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PubMed2001

Pharmacokinetics of a transdermal testosterone system in men with end stage renal disease receiving maintenance hemodialysis and healthy hypogonadal men.

Androgen deficiency is common in men with end stage renal disease (ESRD) on maintenance hemodialysis. Pharmacokinetics of transdermal testosterone in men receiving maintenance hemodialysis have not been studied. Our objective was to compare the pharmacokinetics of a transdermal testosterone system in healthy hypogonadal men and in men with ESRD on maintenance hemodialysis. We recruited 10 healthy hypogonadal men and 8 medically stable men on maintenance hemodialysis, 18--70 yr old, who had serum testosterone less than 300 ng/dL. After baseline sampling during a 24-h control period, two testosterone patches were applied daily for 28 days, to achieve a nominal delivery of 10-mg testosterone daily. In addition to single, pooled samples on days 7, 14, and 21, blood was drawn at 0, 2, 4, 6, 8, and 24 h on day 28 in healthy hypogonadal men and on an interdialytic day (day 21 or 28) as well as a dialysis day (day 21 or 28) in men on hemodialysis. On the dialysis day (day 21 or 28), serum free and total testosterone levels were measured hourly for 4 h before hemodialysis and for 4 h during hemodialysis. The dialysate was sampled for testosterone measurement. Baseline mean + SD total (92 +/- 82 vs. 222 +/- 50 ng/dL) and free (11 +/- 9 vs. 27 +/- 6 pg/mL) testosterone concentrations were lower in healthy hypogonadal men than in men with ESRD. After application of two testosterone patches, serum total and free testosterone concentrations rose into the midnormal range in both groups of men. Time-average, steady state (total testosterone, 506 +/- 88 vs. 516 +/- 86 ng/dL; free testosterone, 55 +/- 9 vs. 67 +/- 11 pg/mL), minimum, and maximum total and free testosterone concentrations were not significantly different between the two groups of men during treatment. Increments in total and free testosterone concentrations above baseline, baseline-subtracted areas under the total and free testosterone curves, and half-life of testosterone elimination (t(1/2), 2.1 +/- 0.1 vs. 2.1 +/- 0.2 h, P = not significant) were not significantly different between the two groups. In men receiving hemodialysis, time-average, steady state, and maximal total and free testosterone concentrations and baseline-subtracted areas under the total and free testosterone curves were higher on dialysis day than on an interdialytic day. On the day of hemodialysis, time-average total and free testosterone concentrations were not significantly different during the 4 h before or during hemodialysis. The amount of testosterone removed in the dialysate (8.4 +/- 1.6 microg during 4 h of hemodialysis) was small compared with the daily testosterone production rates in healthy young men. Serum dihydrotestosterone and estradiol concentrations increased into the normal male range and were not significantly different between the two groups. Percent suppression of LH was greater in men with ESRD than in healthy hypogonadal men. A regimen of two Testoderm TTS testosterone patches (Alza Corp., Mountain View, CA) daily can maintain serum concentrations of total and free testosterone and its metabolites dihydrotestosterone and estradiol in the midnormal range in healthy hypogonadal men and men on hemodialysis. The amount of testosterone cleared by hemodialysis is small, and hemodialysis does not significantly affect serum total and free testosterone concentrations in men treated with the testosterone patch.

Administration, Cutaneous↗
PubMed1995

Testosterone relaxes rabbit coronary arteries and aorta.

BACKGROUND: Until menopause, women appear to be protected from coronary heart disease. Evidence suggests that estrogen may play a role in the protection of the cardiovascular system by exerting a beneficial effect on risk factors such as cholesterol metabolism and by a direct effect on the coronary arteries. To date there has been no evidence linking testosterone with the occurrence of coronary heart disease. Testosterone may affect the cardiovascular system directly, thus partially explaining the difference in the incidence of coronary artery disease in men and premenopausal women. The purpose of this study was to assess the direct effect of testosterone and a number of testosterone analogues on rabbit coronary arteries and aorta in vitro. METHODS AND RESULTS: Rings of coronary artery and aorta of adult male or nonpregnant female New Zealand White rabbits were suspended in organ baths containing Krebs solution; isometric tension then was measured. The response to testosterone was investigated in prostaglandin F2 alpha (PGF 2 alpha)- and KCl-contracted rings. The effects of endothelium and nitric oxide synthase, prostaglandin synthetase, and guanylate cyclase inhibition on testosterone-induced relaxation were investigated. The effects of ATP-sensitive potassium channels and potassium conductance were also assessed. Relaxing responses in the presence of aromatase inhibition and testosterone receptor blockade were performed. The relaxing responses to the testosterone analogues etiocholan-3 beta-ol-17-one, epiandrosterone, 17 beta-hydroxy-5 alpha-androst-1-en-3-one, androst-16-en-3-ol, and testosterone enanthanate were measured. Testosterone relaxed rabbit coronary arteries and aorta. There was no significant difference between the relaxation effect of testosterone with or without endothelium. Similar results were obtained from male and nonpregnant female rabbits. The relaxing response of testosterone in the coronary artery was significantly greater than in the aorta. The relaxing response of testosterone in the coronary artery was significantly reduced by the potassium channel inhibitor barium chloride but not by the ATP-sensitive potassium channel inhibitor glibenclamide. The relaxing response to testosterone was greater in PGF 2 alpha-contracted rings compared with KCl-contracted rings. Inhibitors of nitric oxide synthase, prostaglandin synthetase, and guanylate cyclase did not affect relaxation induced by testosterone. Inhibition of aromatase and testosterone receptors did not affect relaxation. Testosterone did not shift the rabbit coronary arterial calcium concentration-dependent contraction curves, whereas verapamil did. There were, however, significant differences in the relaxing response to testosterone compared with testosterone analogues. Testosterone was the most potent relaxing agent, suggesting that there may be a structure-function relation in the relaxing response. CONCLUSIONS: Testosterone induces endothelium-independent relaxation in isolated rabbit coronary artery and aorta, which is neither mediated by prostaglandin I2 or cyclic GMP. Potassium conductance and potassium channels but not ATP-sensitive potassium channels may be involved partially in the mechanism of testosterone-induced relaxation. The in vitro relaxation is independent of sex and of a classic receptor. The coronary artery is significantly more sensitive to relaxation by testosterone than the aorta. Testosterone is a more potent relaxing agent of rabbit coronary artery than other testosterone analogues.

Animals↗
PubMed2004

Testosterone therapy--what, when and to whom?

Testosterone therapy has been used for more than 60 years in the treatment of male hypogonadism. The classical forms of hypogonadism are comprised of primary testicular failure or insufficient testicular stimulation due to the lack of pituitary gonadotropins. Typical causes of primary hypogonadism are Klinefelter's syndrome, anorchia or acquired disturbances of testicular function. Secondary hypogonadism is characterized by insufficient production of pituitary gonadotropins, due either to pituitary failure or defects at the hypothalamic level. It is unequivocally accepted in clinical practice that any male with inadequately low testosterone production for his age will require androgen therapy. In addition to the classical forms of hypogonadism, the past decade of research has clearly demonstrated that, with increasing age, many men will suffer from decreasing testosterone production. About 15-25% of men over the age of 50 years will experience serum testosterone levels well below the threshold considered normal for men between 20 and 40 years of age. Studies substituting testosterone in elderly men with low serum testosterone have shown that men with clinical symptoms identical to the symptomatology of classical hypogonadism will benefit most from such therapy. Therefore, it is the general consensus to treat men with age-related hypogonadism only when clinical symptoms are present that can be potentially corrected by testosterone administration. Until recently, intramuscular injections of esters, such as testosterone enanthate, have been the mainstay of testosterone therapy. The introduction of testosterone patches has not challenged this approach, since many users of patches suffer from moderate to severe skin reactions. Some oral testosterone formulations have proven to be problematic, as absorption can be variable, bioavailability is frequently poor, due to the first-pass effect of the liver, and frequent administration is often required. Oral testosterone undecanoate avoids, at least partially, the first-pass effect of the liver. However, plasma testosterone levels generally undergo large fluctuations. The large fluctuations in serum testosterone levels caused by conventional intramuscular injections result in unsatisfactory shifts in mood and sexual function in some men, which, combined with the frequency of injections, make the intramuscular mode of delivery far from ideal. Recently, a hydroalcoholic gel containing 1% testosterone has proven to be as efficient as a testosterone patch, but with fewer side-effects and a higher grade of patient satisfaction. Doses of 50-100 mg gel applied once daily on the skin deliver sufficient amounts of testosterone to restore normal hormonal values and correct the signs and symptoms of hypogonadism. The gel has been shown to be effective and successful in patients in the United States, who have benefited from its availability for almost 3 years. In the near future, intramuscular injections of testosterone undecanoate will become commercially available. Such injections have a very favorable pharmacokinetic profile, with one injection every 3 months maintaining serum testosterone well within the normal range. In phase III studies, intramuscular testosterone undecanoate proved to be as efficient as testosterone enanthate, with only one-quarter of the number of injections required and more stable serum testosterone levels. Thus, the new application modes--hydroalcoholic gel (for example, Testogel, Schering AG, Germany) and intramuscular testosterone undecanoate (Nebido, Schering AG, Germany)--appear to be the methods of choice in the near future, one being very suitable for hormone therapy in elderly men, the other for long-term substitution in classical forms of hypogonadism.

Age Factors↗
PubMed2000

Skin permeation of testosterone and its ester derivatives in rats.

To establish the optimum conditions for improving the transdermal delivery of testosterone, we studied the relationship between the lipophilicity of testosterone ester derivatives and the rat skin permeation rate of testosterone. We performed a rat skin permeation study of testosterone and its commercially available ester derivatives, testosterone hemisuccinate, testosterone propionate and testosterone-17beta-cypionate, using an ethanol/water co-solvent system. The aqueous solubility and rat skin permeation rate of each drug, saturated in various compositions of an ethanol/water system, was determined at 37 degrees C. The aqueous solubility of testosterone and its ester derivatives increased exponentially as the volume fraction of ethanol increased up to 100% (v/v). The stability of testosterone propionate in both the skin homogenate and the extract was investigated to observe the enzymatic degradation during the skin permeation process. Testosterone propionate was found to be stable in the isotonic buffer solution and in the epidermis-side extract for 10h at 37 degrees C. However, in the skin homogenate and the dermis-side extract testosterone propionate rapidly degraded producing testosterone, implying that testosterone propionate rapidly degraded to testosterone during the skin permeation process. The steady-state permeation rates of testosterone in the ethanol/water systems increased exponentially as the volume fraction of ethanol increased, reaching the maximum value (2.69+/-0.69 microg cm(-2)h(-1)) at 70% (v/v) ethanol in water, and then decreasing with further increases in the ethanol volume fraction. However, in the skin permeation study with testosterone esters saturated in 70% (v/v) ethanol in water system, testosterone esters were hardly detected in the receptor solution, probably due to the rapid degradation to testosterone during the skin permeation process. Moreover, a parabolic relationship was observed between the permeation rate of testosterone and the log P values of ester derivatives. Maximum flux was achieved at a log P value of around 3 which corresponded to that of testosterone (log P = 3.4). The results showed that the skin permeation rate of testosterone and its ester derivatives was maximized when these compounds were saturated in a 70% ethanolic solution. It was also found that a log P value of around 3 is suitable for the skin permeation of testosterone related compounds.

Animals↗
PubMedDate not supplied

Serum dihydrotestosterone and testosterone concentrations in human immunodeficiency virus-infected men with and without weight loss.

Weight loss is an important determinant of disease outcome in human immunodeficiency virus (HIV)-infected men. Others have suggested that a defect in dihydrotestosterone (DHT) generation contributes to weight loss in HIV-infected men. To determine whether DHT levels correlate with weight loss independently of changes in testosterone levels, we prospectively measured serum total- and free-testosterone and DHT levels in 148 consecutive HIV-infected men and 42 healthy men. Thirty-one percent of HIV-infected men had serum testosterone levels less than 275 ng/dL, the lower limit of the normal male range; of these, 81% had normal or low LH and FSH levels (hypogonadotropic), and 19% had elevated LH and FSH levels (hypergonadotropic). Overall, serum testosterone, free-testosterone, and DHT levels were lower in HIV-infected men than in healthy men, but serum DHT-to-testosterone ratios were not significantly different between the two groups. Serum total- and free-testosterone levels were lower in HIV-infected men who had lost 5 lb or more of weight in the preceding 12 months than in those who had not lost any weight. Serum DHT levels and DHT-to-testosterone ratios did not differ between those who had lost weight and those who had not. Serum testosterone and free-testosterone levels, but not DHT levels, correlated with weight change and with Karnofsky performance status. We also performed a retrospective analysis of data from a previous study in which HIV-infected men with serum testosterone levels less than 400 ng/dL had been treated with placebo or testosterone patches designed to nominally release 5 mg testosterone over 24 hours. Serum testosterone-to-DHT ratios did not change after testosterone treatment. Changes in fat-free mass were correlated with changes in both serum testosterone (r = 0.42, P = 0.018) and DHT (r = 0.35, P = 0.049) levels. Serum total- testosterone and DHT levels were highly correlated with one another, and when the change in serum testosterone was taken into account, serum DHT levels no longer showed a significant correlation with change in fat-free mass. We conclude that DHT levels are lower in HIV-infected men than in healthy men but that neither DHT levels nor DHT-to-testosterone ratios correlate with weight loss. During testosterone treatment, serum DHT levels increase proportionately, but the increments in serum testosterone correlate with the change in fat-free mass. Our data do not support the hypothesis that a defect in DHT generation contributes to weight loss in HIV-infected men independently of changes in testosterone levels; it is possible that such a defect might exist in HIV-infected men with more severe weight loss.

Adolescent↗
PubMed2005

The role of testosterone therapy in postmenopausal women: position statement of The North American Menopause Society.

OBJECTIVE: To create an evidence-based position statement regarding the role of exogenous testosterone in postmenopausal women. DESIGN: The North American Menopause Society (NAMS) enlisted a panel of clinicians and researchers acknowledged to be experts in the field of testosterone therapy to review the evidence obtained from the medical literature, compile supporting statements and conclusions, and reach consensus on recommendations. The document was reviewed and approved by the NAMS Board of Trustees. RESULTS: Endogenous testosterone levels have not been clearly linked to sexual function in postmenopausal women. Published evidence from randomized controlled trials, although limited, indicates that exogenous testosterone, both oral and nonoral formulations, has a positive effect on sexual function, primarily desire, arousal, and orgasmic response, in women after spontaneous or surgically induced menopause. Data are inadequate to support recommending testosterone use for any other indication, including preserving or increasing bone mineral density, reducing hot flashes, increasing lean body mass, or improving well-being. Hirsutism and acne have been associated with testosterone therapy, but the actual risks are not well defined. It is not known whether testosterone therapy increases the risk of breast cancer, cardiovascular disease, or thromboembolic events. There are few data regarding the safety and efficacy of testosterone therapy in women not using concomitant estrogen therapy or for the use of testosterone therapy for longer than 6 months. Clinically available laboratory assays do not accurately detect testosterone concentrations at the values typically found in women, and no testosterone level has been clearly linked to a clinical syndrome of hypoandrogenism or testosterone insufficiency. CONCLUSIONS: Postmenopausal women with decreased sexual desire associated with personal distress and with no other identifiable cause may be candidates for testosterone therapy. Testosterone treatment without concomitant estrogen therapy cannot be recommended because of a lack of evidence. When evaluating a woman for testosterone therapy, recommendations are to rule out causes not related to testosterone levels (eg, physical and psychosocial factors, medications) and to ensure that there is a physiologic cause for reduced testosterone levels (eg, bilateral oophorectomy). Laboratory testing of testosterone levels should be used only to monitor for supraphysiologic levels before and during therapy, not to diagnose testosterone insufficiency. Monitoring should also include subjective assessments of sexual response, desire, and satisfaction as well as evaluation for potential adverse effects. Transdermal patches and topical gels or creams are preferred over oral products because of first-pass hepatic effects documented with oral formulations. Custom-compounded products should be used with caution because the dosing may be more inconsistent than it is with government-approved products. Testosterone products formulated specifically for men have a risk of excessive dosing, although some clinicians use lower doses of these products in women. Testosterone therapy is contraindicated in women with breast or uterine cancer or in those with cardiovascular or liver disease. It should be administered at the lowest dose for the shortest time that meets treatment goals. Counseling regarding the potential risks and benefits should be provided before initiating therapy.

Androgens↗
PubMed1989

The effects of exogenously administered testosterone on spermatogenesis in intact and hypophysectomized rats.

The effects of exogenously administered testosterone on the maintenance of spermatogenesis in intact and hypophysectomized rats were examined. Adult male rats were given Silastic implants containing testosterone in lengths ranging from 0.5-20 cm, and their effects on daily sperm production (DSP); serum FSH, LH, and testosterone; and interstitial fluid testosterone were determined in intact and hypophysectomized rats over a 13-week period. In intact rats, DSP levels were suppressed to 4-30% of control values at lower testosterone doses (2- to 6-cm implants), while DSP levels were partially maintained (65-93%) at higher doses (greater than or equal to 8 cm implants). Under these conditions LH levels were suppressed while FSH levels were reduced to 30-60% of control values. A steep testosterone-induced change in DSP levels was observed in both intact (2- to 3-fold) and hypophysectomized (18-fold) animals over a narrow testosterone dose range (implant lengths, 6-8 cm). Interstitial fluid testosterone levels associated with this change in DSP levels range from 6-8% of control values, while serum testosterone levels were elevated 1- to 2-fold above control values. A comparison of the testosterone implant lengths that caused a 50% change in DSP levels after 7 weeks of treatment was similar in intact and hypophysectomized rats. At high testosterone doses (greater than or equal to 10-cm implants), maximal DSP levels decreased 10% by 7 weeks and 35% by 13 weeks. DSP and serum testosterone levels were highly correlated (r = 0.54-0.83), while DSP and interstitial fluid testosterone showed a less correlation (r = 0.36-0.70) under the various experimental conditions examined. In conclusion, the testosterone-induced maintenance of DSP in rats is associated with several dose-related responses or events that appear to be differentially regulated. At low testosterone concentrations, DSP levels are partially maintained in intact rats but are totally suppressed in hypophysectomised rats, suggesting that a pituitary factor, probably FSH, has a potentiating effect at these testosterone concentrations. At intermediate testosterone doses resulting in the testosterone-induced maintenance of DSP, the similarity of dose-response curves (ED50 and maximum response) in intact and hypophysectomised rats would suggest that pituitary hormones are not required for this aspect of the process. The observation that the maintenance of DSP by testosterone under some experimental conditions is poorly correlated with interstitial fluid testosterone levels raises questions as to the mechanisms by which testosterone acts to stimulate spermatogenesis.

Animals↗
PubMed1994

[Changes in the salivary testosterone level in aged].

Measurement of the level of free testosterone is important in the evaluation of testicular function. Because most of the testosterone in the saliva is in the free form, measurement of the salivary testosterone level is considered to be effective for the evaluation of testicular function. In the present study, a commercial kit was employed to measure the salivary testosterone level, and the change in the salivary testosterone level with age was investigated. The subjects of this study were 76 males, 20-89 years of age, with no endocrinological diseases. The concentration of testosterone in the saliva was measured for each of the subjects, and for 34 of the subjects the concentrations of total testosterone and free testosterone in the serum were also measured at the same time. Standard serum was diluted to have a testosterone concentration of 50 pg/ml, and the results indicated that it was sufficiently possible to measure the salivary testosterone. The coefficient of correlation between the salivary testosterone concentration and the serum total testosterone concentration was 0.479 (p < 0.01), while the coefficient of correlation between the salivary testosterone concentration and the serum free testosterone concentration was 0.732 (p < 0.001). These findings thus indicate that the correlation between the salivary testosterone concentration and the serum free testosterone concentration is better than that between the salivary testosterone concentration and the serum total testosterone concentration. It was also demonstrated that the salivary testosterone concentration decreased significantly with aging after the fifth decade of life. The correlation coefficient for that relationship was -0.606 (p < 0.001), and the change was similar to that seen in the serum free testosterone concentration as a function of aging. The findings suggested that measurement of the salivary testosterone concentration with the commercial kit is useful for the evaluation of testicular function.

Adult↗
PubMed1997

Serum testosterone--a significant determinant of metastatic relapse for irradiated localized prostate cancer.

OBJECTIVES: To determine if the serum total testosterone concentration correlates with the outcome for men irradiated for clinically localized prostate cancer. METHODS: The outcome-local, nodal, distant metastatic, and biochemical--for 486 men with clinically localized prostate cancer treated by radiation and for whom testosterone levels were available was analyzed. No patient received adjuvant androgen ablation. Patient tumor stages were T1: 129 (27%); T2: 187 (38%); and T3/T4: 170 (35%). Median follow-up was 41 months. RESULTS: Pretreatment testosterone values ranged from 109 to 1121 ng/dL, with a mean of 417 ng/dL and a median of 398 ng/dL. The distribution of patients according to a four-tier testosterone grouping was testosterone level of 300 ng/dL or less, 108 (22%); testosterone level greater than 300 ng/dL but not more than 400 ng/dL, 141 (29%); testosterone level greater than 400 ng/dL but not more than 500 ng/dL, 123 (25%); and testosterone level greater than 500 ng/dL, 114 (23%). There were statistically significant but trivial correlations between testosterone level and age, T-stage, and acid phosphatase level. There was no correlation between testosterone and prostate-specific antigen (PSA) levels. There was a highly significant correlation between testosterone level and metastatic relapse. Patients with testosterone level greater than 500 ng/dL had a markedly higher 6-year metastatic rate (16%) than those with a testosterone level of 500 ng/dL or less (4%) (P = 0.001). In multivariate analysis, testosterone level was an independent determinant of metastatic relapse, second only to PSA level and of about the same power as T-stage. Gleason grade, although significant, was less so than testosterone level. The correlation of testosterone level to outcome appeared to be specific for metastatic relapse having no relation to local outcome. Likewise, high testosterone levels were not associated with acceleration of postradiation serum PSA kinetics. CONCLUSIONS: There is a highly significant correlation between pretreatment testosterone level and metastatic relapse in patients with clinically localized prostate cancer treated with radiation. As serum testosterone increases, so too does metastatic relapse. This relationship appears to take a decided turn for the worse at testosterone levels exceeding 500 ng/dL.

Aged↗