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PubMed1997

Strong association between serum levels of leptin and testosterone in men.

OBJECTIVE: Leptin serves as a hormonal signal linking food intake and energy expenditure to fat mass. As significant effects of testosterone administration on body composition and adipose tissue have been described recently, we examined a possible association between serum levels of leptin and testosterone which has not been reported so far. SUBJECTS: Three groups comprising a total of 58 adult age-matched males were included in this cross-sectional analysis by computer-assisted clinical database selection. Group 1 (n = 22) consisted of untreated hypogonadal patients with testosterone serum levels lower than 7 nmol/l. The inclusion criterion for Groups II (n = 20) and III (n = 16) was a serum testosterone level higher than 30 nmol/l. Group II involved hypogonadal patients under effective androgen substitution therapy; Group III comprised males without any endocrine disorder attending our clinic. MEASUREMENTS: Morning blood samples were taken for determination of serum levels of leptin, testosterone, oestradiol and sex-hormone binding globulin (SHBG). Serum levels of leptin were measured by homologous radioimmunoassay, the other hormones by standard immunoassays. RESULTS: No significant differences in serum leptin, serum testosterone, and body mass index (BMI) were detected between Group II (3.7 +/- 1.5 micrograms/l, 40.3 +/- 7.6 nmol/ l, 24.4 +/- 4.9 kg/m2, respectively (mean +/- SD)), and Group III (4.0 +/- 2.0 micrograms/l, 35.9 +/- 6.5 nmol/l, 24.8 +/- 2.6 kg/m2, respectively). However, hypogonadal patients of Group I who were selected for low testosterone serum levels (4.3 +/- 1.7 nmol/l) had significantly higher leptin serum levels of 18.8 +/- 9.7 micrograms/l (P < 0.001) and significantly higher BMI of 30.0 +/- 6.6 kg/m2 (P < 0.001). Multiple linear regression analysis revealed a significant independent association of leptin with testosterone serum levels (partial correlation coefficient = -0.84; P < 0.001) and with BMI (partial correlation coefficient = 0.44; P = 0.001), whereas serum levels of oestradiol and SHBG had no additional influence. CONCLUSIONS: This study demonstrates a close association between serum levels of testosterone and leptin in males which has not been described previously. Serum testosterone levels could be an important contributor to the known gender difference in serum leptin levels which can be found even after correction for body composition. These findings might be of clinical relevance for testosterone substitution therapy of hypogonadal as well as ageing men.

Adult↗

PubMed1996

Sequential exposure to estrogen and testosterone (T) and subsequent withdrawal of T increases the level of arginine vasopressin messenger ribonucleic acid in the hypothalamic paraventricular nucleus of the female rat.

The hypothalamic peptides arginine vasopressin (AVP) and oxytocin (OT) have been implicated as mediators of socio-sexual behaviors in addition to their roles in osmolar homeostasis (AVP), milk ejection and uterine contractility (OT). Within 24 h of parturition, OT and AVP messenger ribonucleic acid (mRNA) levels increase in the hypothalamic paraventricular, and to a lesser degree, the supraoptic nucleus (PVN and SON) of the rat. We previously reported that the prepartum increase in OT mRNA is related to the spontaneous decline in progesterone levels prior to parturition. We also reported that increases in PVN and SON OT mRNA can be induced by exposing the ovariectomized rat to a steroid regimen that mimics the steroid milieu of pregnancy, namely sequential estrogen and progesterone and subsequent progesterone withdrawal. Levels of PVN and SON AVP mRNAs were not affected by progesterone withdrawal in late pregnant rats or the steroid regimen that increased OT mRNA in ovariectomized rats. These observations suggest that other factors, perhaps hormonal, may influence AVP mRNA levels. A decline in testosterone coincident with waning progesterone levels also occurs prepartum. Since peak levels of AVP mRNA prepartum coincide with the prepartum decline in testosterone, we questioned whether declining testosterone levels are important for the increase in AVP mRNA levels. To examine a possible role for testosterone in the increased level of AVP mRNA in late pregnancy, we sequentially administered estradiol and testosterone long-term (2 weeks) and removed testosterone 48 h prior to sacrifice. This steroid regimen mimics the estrogen and testosterone pattern of late pregnancy in rats. AVP, but not OT, mRNA levels increased significantly in the PVN of ovariectomized rats receiving this steroid regimen. We also found that implantation of late pregnant rats with testosterone capsules to prevent the spontaneous prepartum decline in testosterone, attenuates the increase in PVN AVP, but not OT, mRNA on day 21 of pregnancy. The data show that sequential estrogen and testosterone and testosterone withdrawal increase the level of PVN AVP mRNA in the female rat.

Animals↗

PubMed2003

A novel testosterone gel formulation normalizes androgen levels in hypogonadal men, with improvements in body composition and sexual function.

OBJECTIVE: To compare the safety and efficacy of two doses of a new testosterone gel formulation (Testim Auxilium Pharmaceuticals, Inc., Norristown, PA, USA) to a permeation-enhanced testosterone patch (Andropatch), GlaxoSmithKline, UK) for treating men with confirmed low serum testosterone levels, and associated signs and symptoms of hypogonadism. PATIENTS AND METHODS: In all, 208 men were randomized and treated at 29 centres in Denmark, Germany, Netherlands, Sweden and the UK. The men were treated for 90 days, and the pharmacokinetics and treatment effectiveness of Testim at two doses (50 and 100 mg/day, delivering a daily dose of 5 and 10 mg testosterone, respectively) and Andropatch (2 x 2.5 mg patches, each delivering 2.5 mg testosterone and containing 12.2 mg of testosterone) were compared. Pharmacokinetic profiles were obtained, body composition measured, and mood and sexual function data recorded. RESULTS: Testim produced dose-dependent improvements in all pharmacokinetic variables compared with Andropatch. The mean increases from baseline to 90 days in testosterone were 12.41, 6.54 and 3.82 nmol/L for Testim 100 and 50 mg/day and the Andropatch, respectively. Both doses of Testim significantly improved positive and negative mood over baseline; Andropatch did not. All three treatments increased lean body mass, and the higher dose of Testim produced a significant decrease in percentage body fat. At all sample times both doses of Testim significantly improved sexual performance, sexual motivation, sexual desire and spontaneous erections. Andropatch provided insignificant improvements from baseline at all sample times for sexual desire, an inconsistent improvement in sexual motivation, but no effect on spontaneous erections. These results are similar to those previously reported for testosterone replacement therapy in hypogonadal men, suggesting that normalization of serum testosterone restores sexual function. However, the present data suggest that higher serum testosterone levels may further improve sexual function. Gel treatment was well tolerated, while patch treatment produced higher rates of application-site reactions and study discontinuation. CONCLUSION: The favourable pharmacokinetic profile and treatment outcome, combined with the enhanced tolerability of Testim, suggest that this new gel formulation is a safe and effective treatment in men with low serum testosterone levels and associated signs and symptoms of hypogonadism.

Administration, Topical↗

PubMed2006

Testosterone therapy in premenopausal women.

Testosterone therapy for postmenopausal women and women with surgical menopause, albeit controversial, is becoming more widespread. However, only limited data are available to support its use in premenopausal women. Androgens have important biological roles in young women, influencing bone and muscle mass, mood and well-being, and libido. Pathophysiological states affecting ovarian and adrenal function or both may result in androgen deficiency in premenopausal women. Young women with hypothalamic amenorrhea, premature ovarian failure, oophorectomy, premenstrual syndrome, acquired immunodeficiency wasting syndrome, adrenal insufficiency, and hypopituitarism may have testosterone deficiency. Young women with loss of libido may also have testosterone deficiency. Medications that may lead to testosterone insufficiency include oral estrogen, oral contraceptives, and corticosteroids. Testosterone deficiency in young women may be underdiagnosed because the symptoms generally are nonspecific and the measurement of total and free testosterone is inaccurate with commonly used techniques. Only a few studies investigating the effects of testosterone therapy have been performed thus far in premenopausal women. Long-term trials evaluating safety and effectiveness of testosterone therapy in premenopausal women are lacking. Common adverse effects include hirsutism and acne, which reverse with discontinuation of treatment. The availability of testosterone regimens specifically designed for women is expected to help maintain testosterone levels within the normal range and clarify whether the apparent beneficial effects of testosterone therapy are physiological or pharmacological.

Adult↗

PubMed1998

Effect of testosterone replacement on whole body glucose utilisation and other cardiovascular risk factors in males with idiopathic hypogonadotrophic hypogonadism.

BACKGROUND: Excessive testosterone in males or estrogens in females could explain their differences in coronary heart disease event rates. As a contraceptive testosterone is likely to be used at large scale the role of testosterone in increasing the risks of coronary heart disease needs investigation. AIM: To look at the role of testosterone in development of insulin resistance and other cardiovascular risk factors. DESIGN: Prospective, before-after study on ten male subjects with idiopathic hypogonadotrophic hypogonadism pre- and post-testosterone replacement therapy; outcome measures: anthropometry, lipoprotein profile and M value (whole body glucose disposal rates on standard hyperinsulinemic euglycemic clamp; at insulin infusion rate: 40 mU x (m-2)). RESULTS: Pre-treatment serum testosterone was 0.43 (0.515) ng x mL(-1), LH was 1.29 (0.08) IU x L(-1), and FSH was 1.54 (0.08) IU x L(-1). None had glucose intolerance. After replacement testosterone levels increased to 9.4 ng x mL(-1) (p=0.0005); weight increase of 5.0 kg (p=0.140), body mass index increase of 1.2 kg x m(-2) (p=0.28), and the change in waist to hip ratio (p=0.31) were not statistically significant. M-value (mg x kg x min(-1)) did not change after testosterone therapy (5.86 [0.72] vs 5.29 [0.82], p=0.62). Insulin levels (mU x L(-1)) achieved during the clamps were 89.5 (14.2) before and 146 (32.2) after androgen therapy (p=0.127). There was no change in glucose area under curve (mg x min x dL(-1)) (14406 [502.2] vs 12557 [826.5], p=0.312). On testosterone replacement therapy total and LDL cholesterol levels (mg x dL(-1)) declined (122.5 [13.4] vs 91.6 [5.0], p=0.04; 65.9 [9.9] vs 39.4 [7.3], p=0.05); Ratio of total cholesterol to HDL ratio also decreased significantly (p=0.05). Changes of serum triglycerides (p=0.25) and HDL cholesterol (p=0.19) did not attain statistical significance. CONCLUSIONS: Insulin sensitivity does not decrease on testosterone replacement therapy of male subjects with idiopathic hypogonadotrophic hypogonadism. Testosterone replacement was associated with decrease in other cardiovascular risk factors.

Adult↗

PubMed2002

Testosterone attenuates expression of vascular cell adhesion molecule-1 by conversion to estradiol by aromatase in endothelial cells: implications in atherosclerosis.

We previously reported that testosterone attenuated atherogenesis in LDLR(-/-) male mice, and that this effect of testosterone was most likely caused by its conversion to estradiol. Estradiol inhibits vascular cell adhesion molecule-1 (VCAM-1) expression, and expression of VCAM-1 is one of the early events in atherogenesis. We assessed the cellular mechanism(s) involved by which testosterone attenuates atherogenesis. We evaluated whether testosterone inhibited TNFalpha-induced VCAM-1 expression via its conversion to estradiol by the enzyme aromatase in human umbilical vein endothelial cells (HUVEC). Aromatase mRNA was dedected by reverse transcription-PCR in these cells. Testosterone (30 nM-1 microM) attenuated VCAM-1 mRNA expression in a concentration-dependent manner. The non aromatizable androgen, dihydrotestosterone, had no effect on VCAM-1 mRNA expression. Testosterone was less effective in attenuating VCAM-1 expression in the presence of anastrozole, an inhibitor of aromatase, indicating that testosterone inhibited VCAM-1 via conversion to estradiol. Estradiol also attenuated VCAM-1 mRNA expression, but this action was not abolished in the presence of anastrozole, indicating that anastrozole itself did not modulate VCAM-1 mRNA expression. The effect of testosterone on VCAM-1 mRNA expression was inhibited in the presence of the estrogen receptor antagonist, ICI-182780. Testosterone also attenuated TNFalpha-induced VCAM-1 protein expression, and this attenuation was abolished in the presence of anastrozole. In conclusion, testosterone inhibited VCAM-1 mRNA and protein expression in HUVEC by its conversion to estradiol via the enzyme aromatase present in the endothelial cells. Results from our study may help explain the mechanism by which testosterone may have beneficial effects on the cardiovascular system.

Anastrozole↗

PubMedDate not supplied

Fluoxetine treatment and testosterone levels.

BACKGROUND: Two published case studies have reported SRI/SNRI-associated low testosterone levels. Apathy and low testosterone, observed during venlafaxine treatment in one report, both resolved upon venlafaxine discontinuation. No studies have investigated the effect of chronic SRI treatment on human testosterone levels. As decreased testosterone has several negative health effects, we conducted a pilot study investigating the effect of fluoxetine treatment on testosterone levels. METHODS: Fourteen depressive disorder patients in good health (BDI = 15) were studied. In addition, 4 non-depressed patients were studied. Testosterone levels were drawn, and an apathy questionnaire (under development, not yet validated) was administered at intake. Fluoxetine was provided (10 mg/day for 7 days then 20 mg/day). To measure outcome, a follow-up testosterone level was drawn after 1 month's treatment. RESULTS: Eleven depressed, and 3 non-depressed, patients completed the study. While there were large differences-both increases and decreases-in some individuals' testosterone levels after fluoxetine treatment, for the study population as a whole, there was no relationship (depressed patients, p = 0.4; non-depressed patients, p 0.3) between fluoxetine treatment and testosterone levels.In patients with BDI = 20, testosterone levels at intake were highly associated with intake apathy levels (p = 0.0033). CONCLUSIONS: Further, larger, studies correlating changes in testosterone levels during SRI treatment with treatment response, apathy levels and possibly sexual dysfunction seem indicated.

Adult↗

PubMed2006

Testosterone and the brain.

Gender differences in spatial recognition, and age-related declines in cognition and mood, point towards testosterone as an important modulator of cerebral functions. Testosterone appears to activate a distributed cortical network, the ventral processing stream, during spatial cognition tasks, and addition of testosterone improves spatial cognition in younger and older hypogonadal men. In addition, reduced testosterone is associated with depressive disorders. The relationship between depression and testosterone appears to partly depend upon the androgen receptor genotype of the patient, and in appropriate patients with low testosterone levels, testosterone substitution can increase positive mood and decrease negative mood. The much publicized link between testosterone and aggression is probably only of importance in athletes who supplement their testosterone levels to excessively high levels, whereas in hypogonadal men, testosterone supplementation only enhances the positive aspects of aggression such as vigour and energy. Current data suggest that testosterone supplementation in hypogonadal men of all ages will enhance many aspects of mood and cognition.

Affect↗

PubMed2005

Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials.

BACKGROUND: We performed a meta-analysis of randomized clinical trials to determine the risks of adverse events associated with testosterone replacement in older men. METHODS: The MEDLINE database was searched from 1966 to April 2004, using testosterone as the indexing term; limits included human, male, > or =45 years old, and randomized controlled trial. Of the 417 studies thus identified, 19 met the inclusion criteria: testosterone replacement for at least 90 days, men > or =45 years old with low or low-normal testosterone level, randomized controlled trial, and medically stable men. Odds ratios (ORs) were pooled using a random effects model, assuming heterogeneous results across studies, and were weighted for sample size. RESULTS: In the 19 studies that met eligibility criteria, 651 men were treated with testosterone and 433 with placebo. The combined rate of all prostate events was significantly greater in testosterone-treated men than in placebo-treated men (OR = 1.78, 95% confidence interval [CI], 1.07-2.95). Rates of prostate cancer, prostate-specific antigen (PSA) >4 ng/ml, and prostate biopsies were numerically higher in the testosterone group than in the placebo group, although differences between the groups were not individually statistically significant. Testosterone-treated men were nearly four times as likely to have hematocrit >50% as placebo-treated men (OR = 3.69, 95% CI, 1.82-7.51). The frequency of cardiovascular events, sleep apnea or death was not significantly different between the two groups. CONCLUSIONS: Testosterone replacement in older men was associated with a significantly higher risk of detection of prostate events and of hematocrit >50% than was placebo; hematocrit increase was the most frequent adverse event associated with testosterone replacement. These data reaffirm the need to monitor hematocrit, PSA, and digital examination of the prostate during testosterone replacement in older men.

Aged↗

PubMed1997

A trial of testosterone therapy for HIV-associated weight loss.

OBJECTIVE: Weight loss in HIV-infected patients is extremely common and is associated with increased morbidity and mortality. Decreased testosterone concentrations occur commonly in patients with HIV disease and are associated with weight loss. This study assessed the effect of testosterone therapy on HIV associated weight loss in patients with AIDS. METHODS: Forty HIV-seropositive patients with CD4+ counts of < 2 x 10(5)/l and weight loss greater than 5% of usual body weight were randomized in a double-blind manner to receive 200 mg of testosterone cypionate of placebo intramuscularly every 2 weeks for 3 months. Patients were then crossed to receive the alternate treatment for the next 3 months. Outcome variables included weight, skin fold measurement, a quality-of-life questionnaire, Karnofsky score, T-cell subset analysis, complete blood count, routine blood chemistry measurements and free testosterone concentration. RESULTS: Thirty-nine patients entered the study. Of these, 35 completed the first 3-month period (18 on placebo, 17 on testosterone) and 23 completed the whole 6 month trial. Analysis of these 23 patients did not show any significant differences between testosterone and placebo treatment. Analysis of the first 3 months only for the 35 patients who completed it did not show any significant difference between the effects of testosterone and placebo treatment on weight gain. Patients treated with testosterone reported improved overall well-being (P = 0.03) and a trend towards increased muscle strength (P = 0.08). There was no difference between the two groups in terms of side-effects or other effects on hematopoetic, liver, renal, or immune function. CONCLUSIONS: Treatment with testosterone cypionate compared with placebo did not result in significant weight gain. Testosterone supplementation did appear to produce an improved overall sense of well-being and possibly some increases in muscle strength. This randomized, double-blinded study does not confirm the results of other recent studies which show potential benefits of testosterone and its analogs when used as a treatment for weight loss in HIV-positive patients.

Acquired Immunodeficiency Syndrome↗

PubMed2001

Testosterone facilitates the baroreceptor control of reflex bradycardia: role of cardiac sympathetic and parasympathetic components.

Reported clinical and experimental findings have shown that baroreflex control of heart rate is attenuated in women compared with men. This study investigated whether the sexual dimorphism in baroreflex function relates to the ability of the male hormone testosterone to facilitate baroreflex responsiveness. Relative contributions of the vagal and sympathetic autonomic components to testosterone modulation of baroreflex function were also investigated. Baroreflex curves relating changes in heart rate to increases or decreases in blood pressure evoked by phenylephrine and sodium nitroprusside, respectively, were constructed in sham-operated rats and castrated rats with and without testosterone replacement. Slope of the curves was taken as an index of baroreflex sensitivity (BRS PE and BRS NP ). Castration (for 10 days) significantly reduced plasma testosterone levels and attenuated reflex bradycardia, as indicated by significantly smaller BRS PE in castrated rats compared with values in sham-operated rats (-0.85 +/- 0.07 vs. -1.51 +/- 0.10 beats/min per mm Hg). Testosterone replacement in castrated rats restored plasma testosterone and BRS PE to levels similar to those of sham-operated rats. Muscarinic blockade by atropine caused 55% reduction in BRS PE in sham-operated rats, an effect that was significantly (p < 0.05) attenuated in castrated rats and restored to intact levels after testosterone supplementation. beta-Adrenergic blockade by propranolol caused slight and insignificant decreases in BRS PE. Castration and testosterone supplementation had no effect on BRS NP, ruling out a modulatory effect of testosterone on reflex tachycardia. These data provide the first experimental evidence of a favorable role for testosterone in baroreceptor control of reflex bradycardia. Further, baroreflex modulation by testosterone appears to be autonomically mediated and involves an enhancement of cardiomotor vagal activity.

Adrenergic beta-Antagonists↗

PubMed2001

A condition dependent link between testosterone and disease resistance in the house finch.

Testosterone has recently been proposed as a link between male quality and health and the expression of sexual traits. We investigated the relationship between testosterone and measures of the individual condition and health of males in a natural population of house finches (Carpodacus mexicanus). We also conducted a captive experiment in order to test for the effects of testosterone on resistance to coccidia, which is a common parasite of house finches. Free-living males in better condition had higher testosterone levels and lower corticosterone levels than free-living males in poor condition. In our captive experiment, increased testosterone accelerated the rate of coccidial infection as compared with sham-implanted or gonadectomized males. Although the differences were not significant, free-living males infected with coccidia had lower levels of testosterone and higher levels of corticosterone than males that were not infected. Thus, experimentally elevating testosterone levels in captive males resulted in a higher percentage of infected males, while free-living males with coccidial infection had low testosterone levels. This apparent discrepancy between captive and free-living males in the association of testosterone and disease may be explained by the condition dependence of testosterone. These results suggest that the testosterone-dependent sexual traits reliably indicate male overall condition and health and, thus, females could benefit from assessing potential mates based on these traits.

Animals↗

PubMed1984

Hormonal effects of GnRH agonist in the human male: II. Testosterone enhances gonadotrophin suppression induced by GnRH agonist.

Superactive analogues of gonadotrophin releasing hormone and testosterone, when administered together, synergistically inhibit gonadotrophin secretion and spermatogenesis in the rat. In order to determine whether testosterone also enhanced gonadotrophin suppression by GnRH agonist in the human male, two groups of four normal male volunteers first received either 10 or 100 micrograms of a GnRH agonist D(Nal2)6GnRH (GnRH-A) daily for 10 d. After at least a 50 d recovery period, the same subjects received a single injection of 200 mg of testosterone oenanthate (TE) on day 1 in addition to the same dose of GnRH-A daily for 10 d. Serum LH, FSH and testosterone (TS) concentrations were measured daily just prior to the next analogue dose, and on days 1 and 10 at 0, 1, 2, 4, 6, 8, 12, 16 and 24 h after the analogue injection. Daily administration of both 10 and 100 micrograms of GnRH-A alone resulted in an early phase of stimulation followed by progressive decline in LH, FSH and testosterone to levels below baseline by day 10 despite continued administration of GnRH-A. Addition of testosterone to 10 micrograms of GnRH-A resulted in hormonal responses identical to those seen with GnRH-A alone. Combined treatment of testosterone with 100 micrograms of GnRH-A did not blunt the peak LH and FSH responses on day 2, but resulted in significantly lower LH (mean integrated responses: 187 +/- 30 vs. 234 +/- 42 mIU-d/ml) and FSH (mean integrated responses: 20.6 +/- 3.3 vs. 32.8 +/- 4.2 mIU-d/ml) responses from days 3 to 11. By day 11, all subjects receiving combined treatment (GnRH-A 100 micrograms + testosterone oenanthate) had undetectable serum FSH levels. In contrast, serum FSH concentrations on day 11 after treatment with GnRH-A alone were 43.6 +/- 8.9% of control and none of the subjects had values below the limit of detection. Serum testosterone levels in the combined treatment group did not fall below baseline by day 10 in either the 10 (161.4 +/- 48%) or the 100 micrograms GnRH-A groups (104.6 +/- 11.2%), while in the group receiving GnRH-A alone, testosterone levels declined to 45.6 +/- 8.3% and 80 +/- 18.8% with the 10 and 100 micrograms dose respectively. We conclude that addition of a suppressive dose of testosterone to an appropriate dose of GnRN-A significantly enhances gonadotrophin suppression by GnRH-A in the human male.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

PubMed1993

Circadian variation in serum free and non-SHBG-bound testosterone in normal men: measurements, and simulation using a mass action model.

OBJECTIVE: We measured the changes in testosterone fractions in serum of normal men over a 24-hour period, and determined whether they could be simulated on the basis of current understanding of the interactions between steroids and binding proteins in the blood. DESIGN: Starting from between 0830 and 0930 h, blood samples were taken every 45 minutes for 25.5 hours. PATIENTS: Five healthy males aged 26-45 years. All participants worked on a hospital campus and while being sampled carried out their normal activities during waking hours. MEASUREMENTS: The concentrations of testosterone (RIA) and albumin, and the percentage non-sex hormone binding globulin-bound testosterone (ammonium sulphate precipitation) and percentage free testosterone (rate dialysis), were measured on each sample. Cortisol (RIA) and sex hormone-binding globulin (SHBG) (IRMA) concentrations were measured on every second sample, and that of corticosteroid-binding globulin on two samples from each series. RESULTS: In all participants the levels of free and non-SHBG-bound testosterone in early morning samples (near 0530 h) were significantly different from those taken before midnight (P < 0.0005). Significant circadian rhythms (P < 0.05) in the concentration of testosterone and in the level of the free fraction were detected in all participants, and in four of the five participants for the non-SHBG-bound fraction. The amplitude of the free testosterone rhythm (34 +/- 2% of basal) was greater than that for testosterone itself (24 +/- 3% of basal). The 24-hour rhythm of the non-SHBG-bound fraction was similar to the total and free fractions except for the period 0330-0900 h when the level of this fraction declined by 15-45% over 1.5-3 hours. This decline was coincident with the initial rise in the concentration of cortisol. A decline of 10.5 +/- SEM 1.0% in the concentration of albumin, and 12.0 +/- 1.1% in that of SHBG occurred when the mean ambulant and supine levels were compared; analysis indicated significant circadian rhythms in the concentrations of these proteins. Simulation was used to investigate possible causes for the circadian rhythms in free and non-SHBG-bound testosterone. Simulation results matched the measured data well in qualitative terms, but quantitatively there were differences. CONCLUSIONS: Increasing saturation of the binding proteins following rises in testosterone production, and the small but significant changes in protein concentration, probably related to postural changes, were implicated as the major factors in the rhythm amplitude. However, the early morning decline in the non-SHBG-bound fraction was not explained by these factors. The rise in cortisol concentration at this time is a probable cause. Alternatively, simulation suggests that a substance appearing in the early morning and competing with testosterone for albumin binding sites may be responsible.

Adult↗

PubMed1994

Longitudinal study of maternal plasma bioavailable testosterone and androstanediol glucuronide levels during pregnancy.

OBJECTIVE: The aim of this study to evaluate during normal pregnancy plasma bioavailable testosterone and androstanediol glucuronide levels. MEASUREMENTS: Bioavailable testosterone, androstanediol glucuronide and SHBG levels were evaluated every 4 weeks from week 6 to week 38 in 10 normal pregnant women. We also measured plasma oestradiol, oestriol, delta 4-androstenedione, 17-hydroxyprogesterone, progesterone and testosterone. RESULTS: The mean bioavailable testosterone levels were within the range of non-pregnant women but with an increasing trend until delivery. Androstanediol glucuronide had increased at weeks 6 and 8, decreased at week 14, remained low at week 30, and increased again at week 34. SHBG was significantly correlated with testosterone, oestradiol and oestriol. No correlation could be established between androstanediol glucuronide and any other parameter. DISCUSSION: Bioavailable testosterone (non-SHBG bound testosterone) represents the sum of free testosterone plus albumin bound testosterone. The increase in testosterone concentrations with decreased albumin levels during pregnancy, could suggest reduced metabolic clearance of testosterone throughout pregnancy. No correlation was established between the decrease in androstanediol glucuronide and increase in progesterone, suggesting that the decrease in androstanediol glucuronide is not a consequence of the inhibitory effect of progesterone on 5 alpha-reductase activity.

17-alpha-Hydroxyprogesterone↗

PubMed1994

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

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

Adult↗

PubMed2004

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

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

Administration, Cutaneous↗

PubMed2006

Testosterone increases lactate transport, monocarboxylate transporter (MCT) 1 and MCT4 in rat skeletal muscle.

We have examined the effects of administration of testosterone for 7 days on monocarboxylate transporter (MCT) 1 and MCT4 mRNAs and proteins in seven metabolically heterogeneous rat hindlimb muscles and in the heart. In addition, we also examined the effects of testosterone treatment on plasmalemmal MCT1 and MCT4, and lactate transport into giant sarcolemmal vesicles prepared from red and white hindlimb muscles and the heart. Testosterone did not alter MCT1 or MCT4 mRNA, except in the plantaris muscle. Testosterone increased MCT1 (20%-77%, P < 0.05) and MCT4 protein (29%-110%, P< 0.05) in five out of seven muscles examined. In contrast, in the heart MCT1 protein was not increased (P> 0.05), and MCT 4 mRNA and protein were not detected. There was no correlation between the testosterone-induced increments in MCT1 and MCT4 proteins. Muscle fibre composition was not associated with testosterone-induced increments in MCT1 protein. In contrast, there was a strong positive relationship between the testosterone-induced increments in MCT4 protein and the fast-twitch fibre composition of rat muscles. Lactate transport into giant sarcolemmal vesicles was increased in red (23%, P< 0.05) and white muscles (21%, P< 0.05), and in the heart (58%, P< 0.05) of testosterone-treated animals (P< 0.05). However, plasmalemmal MCT1 protein (red, +40%, P< 0.05; white, +39%, P< 0.05) and plasmalemmal MCT4 protein (red, +25%, P< 0.05; white, +48%, P< 0.05) were increased only in skeletal muscle. In the heart, plasmalemmal MCT1 protein was reduced (-20%, P< 0.05). In conclusion, these studies have shown that testosterone induces an increase in both MCT1 and MCT4 proteins and their plasmalemmal content in skeletal muscle. However, the testosterone-induced effect was tissue-specific, as MCT1 protein expression was not altered in the heart. In the heart, the testosterone-induced increase in lactate transport cannot be explained by changes in plasmalemmal MCT1 content, but in skeletal muscle the increase in the rate of lactate transport was associated with increases in plasmalemmal MCT1 and MCT4.

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