male veterans. Further prospective studies are needed to examine the association between low testosterone levels and mortality.

Aged↗

PubMed2006

Testosterone therapy in men with Parkinson disease: results of the TEST-PD Study.

BACKGROUND: Testosterone deficiency has been reported in patients with Parkinson disease (PD), Alzheimer disease, and Huntington disease. It is not known whether testosterone therapy (TT) in men with borderline hypogonadism and neurodegenerative diseases will be of substantial benefit. Previously, we reported that testosterone deficiency is more common in patients with PD compared with age-matched control subjects, and we also reported in 2 small open-label studies that some nonmotor symptoms responded favorably to TT. OBJECTIVE: To define the effects of TT on nonmotor and motor symptoms in men with PD and probable testosterone deficiency. DESIGN: Double-masked, placebo-controlled, parallel-group, single-center trial. PATIENTS: Two experimental groups: patients with PD who were receiving either TT or placebo. INTERVENTIONS: Participants received either the study drug by intramuscular injection (200 mg/mL of testosterone enanthate every 2 weeks for 8 weeks) or placebo (isotonic sodium chloride solution injections). In patients in each group, the testosterone serum concentration was obtained at each study visit. During 2 study visits, testosterone levels were blindly evaluated and the intramuscular testosterone dose was increased by 200 mg/mL if the free testosterone value failed to double from the baseline value. MAIN OUTCOME MEASURES: The primary outcome variable was the St Louis Testosterone Deficiency Questionnaire, and secondary outcome measures included measures of mood, cognition, fatigue, motor function, and frequency of adverse events. At the end of the double-blind phase, all patients were offered open-label TT and were followed up after 3 and 6 months. RESULTS: Fifteen patients in the placebo group (mean age, 69.9 years), receiving a mean total levodopa equivalent dose of 924 mg/d, had a baseline free testosterone level of 47.91 pg/mL, compared with 15 patients in the TT group (mean age, 66.7 years), receiving an average total levodopa equivalent dose of 734 mg/d, who had a baseline free testosterone level of 63.49 pg/mL. Testosterone was generally well tolerated. More subjects in the TT group experienced lower extremity edema (40% vs 20%). In 2 patients, 1 in each group, prostate-specific antigen levels were elevated from baseline. The improvement in the TT group compared with the placebo group (1.7 vs 1.1) on the St Louis Testosterone Deficiency Scale was not statistically significant. In addition, there were no significant differences in motor and nonmotor features of PD between the 2 groups, although a few subscales showed improvements (Hopkins Verbal Learning Test, P<.04; and Backward Visual Span subtrial, P<.03). However, long-term open-label TT resulted in delayed but sustained improvement in subjects in the TT group who continued to receive treatment (n = 6) compared with subjects in the placebo group who elected not to receive TT (n = 3). CONCLUSIONS: Testosterone therapy was generally well tolerated in elderly men with PD and probable testosterone deficiency. While there was no significant difference in the motor and nonmotor scales between the TT and placebo groups at the end of 8 weeks compared with baseline, this may be due to several study limitations, including small sample size, a strong placebo effect with intramuscular therapy, and short follow-up that did not allow measurement of delayed effects of TT in some subjects. Until more definitive studies are reported, practitioners should be particularly cautious in treatment of low testosterone concentrations in men with PD and borderline testosterone deficiency, and careful consideration should be given to the risks vs the benefits of TT.

Affect↗

PubMed1997

Androgen action on the restoration of spermatogenesis in adult rats: effects of human chorionic gonadotrophin, testosterone and flutamide administration on germ cell number.

Spermatogonial proliferation is a critical but poorly understood determinant of the spermatogenic process. In rats, exogenous testosterone plus oestradiol (TE) markedly suppresses serum LH and testicular testosterone levels. In the TE-treated rat, spermatogonial number declines to approximately 65% of control levels while round to elongated spermatid maturation is interrupted. The partial restoration of testicular testosterone levels by exogenous testosterone administration restores spermatid maturation but neither testicular weight nor spermatogonial number are normalized. This study aimed to determine the role of testosterone and/or non-androgenic Leydig cell factors in the restoration of spermatogonial number in the testosterone-treated rat. Germ cell numbers were assessed using stereological methods and expressed as germ cell number per testis. Adult Sprague Dawley rats initially received 3 cm testosterone plus 0.4 cm oestradiol Silastic implants for 9 weeks to suppress spermatogenesis, followed by 10 days of either (i) exogenous testosterone using implants (T24 cm) or testosterone esters (5 or 25 mg sc every third day), or (ii) human chorionic gonadotrophin (hCG; 0.5, 1.25, 2.5 or 10 IU/kg sc daily) as an LH substitute to restore Leydig cell function. Following TE treatment, testicular weights and testicular testosterone levels were reduced to 31% and 1.3% of control levels, respectively. In response to exogenous testosterone administration, testicular weight was restored to 52-58% of controls while testicular testosterone levels increased to only 3.5-17.3% of controls despite serum testosterone levels 4.5-24-fold above control. In response to hCG treatment, a graded increase in testicular testosterone levels was achieved (2.6-20.5% of control) and testicular weights increased to 38-56% of control. TE suppression reduced (p < 0.05) type A spermatogonia and type B spermatogonia/preleptotene spermatocyte numbers per testis to 61% and 77% of control, respectively; however, neither subsequent testosterone nor hCG treatments significantly increased either germ cell number. In a second study, hCG (1.25 IU/kg) was administered alone or in combination with the androgen receptor antagonist, flutamide (100 mg/kg sc daily), to withdraw androgenic effects at all stages of spermatogenesis. The TE-induced suppression of type A spermatogonia (59% control) and type B spermatogonia/preleptotene spermatocytes (68% control) was not affected by hCG +/- flutamide. On the other hand, as expected, hCG increased the number of elongated spermatids (p < 0.05). The co-administration of flutamide reduced (p < 0.05) the numbers of all pachytene spermatocyte forms, round and elongated spermatids below those of TE-treated animals. We conclude that neither exogenous testosterone nor hCG is capable of restoring spermatogonial number in the TE-treated rat within 10 days despite the partial or full restoration of testicular testosterone levels. No evidence was found for the involvement of non-androgenic Leydig factors in the control of spermatogonial numbers. The data from flutamide-treated animals demonstrates that residual androgen effects are present in the TE model as, even in the presence of testicular testosterone levels below that needed for spermatid maturation, further inhibition of spermatocyte development and meiosis is apparent.

Animals↗

PubMed1988

Randomized clinical trial of testosterone replacement therapy in hypogonadal men.

We have compared the pharmacokinetics and pharmacodynamics of the three commonly used testosterone formulations in a prospective, randomized cross-over clinical trial. Plasma free and total testosterone and their ratio (proportion of unbound testosterone), sex hormone-binding globulin (SHBG), oestradiol, LH and FSH were measured in 15 hypogonadal men (nine hyper- and six hypogonadotrophic) who underwent, in a randomized sequence, three treatment periods each separated by an intervening washout period. The treatments were: (i) intramuscular injection of 250 mg mixed testosterone esters at 2-weekly intervals, (ii) oral testosterone undecanoate 120 mg bd, and (iii) subcutaneous testosterone pellets (6 x 100 mg). Pellet implantation gave the most prolonged effect with free and total testosterone levels being elevated for up to 4 months. This was accompanied by prompt and sustained suppression of plasma LH and FSH, an increase in plasma levels of oestradiol but no change in SHBG levels. In contrast, intramuscular injections induced marked but reproducible week-to-week fluctuations in free and total testosterone, which resulted in a small decrease in plasma SHBG levels, less marked suppression of LH and FSH and a smaller increase in plasma levels of oestradiol. Oral testosterone undecanoate produced the most variable plasma levels of free and total testosterone with a peak in the first treatment week and a fall thereafter and, despite maintenance of testosterone levels within the physiological range, there was no significant suppression of plasma levels of LH and FSH, and oestradiol levels were unchanged but levels of SHBG and total cholesterol were decreased. Free testosterone levels were increased disproportionately during testosterone treatment as the proportion of unbound testosterone was increased by all three treatments. All three testosterone preparations lowered plasma levels of urea and all were without biochemical or haematological toxicity. Reported sexual function was better maintained and side-effects were fewer with parenteral compared with oral treatments. The marked decrease in SHBG and cholesterol levels during oral testosterone undecanoate, when compared with parenteral treatments, occurred despite lesser androgenic effects (suppression of gonadotrophin levels and reported sexual function), which suggests that the liver is exposed to excessive androgenic load via the portal vein during oral treatment with testosterone esters. It is concluded that testosterone pellets give the closest approximation to zero-order (steady-state) delivery conditions for up to 4 months after a single insertion.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1984

Serum and CSF concentrations of testosterone and LH related to negative feedback in male rhesus monkeys.

Testosterone and LH concentrations were studied in blood and cerebrospinal fluid (CSF) in 8 adult male rhesus monkeys. All males were initially intact and 7 were subsequently castrated and implanted with an ascending series of testosterone capsules. In 4 of the males, serum testosterone levels were significantly higher at 21.00 h than at 09.00 h when the monkeys were intact. Following castration of these 4 males, 4-10 testosterone capsules produced serum concentrations similar to those previously found at 09.00 h; levels equivalent to those at 21.00 h were attained with 12-14 capsules. The proportion of unbound testosterone in serum represented 2% of total serum concentrations, but increased to 4% at high serum concentrations (12-14 capsules). In contrast, the proportion of unbound testosterone in CSF represented 100% of CSF levels. The levels of testosterone in CSF remained at values equal to 2-3% of total serum concentrations throughout the study. The levels of unbound serum testosterone and testosterone levels in the CSF were similar throughout the study in 3 of the 4 monkeys. In the fourth animal, supraphysiological serum testosterone levels occurred with 12 and 14 implants, and, at this time, the level of testosterone in CSF was less than the concentrations of unbound testosterone in serum. Following an intravenous bolus injection of testosterone, the steroid rapidly entered CSF when either 6 or 14 capsules were in place. Although the clearance of testosterone was similar within either compartment during both treatments, the half-life of testosterone in CSF was significantly shorter than in serum at high serum concentrations (14 capsules). Serum and CSF LH levels rose rapidly after castration, reaching maximal levels 8-12 days later with CSF LH levels consistently representing 2-3% of serum concentrations. Post-castration LH concentrations did not change until nocturnal testosterone levels were reached (12-14 capsules), when LH levels were suppressed in both serum and CSF. Subsequent reduction of serum testosterone levels (to 6 capsules) maintained the low LH concentrations. Seemingly, high testosterone concentrations in either serum or CSF, equivalent to nocturnal levels in intact males, were required to initiate LH suppression, but not to maintain it.

Animals↗

PubMed2006

Effects of testosterone supplementation on whole body and regional fat mass and distribution in human immunodeficiency virus-infected men with abdominal obesity.

BACKGROUND: Whole body and abdominal obesity are associated with increased risk of diabetes mellitus and heart disease. The effects of testosterone therapy on whole body and visceral fat mass in HIV-infected men with abdominal obesity are unknown. OBJECTIVE: The objective of this study was to determine the effects of testosterone therapy on intraabdominal fat mass and whole body fat distribution in HIV-infected men with abdominal obesity. METHODS: IN this multicenter, randomized, placebo-controlled, double-blind trial, 88 HIV-positive men with abdominal obesity (waist-to-hip ratio > 0.95 or mid-waist circumference > 100 cm) and total testosterone 125-400 ng/dl, or bioavailable testosterone less than 115 ng/dl, or free testosterone less than 50 pg/ml on stable antiretroviral regimen, and HIV RNA less than 10,000 copies per milliliter were randomized to receive 10 g testosterone gel or placebo daily for 24 wk. Fat mass and distribution were determined by abdominal computerized tomography and dual energy x-ray absorptiometry during wk 0, 12, and 24. We used an intention-to-treat approach and nonparametric statistical methods. RESULTS: Baseline characteristics were balanced between groups. In 75 subjects evaluated, median percent change from baseline to wk 24 in visceral fat did not differ significantly between groups (testosterone 0.3%, placebo 3.1%, P = 0.75). Total (testosterone -1.5%, placebo 4.3%, P = 0.04) and sc (testosterone-7.2%, placebo 8.1%, P < 0.001) abdominal fat mass decreased in testosterone-treated men, but increased in placebo group. Testosterone therapy was associated with significant decrease in whole body, trunk, and appendicular fat mass by dual energy x-ray absorptiometry (all P < 0.001), whereas whole body and trunk fat increased significantly in the placebo group. The percent of individuals reporting a decrease in abdomen (P = 0.01), neck (P = 0.08), and breast size (P = 0.01) at wk 24 was significantly greater in testosterone-treated than placebo-treated men. Testosterone-treated men had greater increase in lean body mass than placebo (testosterone 1.3%, placebo -0.3, P = 0.02). Plasma insulin, fasting glucose, and total high-density lipoprotein and low-density lipoprotein cholesterol levels did not change significantly. Testosterone therapy was well tolerated. CONCLUSIONS: Testosterone therapy in HIV-positive men with abdominal obesity and low testosterone was associated with greater decrease in whole body, total, and sc abdominal fat mass and a greater increase in lean mass compared to placebo. However, changes in visceral fat mass were not significantly different between groups. Further studies are needed to determine testosterone effects on insulin sensitivity and cardiovascular risk.

Abdominal Fat↗

PubMed1979

Inhibition of steroid 5 alpha-reductase in vivo: effect on suppression of luteinizing hormone and stimulation of accessory sex organs by testosterone in the orchidectomized rat.

An inhibitor of 5 alpha-reductase, the 17 beta-carboxylic acid derivative of testosterone (testosterone-17 beta CA), has been used to evaluate the importance of the 5 alpha-reduction of testosterone in its action on the suppression of LH secretion in male rats. The potential of testosterone-17 beta CA to inhibit the formation of 5 alpha-dihydrotestosterone (DHT) was first demonstrated in vitro. When homogenates of hypothalami or anterior pituitary glands were incubated with [3H]Testosterone in the presence of a 50-fold excess of testosterone-17 beta CA, the formation of labelled DHT was inhibited by more than 80%. Adult male rats that had been castrated for 1-2 months were fitted with chronic intravenous catheters and implanted with silicone elastomer sheets: one group received one sheet, 0.5-2.0 cm2 in size containing 1.6% testosterone, a second group received one 50 cm2 sheet containing 1.6% testosterone-17 beta CA and a third group received two sheets, one sheet 50 cm2 in size containing 1.6% testosterone-17 beta CA and the second ranging in size from 0.5 to 2.0 cm2 and containing 1.6% testosterone. Blood was withdrawn daily from each rat over a 4-5 day period after implantation of the steroids and the level of LH in the plasma was measured by radioimmunoassay. The seminal vesicles and the ventral prostate gland were removed at autopsy on day 4 or 5; the weights of these organs were shown to have increased progressively as the size of the implant of testosterone increased. In contrast, the level of LH in the plasma was suppressed to a comparable extent by implants of testosterone between 0.6 and 2 cm2, whereas a 0.5 cm2 implant of testosterone had no effect. Implants of testosterone-17 beta CA alone did not influence the weight of the accessory organs or the level of LH. When testosterone-17 beta CA and testosterone were implanted together, the growth-promoting effect of the latter on the accessory sex organs was significantly reduced. The effectiveness of testosterone in suppressing the level of LH in the plasma of these animals was not influenced by the presence of testosterone-17 beta CA and in certain instances the level was raised.

5-alpha Reductase Inhibitors↗

PubMed1987

Direct radioimmunoassay of free testosterone in the evaluation of androgenetic manifestations in women.

The determination or calculation of the non-protein bound fraction of testosterone in serum had been suggested to be superior to the measurement of total testosterone levels in the evaluation of women with clinical signs of hyperandrogenism. We therefore compared the serum concentrations of free testosterone, as determined directly by radioimmunoassay, with the levels of various serum parameters in 317 women with hirsutism or acne. Total testosterone was elevated in 33%, free testosterone in 59%, and DHEA-S in 65% of the patients. Among the women with high levels of free testosterone, 24% showed serum concentrations both of total testosterone and SHBG within the normal range, indicating that the calculation of the testosterone:SHBG ratio (free androgen index) would be of limited value for androgen diagnostics. Serum free testosterone correlated positively with total testosterone and negatively with SHBG. No significant correlation was found between DHEA-S and free or total testosterone, and between total testosterone and SHBG. The stimulation of the adrenal cortex by ACTH resulted only in a significant rise in 17 alpha-hydroxyprogesterone levels. During the dexamethasone suppression test there was a significant suppression of the serum concentrations of total and free testosterone, DHEA-S, and 17 alpha-hydroxyprogesterone, while SHBG did not change. In several of the women with normal testosterone levels, free testosterone decreased by more than 50%, although the suppression of total testosterone was only slight. This was possibly due to the suppression of adrenal androgens which may compete with testosterone for the binding sites of SHBG. The direct measurement of free testosterone appears to be a valuable approach to the evaluation of women with androgenetic manifestations.

17-alpha-Hydroxyprogesterone↗

PubMed2002

Beneficial effects of testosterone replacement for the nonmotor symptoms of Parkinson disease.

OBJECTIVE: To investigate whether a single daily dose of testosterone replacement gel has beneficial effects on testosterone deficiency symptoms, cognitive function, nonmotor symptoms of Parkinson disease (PD), and motor symptoms of PD. BACKGROUND: Recently it has been observed that testosterone replacement therapy improves refractory nonmotor symptoms in testosterone-deficient men with PD. Many of the symptoms of testosterone deficiency are nonspecific and overlap with the nonmotor symptoms of PD, such as decreased enjoyment of life, lack of energy, sexual dysfunction, and depression. Replacement therapy for men with PD and comorbid testosterone deficiency may be an important addition to antiparkinsonian management strategies. METHODS: A prospective open-labeled pilot study of testosterone topical gel (5 g of AndroGel; Unimed Pharmaceutical Inc, Deerfield, Ill) administered daily to testosterone-deficient (free testosterone <80 pg/mL) men with PD. All 10 patients were followed up for 1 month and 6 patients were followed up for a total of 3 months. Patients were administered a battery of testosterone deficiency questionnaires, cognitive studies, and scales of PD nonmotor and motor function at baseline, 1, and 3 months. RESULTS: With the daily transdermal testosterone gel, patients had an average increase in levels of free testosterone from baseline (53 pg/mL) to a 1-month follow-up visit (131 pg/mL; P =.06) and to a 3-month follow-up visit (98 pg/mL; P =.04). Testosterone deficiency symptoms improved in these patients (St Louis Testosterone Deficiency Questionnaire) from baseline (7.9 deficiency symptoms) to 1 month (5.6 deficiency symptoms, P =.04) and 3 months (5.8 deficiency symptoms, P =.08). The Unified Parkinson's Disease Rating Scale IV showed improvement at 1 month (P =.008). Additionally, there were trends toward improvement in the following scales: Unified Parkinson's Disease Rating Scale I at the 3-month follow-up (P =.09), Letter Fluency at the 3-month follow-up (P =.08), and the Hamilton Anxiety Scale at the 1-month follow-up (P =.09). CONCLUSIONS: A daily dose of transdermal testosterone gel improved testosterone deficiency symptoms in men with PD. Although there were trends in improvement in other nonmotor and motor symptoms of PD, future placebo control studies will need to be powered to answer these important questions. Whether testosterone deficiency is simply a comorbidity in PD or whether it plays a role in the pathogenesis of disease also remains for future study.

Administration, Topical↗

PubMed1999

Obesity regulates bioavailable testosterone levels in women with or without polycystic ovary syndrome.

OBJECTIVE: To evaluate [1] the effects of levels of sex hormone-binding globulin (SHBG), albumin, and total testosterone on the distribution of testosterone between SHBG-bound and non-SHBG-bound fractions; [2] the independent effects of polycystic ovary syndrome (PCOS) and body mass index on serum levels of total testosterone, non-SHBG-bound testosterone, SHBG, and albumin; and [3] the usefulness of levels of total testosterone and non-SHBG-bound testosterone and of the free androgen index in the diagnosis of PCOS. DESIGN: Retrospective clinical study. SETTING: An academic research environment. PATIENT(S): Forty-three women with oligomenorrhea and PCOS. Twenty-five women with regular menstrual cycles and without hirsutism served as controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Levels of non-SHBG-bound testosterone, total testosterone, SHBG, and albumin in serum. RESULT(S): Levels of total testosterone and non-SHBG-bound testosterone, and the free androgen index were higher in patients with PCOS than in healthy controls. PCOS did not have an effect on the levels of SHBG or albumin, or on the percentage of non-SHBG-bound testosterone. Levels of SHBG and albumin were inversely related to body mass index. The percentage and concentration of non-SHBG-bound testosterone and the free androgen index were directly related to body mass index. Hirsutism did not have an effect on any outcome measure. CONCLUSION(S): The distribution of total testosterone into SHBG-bound and non-SHBG-bound fractions is associated with body mass index, not with PCOS. The high levels of non-SHBG-bound testosterone and the high free androgen index in patients with PCOS reflect mainly high levels of total testosterone. Thus, the measurement of levels of non-SHBG-bound testosterone and the calculation of the free androgen index provide no further information in the diagnosis of PCOS beyond that provided by the measurement of levels of total testosterone.

Adult↗

PubMed1998

Serum testosterone concentration, efficiency of estrus detection and libido expression in androgenized beef cows.

Twenty multiparous, cyclic, nonlactating beef cows were blocked by dominance rank and randomly and equally allotted to 1 of 4 treatment groups: an untreated control group, a synovex-treated group which received 8 Synovex-H implants with no additional hormones, a testosterone-treated group which received 500 mg, i.m. and 1500 mg, s.c. testosterone enanthate on Day 1 with additional 1000 mg, s.c. doses of testosterone enanthate every 14 d, and a synovex + testosterone-treated group which received 8 Synovex-H implants with 500 mg, i.m. and 1500 mg, s.c. testosterone enanthate on Day 1 only. Blood samples were collected via jugular venipuncture once a week beginning 3 wk prior to start of treatment. In addition, samples were collected just prior to treatment; once a day for 1 wk after initiation of treatment; and then twice a week until 225 d after treatment. Efficiency of estrus detection was assessed 22 d prior to start of treatment and every 14 d thereafter for 98 d, using estrus detection trials with synchronized females or modified libido tests. Scores for estrus detection trials included total mounts in 1 h and the percentage of estrous cows detected. Libido was scored on a scale of 0 through 6. All testosterone treatments raised plasma testosterone concentrations above control and pretreatment levels (testosterone and synovex + testosterone > synovex > control; all P < 0.05). Synovex-, testosterone- and synovex + testosterone-treated females performed more mounts in 1 h than the controls (18, 9, 6 and 1, respectively; all P < 0.05). All testosterone-treated cows mounted a higher number of estrous females than the controls (P < 0.05). Only synovex + testosterone- and testosterone-treated cows received libido scores above pretreatment and control values. However, libido of testosterone-treated cows decreased over time, while that of synovex + testosterone-treated females remained high until Day 98. Libido scores correlated positively with the number of mounts in 1 h and the percentage of estrous females detected (0.70 and 0.44, respectively), and the correlation coefficient for these two factors was 0.63. In conclusion, the synovex + testosterone treatment was most effective for producing estrus detector females and libido testing was useful for evaluating sexual activity in androgenized females.

Animals↗

PubMed2003

Testosterone supplementation therapy for older men: potential benefits and risks.

Serum testosterone levels decline gradually and progressively with aging in men. Many manifestations associated with aging in men, including muscle atrophy and weakness, osteoporosis, reduced sexual functioning, and increased fat mass, are similar to changes associated with testosterone deficiency in young men. These similarities suggest that testosterone supplementation may prevent or reverse the effects of aging. A MEDLINE search was performed to identify studies of testosterone supplementation therapy in older men. A structured, qualitative review was performed of placebo-controlled trials that included men aged 60 and older and evaluated one or more physical, cognitive, affective, functional, or quality-of-life outcomes. Studies focusing on patients with severe systemic diseases and hormone deficiencies related to specific diseases were excluded. In healthy older men with low-normal to mildly decreased testosterone levels, testosterone supplementation increased lean body mass and decreased fat mass. Upper and lower body strength, functional performance, sexual functioning, and mood were improved or unchanged with testosterone replacement. Variable effects on cognitive function were reported, with improvements in some cognitive domains (e.g., spatial, working, and verbal memory). Testosterone supplementation improved exercise-induced coronary ischemia in men with coronary heart disease, whereas angina pectoris was improved or unchanged. In a few studies, men with low testosterone levels were more likely to experience improvements in lumbar bone mineral density, self-perceived functional status, libido, erectile function, and exercise-induced coronary ischemia with testosterone replacement than men with less marked testosterone deficiency. No major unfavorable effects on lipids were reported, but hematocrit and prostate specific antigen levels often increased. Based on these results, testosterone supplementation cannot be recommended at this time for older men with normal or low-normal testosterone levels and no clinical manifestations of hypogonadism. However, testosterone replacement may be warranted in older men with markedly decreased testosterone levels, regardless of symptoms, and in men with mildly decreased testosterone levels and symptoms or signs suggesting hypogonadism. The long-term safety and efficacy of testosterone supplementation remain uncertain. Establishment of evidence-based indications will depend on further demonstrations of favorable clinical outcomes and symptomatic, functional, and quality-of-life benefits in carefully performed, long-term, randomized, placebo-controlled clinical trials.

Aged↗

PubMed2004

Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle.

Although testosterone levels and muscle mass decline with age, many older men have serum testosterone level in the normal range, leading to speculation about whether older men are less sensitive to testosterone. We determined the responsiveness of androgen-dependent outcomes to graded testosterone doses in older men and compared it to that in young men. The participants in this randomized, double-blind trial were 60 ambulatory, healthy, older men, 60-75 yr of age, who had normal serum testosterone levels. Their responses to graded doses of testosterone were compared with previous data in 61 men, 19-35 yr old. The participants received a long-acting GnRH agonist to suppress endogenous testosterone production and 25, 50, 125, 300, or 600 mg testosterone enanthate weekly for 20 wk. Fat-free mass, fat mass, muscle strength, sexual function, mood, visuospatial cognition, hormone levels, and safety measures were evaluated before, during, and after treatment. Of 60 older men who were randomized, 52 completed the study. After adjusting for testosterone dose, changes in serum total testosterone (change, -6.8, -1.9, +16.1, +49.5, and +101.9 nmol/liter at 25, 50, 125, 300, and 600 mg/wk, respectively) and hemoglobin (change, -3.6, +9.9, +20.9, +12.6, and +29.4 g/liter at 25, 50, 125, 300, and 600 mg/wk, respectively) levels were dose-related in older men and significantly greater in older men than young men (each P < 0.0001). The changes in FFM (-0.3, +1.7, +4.2, +5.6, and +7.3 kg, respectively, in five ascending dose groups) and muscle strength in older men were correlated with testosterone dose and concentrations and were not significantly different in young and older men. Changes in fat mass correlated inversely with testosterone dose (r = -0.54; P < 0.001) and were significantly different in young vs. older men (P < 0.0001); young men receiving 25- and 50-mg doses gained more fat mass than older men (P < 0.0001). Mood and visuospatial cognition did not change significantly in either group. Frequency of hematocrit greater than 54%, leg edema, and prostate events were numerically higher in older men than in young men. Older men are as responsive as young men to testosterone's anabolic effects; however, older men have lower testosterone clearance rates, higher increments in hemoglobin, and a higher frequency of adverse effects. Although substantial gains in muscle mass and strength can be realized in older men with supraphysiological testosterone doses, these high doses are associated with a high frequency of adverse effects. The best trade-off was achieved with a testosterone dose (125 mg) that was associated with high normal testosterone levels, low frequency of adverse events, and significant gains in fat-free mass and muscle strength.

Adult↗