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PubMed1989

Identification of the cytochrome P-450 isozymes responsible for testosterone oxidation in rat lung, kidney, and testis: evidence that cytochrome P-450a (P450IIA1) is the physiologically important testosterone 7 alpha-hydroxylase in rat testis.

Previous studies have shown that several forms of cytochrome P-450 present in rat liver microsomes oxidize testosterone with a high degree of regio- and stereospecificity. The aim of this study was to characterize the pathways of testosterone oxidation catalyzed by rat extrahepatic microsomes. Lung, kidney, testis, prostate, and brain were isolated from 3- and 14-week-old-male Sprague-Dawley rats. Microsomes from lung, kidney, and testis catalyzed distinctly different pathways of testosterone oxidation, whereas microsomes from prostate and brain failed to hydroxylate testosterone directly in a time- and protein-dependent manner. Lung microsomes from immature and mature rats converted testosterone to 16 alpha-hydroxytestosterone, 16 beta-hydroxytestosterone, and androstenedione. Lung microsomes were shown by Western immunoblot to contain cytochrome P-450b (P450IIB1), which has been shown previously to catalyze these three pathways of testosterone oxidation. Antibody against cytochrome P-450b strongly inhibited (greater than 80%) androstenedione formation and completely inhibited (greater than 95%) the 16 alpha- and 16 beta-hydroxylation of testosterone catalyzed by lung microsomes (as did carbon monoxide and antibody against NADPH-cytochrome P-450 reductase). Kidney microsomes from mature male rats converted testosterone to 2 alpha-hydroxytestosterone, 16 alpha-hydroxytestosterone, and androstenedione, whereas only the latter pathway was catalyzed by kidney microsomes from immature rats. Kidney microsomes from mature male rats were shown by Western immunoblot to contain cytochrome P-450h (P450IIC11), which has been shown previously to convert testosterone to 2 alpha-hydroxytestosterone, 16 alpha-hydroxytestosterone, and androstenedione. Antibody against cytochrome P-450h completely inhibited (greater than 95%) the 2 alpha- and 16 alpha-hydroxylation of testosterone by kidney microsomes, but had little effect on androstenedione formation, which is catalyzed by 17 beta-hydroxysteroid dehydrogenase. Testicular microsomes from mature, but not immature, rats catalyzed the 7 alpha-hydroxylation of testosterone. Previous studies have shown that this reaction is catalyzed in liver microsomes by cytochrome P-450a (P450IIA1). Testicular microsomes from mature, but not immature, rats were shown by Western immunoblot to contain cytochrome P-450a. Antibody against cytochrome P-450a or NADPH-cytochrome P-450 reductase completely inhibited (greater than 95%) the 7 alpha-hydroxylation of testosterone by testicular microsomes. A 90:10 atmosphere of carbon monoxide and oxygen did not appreciably block the 7 alpha-hydroxylation of testosterone by testicular microsomes, wh

Animals↗
PubMed1992

A biodegradable testosterone microcapsule formulation provides uniform eugonadal levels of testosterone for 10-11 weeks in hypogonadal men.

Limitations of presently available testosterone esters (enanthate and cypionate) include the fluctuating serum testosterone levels and the need for relatively frequent injections (every 10-21 days). These limitations of testosterone esters have prompted the development of more physiological and longer acting systems for androgen delivery. This paper reports pharmacokinetic and pharmacodynamic data with a second generation long-acting testosterone microcapsule formulation in hypogonadal men. This was a single dose, open label, nonrandomized study. Ten hypogonadal men with primary (n = 6) or secondary (n = 4) hypogonadism, otherwise in good health, received 630 mg microencapsulated testosterone in dextran solution (IM) on day 1. Serum total and free testosterone; LH; FSH; dihydrotesterone; estradiol; sex hormone-binding globulin; total cholesterol; high, low, and very low density lipoprotein cholesterol; triglycerides; and apoprotein-AII and -B were measured on multiple occasions during the 2-week control period and the 16-week treatment period. In addition, on days 0, 1, 28, 56, and 84, subjects were hospitalized for detailed hormone analyses over the 24-h period. Serum total and free testosterone levels rose quickly into the midnormal range and stayed uniformly in the eugonadal range for about 70-77 days, after which serum testosterone levels declined gradually into the hypogonadal range. Testosterone release from the microcapsule formulation over the first 10 weeks approximated zero order kinetics. Serum dihydrotestosterone levels rose into the normal range, and testosterone to dihydrotestosterone ratios remained in the physiological range. Serum estradiol levels rose and stayed in the midnormal male range. Serum sex hormone-binding globulin levels decreased significantly during treatment. Serum LH and FSH levels also significantly decreased in the six hypergonadotropic men. Total cholesterol low and very low density lipoprotein cholesterol and triglyceride levels did not change, but plasma high density lipoprotein cholesterol levels decreased significantly during treatment. These data indicate that testosterone microcapsule formulation provides uniform eugonadal levels of testosterone for about 10 weeks. The long duration and zero order kinetics make it an attractive alternative to existing methods of androgen replacement.

Adolescent↗
PubMedDate not supplied

Concentrations of free testosterone, total testosterone, and androgen binding protein in the peripheral serum of male rats during sexual maturation.

To investigate the relationship between free testosterone and sexual maturation in the male rat, animals were decapitated every 5 days from 25 through 75 days of life. Serum was assayed for androgen binding protein and total testosterone by radioimmunoassay. Free testosterone concentrations were calculated from the total testosterone concentration and the free testosterone fraction. The free testosterone fraction was determined by ultrafiltration. The pubertal increase in relative prostate and relative seminal vesicle weights began between 45 and 50 days and 40 and 45 days, respectively. Although the over-all trend in the free testosterone fraction was to increase with increasing age (r = 0.46, P less than 0.0001), there was a significant secondary peak at 50 days. The serum concentration of androgen binding protein was highest on day 25, fell rapidly until day 40, and declined slowly thereafter. Despite these variations in both androgen binding protein and the free testosterone fraction during sexual maturation, the calculated serum concentration of free testosterone was remarkably similar in pattern to that of total testosterone (r = 0.99, P less than 0.0001). These data indicate that the serum concentration of total testosterone is an accurate reflection of the serum concentration of free testosterone during the sexual maturation of the male rat.

Aging↗
PubMed2002

Interpersonal testosterone transfer after topical application of a newly developed testosterone gel preparation.

OBJECTIVE: Transdermal testosterone gel treatment is an effective androgen substitution therapy with several advantages over conventional substitution therapies. Whereas side-effects due to overdosing of hypogonadal patients are unlikely, testosterone gel application without protection may cause severe side-effects in other subjects (partners, family members) by contamination. Therefore, the risk of testosterone transfer of a newly developed 2.5% testosterone gel preparation was evaluated. DESIGN: In two clinical randomized open single-centre studies on healthy male volunteers the percentage of testosterone remaining on the skin after gel application over time (n = 12) and the possibility of a transfer of testosterone to another person (n = 28) was evaluated. In the second study the endogenous testosterone production in the receiving subjects was suppressed by injecting 400 mg norethisterone enanthate (NETE). RESULTS: After 8 h approximately 60% of testosterone applied to the skin could be recovered. When the skin had been previously washed with water, only about 14% of applied testosterone could be recovered. After intense skin contact with a volunteer who had applied testosterone before on his forearm, no increase in testosterone serum levels could be found in NETE-suppressed men. CONCLUSION: Although considerable amounts of testosterone remain on the intact skin for several hours after evaporation of the alcohol vehicle, contamination of a second, especially female or prepubertal, subject causing side-effects seems very unlikely.

Administration, Cutaneous↗
PubMed2002

Effects of transdermal testosterone on lipids and vascular reactivity in older men with low bioavailable testosterone levels.

BACKGROUND: Sex hormones are known to affect cholesterol levels and vascular tone in women. The effects of testosterone on cholesterol and vascular tone in men are less well understood. Low testosterone levels have been associated with higher cholesterol levels in epidemiologic studies, but testosterone replacement has resulted in variable changes in cholesterol levels. Similarly, clinical studies suggest that testosterone may be vasodilatory, but few studies have directly evaluated the effects of testosterone on vascular tone. METHODS: Sixty-seven men (mean age 76 +/- 4 years, range 65-87) with bioavailable testosterone levels below 4.44 nmol/l (lower limit for adult normal range) were randomized to receive transdermal testosterone (2-2.5 mg patches/d) or placebo patches for 1 year. Twenty-three men (34%) withdrew from the study; 44 men completed the trial. RESULTS: While total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels did not significantly change during the year of therapy, high-density lipoprotein (HDL) levels (p =.004) and, specifically, HDL(2) subfraction (p =.02) decreased in men receiving testosterone supplementation. Vascular tone was measured by brachial artery reactivity in 36 men. Endothelium-dependent brachial artery reactivity did not change from baseline measurements in men receiving transdermal testosterone (0.3 +/- 6.7% to 1.6 +/- 4.6%; p =.58) or in the placebo group (3.2 +/- 5.5% to 0.7 +/- 5.5%; p =.23). CONCLUSIONS: Transdermal testosterone decreased HDL(2) cholesterol but did not affect vascular reactivity in men older than 65 years selected for low testosterone levels. No study to date has addressed the direct relationship between testosterone replacement and cardiovascular events.

Administration, Cutaneous↗
PubMed2004

Testosterone release rate and duration of action of testosterone pellet implants.

OBJECTIVE: Testosterone pellets are a highly effective subdermal depot administered at regular intervals with the timing individualized depending upon return of the patient's characteristic androgen deficiency symptoms. Yet the in vivo testosterone release rate and effective duration of action of these pellets has been little studied systematically. DESIGN: Analysis of prospectively collected data from three randomized controlled clinical trials. Collection of extruded pellets. PATIENTS: Androgen-deficient men (n = 136) undergoing long-term androgen replacement therapy with a standard dose (800 mg) of testosterone pellets implanted subdermally at intervals from 5 to 7 months. MEASUREMENTS: Testosterone release rate of pellets, consisting of pure crystalline testosterone without excipients, is estimated by measuring the dry weight lost by pellets (n = 179) over their time in situ. The effective duration of the standard regimen, and the influence of extrusion and patient or procedural characteristics on it, was estimated by timing of return for re-implantation due to recurrence of the patient's familiar androgen deficiency symptoms. RESULTS: The loss of dry weight of intact (n = 112) pellets was strongly correlated with time in situ (r2 = 0.969) providing an estimate of daily testosterone release rate per 200 mg pellet of 1.34 +/- 0.02 mg/pellet/day (95% CI 1.30-1.37 mg/day) for the first 3 months. After 756 implantations of the standard dose, men return for re-implantation at 5.8 calendar months following no or only a single pellet extrusion, but the time to return was significantly shorter after multiple extrusions. No patient or procedural features influenced the timing of return. Among men with primary hypogonadism, increases in plasma LH and FSH were more sensitive than plasma total or free testosterone to changes in testosterone delivery following an extrusion. CONCLUSION: Testosterone pellet implants release testosterone at a steady rate of 1.3 mg/200 mg implant/day (95% CI). The duration of action is about 6 months in an uncomplicated cycle with timing of return shortened by extrusions only in the 3.6% of procedures followed by multiple extrusions. No other patient or procedural features influenced duration of action. Among men with an intact hypothalamo-pituitary unit, plasma gonadotropins are more sensitive than blood total or free testosterone to reduced testosterone delivery following an extrusion.

Adolescent↗
PubMed2006

Differences in the apparent metabolic clearance rate of testosterone in young and older men with gonadotropin suppression receiving graded doses of testosterone.

BACKGROUND: Recently we found that testosterone levels are higher in older men than young men receiving exogenous testosterone. We hypothesized that older men have lower apparent testosterone metabolic clearance rates (aMCR-T) that contribute to higher testosterone levels. OBJECTIVE: The objective of the study was to compare aMCR-T in older and young men and identify predictors of aMCR-T. METHODS: Sixty-one younger (19-35 yr) and 60 older (59-75 yr) men were given a monthly GnRH agonist and weekly testosterone enanthate (TE) (25, 50, 125, 300, or 600 mg) for 5 months. Estimated aMCR-T was calculated from the amount of TE delivered weekly and trough serum testosterone concentrations, corrected for real-time absorption kinetics from the im testosterone depot. RESULTS: Older men had lower total (316 +/- 13 vs. 585 +/- 26 ng/dl, P < 0.00001) and free testosterone (4 +/- 0.1 vs. 6 +/- 0.3 ng/dl, P < 0.00001) and higher SHBG (52 +/- 3 vs. 33 +/- 2 nmol/liter, P < 0.00001) than younger men at baseline. Total and free testosterones increased with TE dose and were higher in older men than young men in the 125-, 300-, and 600-mg dose groups. aMCR-T was lower in older men than young men (1390 +/- 69 vs. 1821 +/- 102 liter/d, P = 0.006). aMCR-T correlated negatively with age (P = 0.0007), SHBG (P = 0.046), and total testosterone during treatment (P = 0.02) and percent body fat at baseline (P = 0.01) and during treatment (P = 0.004). aMCR-T correlated positively with lean body mass at baseline (P = 0.03) and during treatment (P = 0.01). In multiple regression models, significant predictors of aMCR-T included lean body mass (P = 0.008), percent fat mass (P = 0.009), and SHBG (P = 0.001). CONCLUSIONS: Higher testosterone levels in older men receiving TE were associated with an age-related decrease in apparent testosterone metabolic clearance rates. Body composition and SHBG were significant predictors of aMCR-T.

Adult↗
PubMed2002

Testosterone metabolism in the estuarine mysid neomysis integer (Crustacea; Mysidacea): identification of testosterone metabolites and endogenous vertebrate-type steroids.

Testosterone metabolism by Neomysis integer (Crustacea; Mysidacea) was assessed to obtain initial data on its metabolic capacity. N. integer were exposed to both testosterone and [(14)C]testosterone. Identification of testosterone metabolites and endogenous steroids was performed using thin-layer chromatography and liquid chromatography with multiple mass spectrometry. Endogenous production of testosterone in mysids was detected for the first time. N. integer were exposed to testosterone and metabolized administered testosterone extensively. At least 11 polar testosterone metabolites (R(f,metabolite) < R(f,testosterone)), androstenedione, dihydrotestosterone, and testosterone were produced in vivo by N. integer. A sex-specific testosterone metabolism was also observed, although this observation requires further confirmation. The anabolic steroid beta-boldenone was also identified for the first time in invertebrates. The metabolic pathway leading to the formation of beta-boldenone remains unknown, since the steroidal precursor androstadienedione could not be detected. These results reveal interesting similarities in enzyme systems in invertebrate and vertebrate species. Alterations in steroid hormone metabolism may be used as a new biomarker for the effects of endocrine disruptors in invertebrates.

Anabolic Agents↗
PubMed2005

Comparison of effects of the rise in serum testosterone by raloxifene and oral testosterone on serum insulin-like growth factor-1 and insulin-like growth factor binding protein-3.

OBJECTIVE: In aging men serum levels of testosterone and insulin-like growth factor-1 (IGF-1) decline, potential factors in the reduced muscle strength, abdominal obesity, sexual dysfunction and impaired general well being of aging. The partial oestrogen agonist and antagonist raloxifene increase serum testosterone levels in aging men, but the effect of raloxifene on serum IGF-1 levels in men is unknown. In this study the effects of raloxifene on IGF-1 levels and the associated increase in serum testosterone were compared to the effects of oral testosterone supplementation. DESIGN AND PATIENTS: Thirty healthy elderly men between 60 and 70 years received raloxifene 120 mg/day or placebo in a randomised double blind fashion for 3 months. Secondly, seven female to male (F to M) transsexuals undergoing hormonal sex reassignment received testosterone undecanoate 160 mg/day. MEASUREMENT: At baseline and after three months serum levels of testosterone, IGF-1 and its most important binding protein, IFGBP-3 was measured. In the group transsexuals also serum gonadotrophins and 17beta-oestradiol was measured. RESULTS: Compared to placebo raloxifene increased serum testosterone by 20% but it decreased serum IGF-1 levels by 24.5% (95% confidence interval (CI): -13.0 to -36.1%). No significant change in serum IGFBP-3 levels was found. The effect of raloxifene on serum IGF-1 has been observed with other oral oestrogens, and, therefore, is likely to be ascribed to the partial oestrogen agonist activity of raloxifene. In the F to M transsexuals, serum testosterone levels increased from median <1.0 nmol/l to 6.2 nmol/l, without significant changes in serum gonadotrophins and 17beta-oestradiol levels. Serum IGF-1 levels increased by 12.1% (95% CI: 1.9-22.3%) versus baseline. No effect was observed on serum IGFBP-3 levels. CONCLUSION: Both raloxifene and oral testosterone increased serum testosterone, but raloxifene significantly decreased serum IGF-1 levels without affecting IGFBP-3. By contrast, oral testosterone supplementation in F to M transsexuals increased IGF-1 levels. In both treatment groups no significant change in serum IGFBP-3 was found.

Administration, Oral↗
PubMed2004

Effect of 12 month oral testosterone on testosterone deficiency symptoms in symptomatic elderly males with low-normal gonadal status.

BACKGROUND: Relative androgen deficiency in ageing males is assumed to have adverse health effects. This study assessed the effect of 12 months' standard dose, oral testosterone, on symptoms attributed to testosterone deficiency in older men with plasma testosterone levels in the low-normal range for young men. METHODS: Testosterone undecanoate (TU, 80 mg bid) or placebo was administered for one year to 76 healthy men, 60 years or older, with a free testosterone index (FTI) of 0.3-0.5 and significant symptoms on a questionnaire designed to evaluate androgen deficiency (ADAM). The ADAM was completed at baseline, 6 and 12 months. Hormone and safety data were collected at baseline, 1, 3, 6 and 12 months. RESULTS: After 12 months, plasma total testosterone was unchanged in both groups and sex hormone binding globulin decreased in the testosterone group (P = 0.01). FTI and calculated bioavailable testosterone (cBT) were greater in the testosterone group as compared with the placebo group (P = 0.021 and 0.025, respectively). There was no significant difference in total symptom score between testosterone and placebo groups after 12 months of oral TU. However, there were trends toward improvements in sadness/grumpiness (P = 0.063), reduced erection strength (P = 0.059) and decreased work performance symptoms (P = 0.077), particularly in men with baseline cBT levels below 3.1 nmol/l. CONCLUSIONS: This study concludes that 80 mg bid oral TU does not improve overall ADAM questionnaire scores in older men with low-normal gonadal status. Oral TU may preserve mood and erectile function, as assessed by this questionnaire, particularly in men with the lowest testosterone levels.

Administration, Oral↗
PubMed1995

Effects of testosterone, testosterone propionate, 17 beta-trenbolone and progesterone on cell transformation and mutagenesis in Syrian hamster embryo cells.

Testosterone, testosterone propionate, 17 beta-trenbolone and progesterone, which represent the main endogenous and synthetic androgens and a progestin, were evaluated for possible cell transformation and genetic effects in Syrian hamster embryo (SHE) cells. Cell growth was reduced by treatment with the steroids at 10-30 micrograms/ml in a dose-related manner. Testosterone and testosterone propionate were less toxic than the other two steroids. Testosterone, testosterone propionate and progesterone induced morphological transformation of SHE cells with similar transformation frequencies. The most potent effects were observed with testosterone propionate, which induced cell transformation at 1-30 micrograms/ml in a dose-related manner. Testosterone and progesterone transformed cells only at the highest dose (30 micrograms/ml). 17 beta-Trenbolone did not induce a statistically significant level of cell transformations at any dose tested (up to 30 micrograms/ml). The transformation frequencies induced by testosterone, testosterone propionate and progesterone were less than one-half that induced by benzo[a]pyrene at 1 microgram/ml. None of these steroids induced significant increases in frequencies of chromosome aberrations or aneuploidy. Gene mutations were not observed for testosterone at the HPRT or Na+/K+ ATPase locus. Because these steroids are also associated with carcinogenic activity in vivo, these in vitro findings provide a model and new insights into the study of the mechanisms of androgen- and progestin-induced cell transformation.

Animals↗
PubMed1999

Identification of testosterone and testosterone esters in human hair.

In 1974, steroids were added to the list of doping agents banned by the International Olympic Committee because of their effects on the performance of the athletes. Testosterone and its esters promote the development of secondary male sexual characteristics and accelerate muscle growth. The mandatory test to detect testosterone abuse is to measure the ratio of testosterone to epitestosterone in the urine. However, because athletes can adjust their dosage to stay within the range permitted, there is a risk of test evasion. Therefore, we developed two original procedures to determine testosterone and its esters in human hair. First, testosterone was investigated in hair obtained from 26 control subjects. After decontamination with dichloromethane, 100 mg of hair was incubated in 1 M NaOH in the presence of 1 ng of testosterone-d3. After neutralization, the extract was purified using solid-phase extraction with Isolute C18 columns followed by liquid-liquid extraction with pentane. After silylation, testosterone was analyzed by gas chromatography-mass spectrometry. Concentrations were in the range 1.2 to 11.4 pg/mg with a mean value of 3.8 pg/mg. To distinguish exogenous abuse from endogenous levels, the incorporation of testosterone esters into hair was investigated. Preparation involved methanolic incubation to avoid the cleavage of the esters. In a panel of eight esters, it was possible to identify testosterone propionate, testosterone enanthate, and testosterone decanoate in the hair of two bodybuilders and one weight lifter. This new technology may find useful applications in anabolic abuse control.

Adolescent↗
PubMed2000

Testosterone treatment is immunosuppressive in superb fairy-wrens, yet free-living males with high testosterone are more immunocompetent.

The immunocompetence handicap hypothesis proposes that the immunosuppressive effect of testosterone enforces honesty of sexual signalling via a physiological trade-off between signal intensity and immunocompetence. However, evidence that testosterone is immunosuppressive is scant, particularly in birds. I studied the correlation between immunocompetence and testosterone in superb fairy-wrens (Malurus cyaneus), a species with intense intersexual selection. Males are seasonally dichromatic and testosterone increases during the moult from dull brown eclipse plumage into bright nuptial plumage. I determined the primary antibody response to immunization with sheep red blood cells (SRBCs) in (i) control and testosterone-implanted males in captivity, and (ii) a cross-section of free-living males with basal and elevated testosterone (in eclipse plumage, moulting and in nuptial plumage). Experimental treatment with testosterone decreased the likelihood of an antibody response to SRBCs in captive birds. In contrast, free-living males which had acquired the nuptial plumage and had naturally elevated testosterone were more likely to respond to SRBCs than males in eclipse plumage with basal testosterone levels. The association between higher immunocompetence and higher immunosuppressive testosterone could arise if both are positively correlated with male phenotypic quality In addition, the association could result if males compensate for potential immunosuppression by enhancing their humoral immune responses, particularly since high testosterone is linked to other demanding activities such as moulting and courtship displays.

Animals↗
PubMed2004

A comparison of a novel testosterone bioadhesive buccal system, striant, with a testosterone adhesive patch in hypogonadal males.

A novel delivery system has been developed for testosterone replacement. This formulation, COL-1621 (Striant), a testosterone-containing buccal mucoadhesive system, has been shown in preliminary studies to replace testosterone at physiological levels when used twice daily. Therefore, the current study compared the steady-state pharmacokinetics and tolerability of the buccal system with a testosterone-containing skin patch (Andropatch or Androderm) in an international multicenter study of a group of hypogonadal men. Sixty-six patients were randomized into two groups; one applied the buccal system twice daily, whereas the other applied the transdermal patch daily, in each case for 7 d. Serum total testosterone and dihydrotestosterone concentrations were measured at d 1, 3 or 4, and 6, and serially over the last 24 h of the study. Pharmacokinetic parameters for each formulation were calculated, and the two groups were compared. The tolerability of both formulations was also evaluated. Thirty-three patients were treated with the buccal preparation, and 34 were treated with the transdermal patch. The average serum testosterone concentration over 24 h showed a mean of 18.74 nmol/liter (SD =; 5.90) in the buccal system group and 12.15 nmol/liter (SD =; 5.55) in the transdermal patch group (P < 0.01). Of the patients treated with the buccal system, 97% had average steady-state testosterone concentrations within the physiological range (10.41-36.44 nmol/liter), whereas only 56% of the transdermal patch patients achieved physiological total testosterone concentrations (P < 0.001 between groups). Testosterone concentrations were within the physiological range in the buccal system group for a significantly greater portion of the 24-h treatment period than in the transdermal patch group (mean, 84.9% vs. 54.9%; P < 0.001). Testosterone/dihydrotestosterone ratios were physiological and similar in both groups. Few patients experienced major adverse effects from either treatment. No significant local tolerability problems were noted with the buccal system, other than a single patient withdrawal. We conclude that this buccal system is superior to the transdermal patch in achieving testosterone concentrations within the normal range. It may, therefore, be a valuable addition to the range of choices for testosterone replacement therapy.

Administration, Buccal↗
PubMed1997

Disparate serum free testosterone concentrations and degrees of hypothalamo-pituitary-luteinizing hormone suppression are achieved by continuous versus pulsatile intravenous androgen replacement in men: a clinical experimental model of ketoconazole-induced reversible hypoandrogenemia with controlled testosterone add-back.

To investigate the neuroendocrine mechanisms underlying the negative feedback actions of testosterone on both the pulsatile mode of LH release and the entropy or disorderliness of the LH release process, we blocked testicular androgen biosynthesis using oral high dose ketoconazole treatment with concomitant low dose glucocorticoid replacement for 48 h in six healthy young men. Volunteers were then infused iv with saline or a total of 8.0 mg testosterone base over the second 24 h via either a continuous or a pulsatile (90-min boluses) delivery pattern. Discrete peak detection (Cluster analysis) was applied to obtain a model-independent estimate of the frequency of serum LH concentration peaks, maximal and incremental LH peak amplitudes, peak area, and interpeak nadir serum LH concentrations. Approximate entropy was used to quantify the relative orderliness/disorderliness of the LH release process over 24 h. Ketoconazole treatment markedly lowered 24-h mean serum total and free testosterone concentrations (by 17- and 9-fold respectively), and significantly increased LH pulse frequency, maximal LH peak height, and interpeak nadir serum LH concentrations. Continuous iv testosterone add-back increased 24-h pooled serum free testosterone concentrations 3-fold more and concomitantly reduced mean (24-h) serum LH concentrations by at least 2-fold more than pulsatile delivery of the same total daily amount of androgen. Both modes of testosterone infusion suppressed pulsatile LH release, but the effects were distinguishable; namely, treatment with continuous vs. intermittent androgen add-back, respectively, decreased LH pulse frequency and incremental LH pulse amplitude. Ketoconazole treatment alone also significantly increased approximate entropy values, indicating greater disorderliness of LH release during androgen removal. Approximate entropy/orderliness was restored to baseline by continuous, but not pulsatile, iv testosterone replacement. In conclusion, the present novel testosterone add-back clinical experimental paradigm indicates that 1) remarkably different 24-h mean serum free testosterone concentrations can result from continuous vs. pulsatile testosterone delivery into the bloodstream; 2) androgen negative feedback can exert frequency- as well as amplitude-dependent suppression of pulsatile LH release; and 3) testosterone is required to maintain an orderly 24-h LH release process in young men.

Adolescent↗
PubMed1995

Injectable testosterone undecanoate has more favourable pharmacokinetics and pharmacodynamics than testosterone enanthate.

Testosterone preparations producing constant physiological testosterone serum levels are desirable for long-term treatment of androgen deficiency. However, all injectable testosterone esters used clinically for substitution of male hypogonadism are characterized by unfavourable pharmacokinetics. We therefore tested two groups of five long-term orchidectomized cynomolgus monkeys (Macaca fascicularis), which received a single intramuscular injection of 10 mg/kg body weight of an injectable testosterone undecanoate (TU) preparation or testosterone enanthate (TE) in a preclinical study to assess the pharmacokinetic and pharmacodynamic characteristics of TU in comparison to TE. The dose was equivalent to 6.3 and 7.2 mg of pure testosterone per kilogram body weight in the TU and TE group, respectively. Following injection of TU, mean serum testosterone rose to 58 +/- 18 nmol/l on day 1 and remained at moderately supraphysiological levels of 40-68 nmol/l for 45 days. Thereafter, testosterone levels were maintained in the normal range of intact monkeys for another 56 days. The TE injection resulted in highly supraphysiological levels of 100-177 nmol/l from immediately after the injection to day 5. A rapid decline followed and testosterone levels reached the lower limit of normal after 31 days. Serum testosterone levels were significantly higher in the TE-than in the TU-treated animals on days 0.5-7 (p < 0.05). Significantly lower testosterone levels were seen in the TE than in the TU group on days 16, 22, 25 and 31 (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Oral testosterone-triglyceride conjugate in rabbits: single-dose pharmacokinetics and comparison with oral testosterone undecanoate.

Development of a safe and effective oral form of testosterone has been inhibited by the rapid hepatic metabolism of nonalkylated androgens. Since triglycerides are absorbed via lymphatics and bypass the liver, we hypothesized that a testosterone-triglyceride conjugate (TTC) might allow for safe and effective oral testosterone therapy. Therefore, we studied the single-dose pharmacokinetics of oral administration of TTC in rabbits. Female New Zealand rabbits were administered 2, 4, or 8 mg/kg of TTC in sesame oil by gastric lavage. Testosterone undecanoate (TU) by gastric lavage was used as a positive control. Blood was sampled from a catheter in the auricular artery at 0, 15, 30, 60, 90, 120, 180, 240, 360, 480, and 600 minutes after drug administration. Samples were assayed for testosterone by a fluoroimmunoassay. Mean serum testosterone, area under the curve (AUC), and terminal half-life were calculated. Oral TTC administration resulted in rapid and marked increases in serum testosterone. Oral TTC resulted in higher maximum serum testosterone concentrations than oral TU at 8 mg/kg (TTC: 28.6 +/- 7.9 nmol/L vs TU: 11.9 +/- 2.1 nmol/L; P <.001) and 4 mg/kg (TTC: 11.5 +/- 4.2 nmol/L vs TU: 3.6 +/- 1.0 nmol/L; P <.001). In addition, the AUC was 1.8 to 2.6 times greater for TTC than TU at both doses (P <.05). The terminal half-life for both TU and TTC was between 3 and 5 hours and was not significantly different. We conclude that oral TTC is rapidly absorbed from the rabbit intestine and results in elevated concentrations of serum testosterone. The absorption of TTC appears to be superior to that of TU; however, the in vivo persistence of the 2 compounds is similar. TTC may offer an alternative to the use of TU for oral testosterone therapy. Further testing of this compound is warranted.

Administration, Oral↗