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PubMed2004

Similar frequency of testosterone surge after repeat injections of goserelin (Zoladex) 3.6 mg and 10.8 mg: results of a randomized open-label trial.

OBJECTIVES: To investigate whether testosterone surges occur on repeat injections of 3.6 or 10.8 mg goserelin (Zoladex) depot and, if so, their extent. METHODS: Men with prostate cancer for whom hormonal therapy was indicated were randomized to open-label goserelin 3.6 mg every 28 days (n = 129) or 10.8 mg every 84 days (n = 118) for 48 weeks. Serum testosterone and luteinizing hormone levels were measured before repeat injection on day 1 of each treatment cycle and then on days 4 and 8. Surges were defined in three ways: type 1, simultaneous increase in both testosterone and luteinizing hormone to within the age-specific normal range; type 2, increase in testosterone to within the age-specific normal range; and type 3, elevation in testosterone from less than to greater than the castrate level (greater than 18.5 ng/dL). RESULTS: Most patients did not experience a testosterone surge. Two patients (1.8%) in the 10.8-mg group had a type 1 surge after one repeat injection and two (1.6%) in the 3.6-mg group had a type 2 surge after one repeat injection. Type 3 surges occurred after one or more repeat injections in 34 (27.0%) and 20 (17.7%) patients in the 3.6-mg and 10.8-mg groups, respectively (P = 0.065); the mean surge (+/- standard deviation) was 11.2 ng/dL (+/-13.5) and 17.3 ng/dL (+/-24.6), respectively. No patient with a testosterone surge had clinical symptoms of a tumor flare reaction. CONCLUSIONS: The testosterone levels were consistently maintained within the castrate range (18.5 ng/dL or less) in most (77.4%) patients receiving long-term 3.6 mg or 10.8 mg goserelin.

Aged↗

PubMed2004

Exogenous testosterone inhibits several forms of male parental behavior and stimulates song in a monogamous songbird: the blue-headed vireo (Vireo solitarius).

Natural variation in circulating testosterone is thought to play a role in creating inter- and intraspecific variation in paternal care in birds. Experimental elevation of plasma testosterone in males has reduced rates of male care in many species. However, a small number of studies suggest that male care is not inhibited by testosterone when there appears to be strong selection for male care. Both genetic monogamy and male incubation are thought to be the result of selection for biparental care, yet the sensitivity of male care to inhibition by T had not been examined in a species with both characteristics. Male blue-headed vireos have been shown to be strictly monogamous and provide extensive parental care, including incubation. Males received subcutaneous implants of testosterone, flutamide (an anti-androgen), or empty controls. Consistent with previous studies, testosterone treatment decreased the relative contribution to incubation by males and increased the average duration that the nest was left unattended during incubation, relative to control and flutamide treatments. The relative and absolute rates of feeding offspring and nest sanitation by T-treated males also decreased relative to controls. Flutamide-treated males incubated eggs and brooded young more than testosterone-treated males, with control males performing at intermediate values. Testosterone-treated males sang more often and at higher rates, and flutamide-treated males sang less often, than controls. These results demonstrate that even in a strictly monogamous songbird with biparental incubation, all forms of paternal care remain sensitive to elevated plasma testosterone, suggesting a shift from parental effort to mating effort.

Animals↗

PubMed2005

Testosterone and group size in cliff swallows: testing the "challenge hypothesis" in a colonial bird.

The "challenge hypothesis" states that increases in testosterone levels of male animals during the breeding season are directly related to the extent of intrasexual competition for resources or mates that they experience. Although often tested in territorial species, the challenge hypothesis has not been evaluated for colonial animals that live in groups of different sizes and that thus experience different intensities of intrasexual competition. We measured circulating testosterone levels of male and female cliff swallows (Petrochelidon pyrrhonota) in southwestern Nebraska, where these birds nest in colonies of widely different sizes. Males had significantly higher testosterone levels than females, as expected. For males especially, there was a seasonal rise in testosterone levels early in the nesting cycle, corresponding to the period when birds were establishing nest ownership and egg laying, and then a fall as they switched to parental duties. Testosterone levels varied significantly with colony size; for both sexes, birds in larger colonies had higher levels of testosterone than those in smaller colonies when controlling for date. Age and body mass were not related to testosterone levels. Higher levels of testosterone for birds of both sexes in larger colonies probably reflect greater competition for matings, often extra pair, in the more social nesting situations. The results support the predictions of the challenge hypothesis.

Analysis of Variance↗

PubMed2004

Is there an effect of prenatal testosterone on aggression and other behavioral traits? A study comparing same-sex and opposite-sex twin girls.

Men and women differ in temperament and personality traits, such as aggression and sensation seeking. The sex hormone testosterone could play a role in the origin of these differences, but it remains unclear how and when testosterone could have these effects. One way to investigate the prenatal exposure effect of testosterone is to compare opposite-sex (OS) and same-sex (SS) female twins. It has been suggested that OS twin girls are exposed prenatally to elevated testosterone levels and that this may result in some masculinization of their personality and behavior. We measured sexually dimorphic traits and circulating testosterone levels in 13-year-old OS (n = 74) and SS (n = 55) twins. Testosterone levels showed a clear circadian rhythm, with higher levels in the morning than in the afternoon. Testosterone was higher in boys than girls, but similar in OS and SS twin girls. Testosterone was not in any way systematically related to the different personality traits. However, a sex difference in aggression proneness was observed, and OS girls showed a more masculine pattern of aggression proneness than the SS girls. It is argued that it is unlikely that this difference is due to social factors, such as a gender-specific upbringing.

Adolescent↗

PubMed2006

Behavioral and physiological responses to experimentally elevated testosterone in female dark-eyed juncos (Junco hyemalis carolinensis).

Testosterone mediates the expression of many fitness-related traits in male vertebrates and is thought to account for numerous sex differences in trait expression. Testosterone is also secreted by females; however, far less is known regarding its effects on female physiology and behavior. Using a bird species in which the effects of testosterone on males are well characterized, the dark-eyed junco (Junco hyemalis), we tested whether an increase in exogenous testosterone in females would alter the phenotypic expression of a suite of behavioral and physiological traits. We found that increased testosterone levels in female dark-eyed juncos led to decreased cell-mediated immune function and increased intrasexual aggression, hypothalamo-pituitary-adrenal (HPA) axis responsiveness, baseline corticosterone and corticosterone-binding globulin (CBG) levels. Furthermore, immunosuppression following testosterone implantation was negatively correlated with total and free testosterone but did not appear to be related to either total or free corticosterone. These results demonstrate that the phenotypic impact of elevated testosterone is not confined to males in dark-eyed juncos, and that the impact in adults can be similar in males and females. We discuss these results in the context of potential endocrine-immune interactions and the evolution of sexual dimorphism.

Aggression↗

PubMed2006

Effects of testosterone and corticosterone on immunocompetence in the zebra finch.

The original immunocompetence handicap hypothesis (ICHH) suggested that testosterone has a handicapping effect in males by both promoting the development of sexual signals and suppressing immune function. A modified version, the stress-linked ICHH, has recently proposed that testosterone is immunosuppressive indirectly by increasing production of corticosterone. To test both the original and stress-mediated versions of the ICHH, we implanted male zebra finches taken from lines selected for divergent maximum stress-induced levels of corticosterone (high, low and control) with either empty or testosterone-filled implants. Their humoral and cell-mediated immune responses were then assessed by challenge with diphtheria:tetanus vaccine and phytohemagglutinin respectively. We found no effect of the hormone manipulations on either PHA or tetanus antibody responses, but found a significant interaction between titers of both testosterone and corticosterone on diphtheria secondary antibody response; antibody response was greatest in individuals with high levels of both hormones. There was also a significant interactive effect between testosterone treatment group and corticosterone titer on body mass; the body mass of males in the elevated testosterone treatment group decreased with increasing corticosterone titer. These results suggest that, contrary to the assumption of the stress-mediated version of the ICHH, high plasma levels of corticosterone are not immunosuppressive, but are in fact immuno-enhancing in the presence of high levels of plasma testosterone. Equally, the central assumption of the ICHH that testosterone is obligately immunosuppressive is also not supported. The same individuals with the highest levels of both hormones and consequently the most robust antibody response also possessed the lowest body mass.

Animals↗

PubMed2001

Intramuscular testosterone esters and plasma lipids in hypogonadal men: a meta-analysis.

PURPOSE: It is unclear whether intramuscular administration of testosterone esters to hypogonadal men is associated with changes in plasma lipids. We therefore analyzed 19 studies published between 1987 and 1999 that focused on male subjects with nonexperimental hypogonadism, treated subjects with an intramuscular testosterone ester and reported pretreatment and post-treatment concentrations of total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol, or total triglyceride. METHODS: We calculated study-specific, post-treatment minus pretreatment differences in each plasma lipid concentration (mean [95% confidence interval]). After testing of between-study homogeneity, we combined the study-specific differences. We then determined whether heterogeneity of differences could be explained in models of the differences on study and patient characteristics (mean +/- SE) before and after excluding extreme values using a multiple outlier procedure. RESULTS: The studies represented 272 hypogonadal men (age 44 +/- 4 years; 20% with hypergonadotropic hypogonadism; total testosterone 0.5 +/- 0.2 ng/mL) who received, on average, 179 +/- 13 mg intramuscular testosterone ester every 16 +/- 1 days for 6 +/- 1 months. Fixed-effects estimates of post-treatment minus pretreatment differences were -14 [-17 to -11] mg/dL (total cholesterol), -5 [-8 to -1] mg/dL (LDL cholesterol), -4 [-5 to -2] mg/dL (HDL cholesterol), and -1 [-6 to + 4] mg/dL (triglyceride). Decreases in HDL cholesterol were larger at lower dosages of testosterone ester (r = -0.54, P = 0.055), but were not explained by attrition, regression to the mean, dosing frequency or duration, concomitant elevation of plasma total testosterone, aromatization of testosterone to estradiol, or other study and patient characteristics. CONCLUSION: Intramuscular administration of testosterone esters to hypogonadal men is associated with a small, dosage-dependent decrease in HDL cholesterol and concomitant declines in total cholesterol and LDL cholesterol. The aggregate effect of these changes on cardiovascular risk remains unknown but deserves further study.

Cholesterol, HDL↗

PubMed1999

The use of a transscrotal testosterone delivery system in the treatment of patients with weight loss related to human immunodeficiency virus infection.

PURPOSE: Weight loss is a strong predictor of morbidity and mortality in human immunodeficiency virus (HIV)-infected patients. Men with acquired immunodeficiency syndrome (AIDS) lose body cell mass. Hypogonadism is also common. This study tested the efficacy of a testosterone transscrotal patch (6 mg/day) in improving body cell mass and treating hypogonadism in these patients. SUBJECTS AND METHODS: This multicenter, randomized, double-blinded, placebo-controlled trial was conducted from August 1995 to October 1996 in 133 men, 18 years of age and older, who had AIDS, 5% to 20% weight loss, and either a low morning serum total testosterone level (<400 ng/dL) or a low free testosterone level (<16 pg/mL). Outcomes included weight, body cell mass as measured using bioelectrical impedance analysis, quality of life, and morning measurements of serum testosterone and dihydrotestosterone levels, lymphocyte subsets, and HIV quantification. RESULTS: There were no significant differences in baseline weight, CD4 cell counts, or HIV serum viral quantification between treatment arms. Morning total and free testosterone levels increased in those treated with testosterone, but not with placebo. Following 12 weeks of treatment there were no differences (testosterone-placebo) in mean weight change (-0.3 kg [95% confidence interval (CI): -1.4 to 0.8]) or body cell mass (-0.2 kg [95% CI: -1.0 to 0.6]) in the two groups. There were also no changes in quality of life in either group. CONCLUSION: Hypogonadal men with AIDS and weight loss can achieve adequate morning serum sex hormone levels using a transscrotal testosterone patch. However, this system of replacement does not improve weight, body cell mass, or quality of life.

Adult↗

PubMed1999

Psychosexual effects of three doses of testosterone cycling in normal men.

BACKGROUND: Testosterone is receiving increased attention for contraceptive and therapeutic indications. The potential psychosexual side effects of testosterone therapy and withdrawal are unclear. METHODS: Healthy men between the ages of 21 and 40 years were recruited via advertisement for a randomized, controlled, double-blind study of acute and withdrawal effects of three doses of testosterone. Two weeks of placebo injections were followed by one of three randomized weekly doses of testosterone cypionate (100 mg, 250 mg, or 500 mg) for the next 14 weeks. Twelve weeks of placebo injections followed during the withdrawal phase of the study. Psychosexual effects were monitored throughout the study. RESULTS: All doses of testosterone demonstrated only minimal effects on measures of mood and behavior during acute and withdrawal phases for all study completers. There were no effects on psychosexual function. There was no evidence of a dose-dependent effect on any measure. One noncompleter on 500 mg of testosterone developed a brief syndrome with symptoms similar to an agitated and irritable mania. CONCLUSIONS: Doses of testosterone up to five times physiologic replacement dose appear to have minimal risk of adverse psychosexual effects in the majority of normal men; however, beginning at around 500 mg per week of testosterone cypionate, a minority of normal men may experience significant adverse psychological effects. Because illicit anabolic steroid users may use larger doses of multiple drugs under less restrictive conditions, our study may significantly underestimate the psychological effect of steroid use in the community.

Adult↗

PubMed1998

Testosterone increases and estradiol decreases middle cerebral artery occlusion lesion size in male rats.

This study was undertaken to determine the effects of estrogen and testosterone on cerebral ischemic lesion size induced by middle cerebral artery (MCA) occlusion in male rats. Rats were gonadectomized and treated with testosterone, estrogen, or testosterone plus estrogen filled Silastic pellets. The animals were divided into 6 groups: intact, intact + estrogen (E2), castrate, castrate + testosterone (T), castrate + E2, and castrate + T + E2. One week after treatment, cerebral ischemia was induced by MCA occlusion for 40 min, followed by reperfusion. After 24 h, rats were sacrificed and slices were then stained to assess lesion size. The presence of testosterone increased and the removal of testosterone decreased lesion size. A strong positive correlation (r2 = 0.922) between plasma testosterone concentrations and ischemic lesion size was observed. Estradiol treatment reduced ischemic area. In summary, the present study provides evidence that testosterone exacerbates and estrogens ameliorate ischemic brain damage in an animal model of cerebral ischemia.

Animals↗

PubMed2000

Acute impairment of relaxation by low levels of testosterone in porcine coronary arteries.

OBJECTIVES: While there are many suggested reasons for the marked gender bias in cardiovascular events, much of the available data indicate that circulating estrogens are cardioprotective. The possibility that endogenous androgens may be detrimental to the cardiovascular system has received relatively less attention. We investigated the short-term modulatory effects of various concentrations of testosterone on vascular function in isolated porcine coronary artery rings. RESULTS: The higher concentrations (> 1 microM) of testosterone relaxed U46619-contracted coronary artery rings in an endothelium-independent manner. This direct effect was insensitive to the testosterone receptor antagonists, flutamide and cyproterone acetate. Short-term exposure (20 min) to low levels of testosterone (1-100 nM), which were ineffective on their own on vascular function, significantly diminished relaxation to bradykinin and calcium ionophore A23187 but not those produced by levcromakalim and sodium nitroprusside. The inhibitory effect observed with 1 nM testosterone was only partially reversed by flutamide and cyproterone acetate and unaltered in the presence of actinomycin D and cycloheximide. CONCLUSIONS: These results demonstrate that acute treatment with testosterone, at concentrations that have no effect on their own, reduces vasorelaxation. Furthermore, they suggest that this modulatory action may be in part independent of the classical testosterone receptor since it was not completely sensitive to the anti-androgens and was not inhibited by the transcriptional and translational inhibitors. These findings support the postulation that testosterone may have unfavorable influences on vascular function.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2003

Testosterone depletion contributes to cyclosporine-induced chronic impairment of acetylcholine renovascular relaxations.

The immunosuppressant drug cyclosporine causes nephrotoxicity mainly via alterations of renovascular reactivity. This study investigated whether this effect of cyclosporine is modulated by the male gonadal hormone testosterone. The endothelium-dependent and -independent relaxations evoked by acetylcholine and sodium nitroprusside, respectively, were evaluated in phenylephrine-preconstricted isolated perfused kidneys obtained from sham-operated, castrated, and testosterone-replaced castrated (CAS+T) male rats in the absence and presence of cyclosporine. Compared with sham-operated values, short-term (10 days) castration or cyclosporine treatment caused significant and equivalent reductions in plasma testosterone levels and vasorelaxant responses to acetylcholine. Treatment of castrated rats with cyclosporine caused no further attenuation of acetylcholine relaxations. Testosterone replacement of castrated (CAS+T) or cyclosporine-treated castrated (CAS+CyA+T) rats restored plasma testosterone and acetylcholine relaxations to near-sham-operated levels. On the other hand, castration caused significant increases in nitroprusside relaxations versus no effect for cyclosporine. The relaxant responses to nitroprusside in castrated rats were restored to sham-operated levels after testosterone replacement. Plasma urea and creatinine were not affected by castration but were significantly increased by cyclosporine. These findings suggest that testosterone exerts directionally opposite modulatory effects on endothelium-dependent and -independent renal relaxations. Further, the results demonstrate that testosterone depletion may contribute, at least partly, to the inhibitory effect of cyclosporine on renovascular endothelial function. These data are clinically important because endothelial dysfunction contributes to vascular abnormalities associating cyclosporine therapy.

Acetylcholine↗

PubMed1980

Persistence of spermatogenesis in hypogonadotropic hypogonadism treated with testosterone.

The case histories are reported of two patients who had persistent spermatogenesis as evidenced by normal semen analyses and fertility in the face of hypogonadotropic hypogonadism and testosterone administration. When not receiving testosterone, both men consistently had normal or low serum gonadotropin levels. Since pooled serum testosterone levels were low simultaneously, these "normal" gonadotropin values are still consistent with hypogonadotropic hypogonadism. Standard testosterone replacement therapy maintained secondary sex characteristics and, surprisingly, spermatogenesis in both men. A review of the literature revealed conflicting evidence concerning the roles of gonadotropins and testosterone in affecting spermatogenesis. In applying this evidence to our patients, it appears that gonadotropins may have only a minimal role in maintaining fertility in patients with established spermatogenesis and "adequate" testosterone levels; it also appears that relatively low doses of exogenous testosterone may maintain or enhance spermatogenesis in certain individuals. We conclude that men with acquired hypogonadotropic hypogonadism should not be presumed to be sterile and that a larger study of fertility in these patients is necessary. Until then, we recommend that the semen of these patients be analyzed at the time of diagnosis and during treatment with testosterone.

Adult↗

PubMed2002

Serum testosterone suppression and potential for agonistic stimulation during chronic treatment with monthly and 3-month depot formulations of leuprolide acetate for advanced prostate cancer.

PURPOSE: The pattern of serum testosterone suppression as well as the potential for agonistic stimulation of serum testosterone during chronic treatment was compared in patients with prostate cancer randomized to receive 4 depot injections of either the monthly or 3-month depot formulations of leuprolide acetate in an open label study. MATERIALS AND METHODS: A total of 71 patients were enrolled in a randomized prospective study comparing the pattern of serum testosterone suppression and the potential for agonistic stimulation of serum testosterone following reinjection ("acute-on-chronic" effect) during treatment of advanced stage prostate cancer with monthly (7.5 mg.) and 3-month (22.5 mg.) depot formulations of leuprolide acetate. RESULTS: The 2 formulations produced nearly identical patterns of testosterone suppression which included uniform suppression throughout the duration of the dosing intervals. A transient minor "escape" from suppression (defined as a single testosterone value greater than 50 ng./dl. once suppression was achieved) occurred in 1 patient receiving each formulation. Assessment of agonistic stimulation ("acute-on-chronic" response) following the second depot injection as well as the depot injection following 3 months of treatment for each formulation revealed no pattern of stimulation. CONCLUSIONS: We conclude that monthly and 3-month sustained release (depot) formulations of leuprolide acetate provide consistent, uniform suppression of serum testosterone throughout the respective dosing intervals, and that the initial depot injection of each formulation provides sufficient pituitary desensitization to prevent agnostic stimulation of serum testosterone during chronic treatment.

Aged↗

PubMed1987

The use of parenteral testosterone therapy in genital reconstructive surgery.

Previously, testosterone cream has been used for penile enlargement before genital surgery. The results not only were inconsistent but the absorption was variable. Therefore, we elected to study the use of parenteral testosterone as an adjunct before reconstructive surgery. In 44 patients with hypospadias (36), epispadias (5) or urethral fistulas (3) 2 mg. per kg. testosterone enanthate were given intramuscularly 5 and 2 weeks before reconstructive surgery. Testosterone caused a mean increase in penile length of 2.7 cm. and in circumference of 2.3 cm. as well as local vascularity in all patients. In addition to surgical results the potential side effects of testosterone treatment were monitored 3 months to 1 year postoperatively. Basal testosterone levels were obtained in patients before and during therapy, and postoperatively. In addition, side effects, such as increased bone age and excessive pubic hair, were not a problem. The use of preoperative testosterone significantly contributed to the successful reconstruction of these patients, particularly those with a paucity of penile skin and those who had undergone previous repairs. Temporary penile stimulation by testosterone enanthate allows for an earlier penile operation as well as provides negligible side effects.

Child, Preschool↗

PubMed1996

Exercise increases serum testosterone and sex hormone-binding globulin levels in older men.

We examined the effects of moderate physical activity on serum luteinizing hormone (LH), sex hormone-binding globulin (SHBG), and testosterone levels in seven sedentary but otherwise healthy men aged 66 to 76 years (mean +/- SD, 70 +/- 4). Blood samples were obtained at 10-minute intervals for 4 hours before, during, and 4 hours after 60 minutes of cycle ergometry. Blood samples were also obtained every 10 minutes for 9 hours during a separate day to control for normal diurnal variation in serum testosterone levels. Serum testosterone increased 39%, SHBG 19%, total serum protein 13%, and the free testosterone index 23% during exercise (P < .01 for all). Testosterone and SHBG levels during the 4-hour sampling period after exercise were similar to values obtained before exercise and on the morning and afternoon of the control day. LH concentrations were unaltered during or after exercise. The change in SHBG levels during exercise correlated positively with the change in testosterone concentrations (r = .74, P = .09). We conclude that short-term exercise produces a transient elevation in serum testosterone levels in elderly men, which is partly due to an increase in serum SHBG concentrations. The concomitant increase in total protein and the rapid return of total protein and SHBG to baseline values after exercise indicate that hemoconcentration partly contributes to the exercise-associated increase in circulating testosterone levels.

Aged↗

PubMed2002

Inhibition of 3beta-hydroxysteroid dehydrogenase-isomerase in mouse adrenal cells: a direct effect of testosterone.

Gonadal steroids modulate adrenal gland size and function in a variety of species, and our previous studies demonstrate that circulating androgens suppress 3beta-hydroxysteroid dehydrogenase-isomerase (3betaHSD) activity in the adrenal cortex of male mice. The present study tests the hypothesis that androgens have a direct, receptor-mediated inhibitory effect on adrenal 3betaHSD. Treatment of cultured adrenal cells from C57BL/6J and C3H/HeJ mice with 0.02-2.0 microM testosterone for 7 days significantly reduces 3betaHSD activity in cells from both strains. However, treatment for 3 days reduces 3betaHSD activity in the adrenal cells from C3H/HeJ, but not C57BL/6J mice. The decreases in 3betaHSD activity in response to testosterone treatment is reflected in decreases in the amount of 3betaHSD immunoreactive protein, such that extended treatment decreases 3betaHSD immunoreactive protein in adrenal cells from both strains, but short-term treatment only decreases 3betaHSD immunoreactive protein in adrenal cells from C3H/HeJ mice. Thus, there appears to be a temporal difference between strains in the effect of the testosterone on 3betaHSD activity and immunoreactive protein. Treatment of the adrenal cells with androgen agonists and an antagonist indicate that the effect of testosterone is androgen receptor mediated. The effect of testosterone appears to be specific for 3betaHSD, since none of the treatments alter P450(scc) in cells from either strain. Testosterone treatment also causes a decrease in the amount of 3betaHSD mRNA. However, in contrast to the effect on activity and immunoreactive protein, there is no strain-related temporal difference because testosterone decreases 3betaHSD mRNA within 24h in adrenal cells from both strains. These results indicate that testosterone can act directly on the adrenal gland to decrease 3betaHSD activity, immunoreactive protein, and mRNA content in mouse adrenal glands, and thus contribute to the sex difference in adrenal function observed in many species.

17-Hydroxysteroid Dehydrogenases↗

PubMed2003

Lansoprazole increases testosterone metabolism and clearance in male Sprague-Dawley rats: implications for Leydig cell carcinogenesis.

Leydig cell tumours (LCTs) are frequently observed during rodent carcinogenicity studies, however, the significance of this effect to humans remains a matter of debate. Many chemicals that produce LCTs also induce hepatic cytochromes P450 (CYPs), but it is unknown whether these two phenomena are causally related. Our aim was to investigate the existence of a liver-testis axis wherein microsomal enzyme inducers enhance testosterone metabolic clearance, resulting in a drop in circulating hormone levels and a consequent hypertrophic response from the hypothalamic-pituitary-testis axis. Lansoprazole was selected as the model compound as it induces hepatic CYPs and produces LCTs in rats. Male Sprague-Dawley rats were dosed with lansoprazole (150 mg/kg/day) or vehicle for 14 days. Lansoprazole treatment produced effects on the liver consistent with an enhanced metabolic capacity, including significant increases in relative liver weights, total microsomal CYP content, individual CYP protein levels, and enhanced CYP-dependent testosterone metabolism in vitro. Following intravenous administration of [14C]testosterone, lansoprazole-treated rats exhibited a significantly smaller area under the curve and significantly higher plasma clearance. Significant reductions in plasma and testicular testosterone levels were observed, confirming the ability of this compound to perturb androgen homeostasis. No significant changes in plasma LH, FSH, or prolactin levels were detected under our experimental conditions. Lansoprazole treatment exerted no marked effects on testicular testosterone metabolism. In summary, lansoprazole treatment induced hepatic CYP-dependent testosterone metabolism in vitro and enhanced plasma clearance of radiolabelled testosterone in vivo. These effects may contribute to depletion of circulating testosterone levels and hence play a role in the mode of LCT induction in lansoprazole-treated rats.

2-Pyridinylmethylsulfinylbenzimidazoles↗