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At least 19 recordsLinked to original sources
PubMed1985

Quantitative determination of methyltestosterone and methyltestosterone-d3 in serum by gas chromatography-mass spectrometry.

A method for the quantitative estimation of methyltestosterone and methyltestosterone-d3 in biological fluids has been developed using gas chromatography-mass spectrometry-selected-ion monitoring. Methyltestosterone-d6 was used as an internal standard. Methyltestosterone and methyltestosterone-d3 in serum were determined based on the peak height ratios of the molecular ions of methyltestosterone, methyltestosterone-d3 and methyltestosterone-d6. Sensitivity, specificity, precision, accuracy and reproducibility of the present method were demonstrated to be satisfactory for application to pharmacokinetic and bioavailability studies.

Biological Availability↗
PubMed2002

Effects of acute 17alpha-methyltestosterone, acute 17beta-estradiol, and chronic 17alpha-methyltestosterone on dopamine, norepinephrine and serotonin levels in the pituitary, hypothalamus and telencephalon of rainbow trout (Oncorhynchus mykiss).

This study investigated: (a) the effects of acute 17alpha-methyltestosterone (MT) or 17beta-estradiol (E(2)) administration on norepinephrine (NE), dopamine (DA), serotonin (5-HT), 3,4, dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA) contents in the hypothalamus, telencephalon and pituitary of previtellogenic female rainbow trout Oncorhynchus mykiss, and (b) the effects of chronic MT administration on the levels of these neurotransmitters in these brain regions in immature male rainbow trout. The acute administration of MT induced a significant decrease in pituitary levels of DOPAC as well as in the DOPAC/DA ratio. On the other hand, the acute administration of E(2) induced an increase in pituitary 5-HT levels as well as a decrease in the 5-HIAA/5-HT ratio. In a second experiment, 20 mg MT per kilogram body weight was implanted for 10, 20 or 40 days into sexually immature male rainbow trout. Implanted rainbow trout showed increased testosterone and decreased E(2) levels. In the pituitary, MT induced long-term decreases in NE, DA, DOPAC and 5-HT levels, as well as in the DOPAC/DA ratio. Hypothalamic and telencephalic DA, NE and 5-HT levels were not affected by MT implantation. However, 5-HIAA levels and the 5-HIAA/5-HT ratio were reduced by MT implantation in both brain regions. These results show that chronic treatment with MT exerts both long-term and region-specific effects on NE, DA, and 5-HT contents and metabolism, and thus that this androgen could inhibit pituitary catecholamine and 5-HT synthesis. A possible role for testosterone in the control of pituitary dopaminergic activity and gonadotropin II release is also discussed.

Animals↗
PubMed2004

Mechanistic basis for estrogenic effects in fathead minnow (Pimephales promelas) following exposure to the androgen 17alpha-methyltestosterone: conversion of 17alpha-methyltestosterone to 17alpha-methylestradiol.

Exposure of adult fathead minnows (Pimephales promelas) to the androgen 17alpha-methyltestosterone (MT) produces both androgenic and estrogenic effects, manifested as nuptial tubercle formation in females, and vitellogenin production in males and females, respectively. The present study was conducted to determine if the unanticipated estrogenic effects are produced by conversion of MT via aromatase activity to 17alpha-methylestradiol (ME2). Aromatase activity at the end of a 7-day waterborne MT exposure (20, 200microg/l) was significantly decreased in ovarian microsomes and brain homogenates from exposed fish, to about 30-50% of control activity. Although aromatase activity was decreased by 7 days, it is possible that the conversion of MT to ME2 occurred soon after initial exposure. In support of this, ME2 was detected in plasma samples of the fish following the 7-day exposure, confirming their ability convert the androgen MT to the estrogen ME2. The concentration of ME2 in plasma was within the range of plasma 17ss-estradiol (E2) found in control female fathead minnows (4-5ng/ml). These results, in conjunction with competitive binding assays that indicate ME2 binds to the fathead minnow estrogen receptor with a relative binding affinity of 68.3% of E2, support the hypothesis that aromatization of MT to ME2 contributes to the estrogenic effects in fathead minnows following exposure to this androgen.

Analysis of Variance↗
PubMed2004

Androgenic and estrogenic effects of the synthetic androgen 17alpha-methyltestosterone on sexual development and reproductive performance in the fathead minnow (Pimephales promelas) determined using the gonadal recrudescence assay.

The effects of the androgen, 17alpha-methyltestosterone were assessed on sexual development and reproductive performance in the fathead minnow (Pimephales promelas) using a gonadal recrudescence assay. In this assay, mature male and female fathead minnow, previously kept under simulated winter conditions (15 degrees C; 8:16 h light:dark regime) were transferred to simulated summer conditions (25 degrees C water temperature; 16:8 h light:dark regime) to induce gonadal recrudescence. To assess sexual development fish were exposed to nominal concentrations of 0, 0.1, 1, 5 and 50 microg/L 17alpha-methyltestosterone. After 3 weeks of chemical exposure, effects on condition (condition factor, CF), plasma vitellogenin (VTG), secondary sex characteristics, gonad growth (gonadosomatic index; GSI) and gonad histology were investigated. Reproductive performance, including reproductive output (egg production), spawning behaviour, and fertilisation rate were measured over a subsequent 3-week-period in breeding adults maintained in clean water. 17alpha-Methyltestosterone had no effects on the condition of fish at any of the doses tested. 17alpha-Methyltestosterone induced both androgenic and estrogenic effects with females generally more affected by 17alpha-methyltestosterone than males: atretic follicles and male-specific sex characteristics (androgenic effect) were induced in females at > or = 0.1 and > or = 1 microg/L 17alpha-methyltestosterone, respectively. An inhibitory effect on ovary growth occurred at an exposure concentration of 50 microg/L 17alpha-methyltestosterone. In males 1 microg/L 17alpha-methyltestosterone induced a concentration-response induction of plasma vitellogenin (estrogenic effect) likely due to its conversion into 17alpha-methylestradiol, rather to the competition with endogenous steroids and their cross reactivity with the estrogen receptor. In the fish breeding studies, concentration-dependent reductions in egg number, fertilisation rate and increases in abnormal sexual behaviour in females were observed. All of these effects occurred at exposure concentrations of > or = 5 microg/L 17alpha-methyltestosterone. Thus, it could be assumed that the observed estrogenic effects in male fathead minnow were likely to the conversion of 17alpha-methyltestosterone into the estrogen 17alpha-methylestradiol, rather to the acting of 17alpha-methyltestosterone itself. In conclusion to this, showing hormonally activity of 17alpha-methyltestosterone in fish down to 100 ng/L, indicates that its potency was close to the range of several naturally occurring estrogens.

Analysis of Variance↗
PubMed1986

Stable-isotope methodology in the bioavailability study of 17 alpha-methyltestosterone using gas chromatography-mass spectrometry.

The application of a stable-isotope coadministration technique for estimating the relative bioavailability of 17 alpha-methyltestosterone is described. Eight healthy male subjects were administered orally a single 10-mg 17 alpha-methyltestosterone tablet together with a 10-mg 17 alpha-methyltestosterone-d3 solution. The serum concentrations of 17 alpha-methyltestosterone and 17 alpha-methyltestosterone-d3 were determined by gas chromatography-mass spectrometry with selected ion monitoring using 17 alpha-methyltestosterone-d6 as an internal standard. The extent of absorption from the tablet formulation was comparable to that from the oral solution. The stable-isotope methodology was compared with the conventional cross-over method for evaluating the bioavailability of 17 alpha-methyltestosterone.

Absorption↗
PubMed1998

Effects of methyltestosterone on insulin secretion and sensitivity in women.

The frequent coexistence of hyperandrogenism and insulin resistance is well established; however, whether a cause and effect relationship exists remains to be established. In this study we tested the hypothesis that short-term androgen administered to women would induce insulin resistance. To test this hypothesis, regularly menstruating, nonobese women were studied before and during methyltestosterone administration (5 mg tid for 10-12 days) by the hyperglycemic (n=8) and euglycemic, hyperinsulinemic (n=7) clamp techniques. Short-term methyltestosterone administration had no significant effects on the fasting levels of glucose, insulin, c-peptide, glucagon, or glucose turnover. During the hyperglycemic clamp studies, the mean glucose level during the final hour was 203+/-2 and 201+/-1 mg/dL in the methyltestosterone and control studies, respectively. The insulin response to this hyperglycemic challenge was slightly but not significantly greater during methyltestosterone treatment (first phase 59+/-8 vs. 50+/-8 microU/mL in controls; second phase 74+/-9 vs. 67+/-9 microU/mL in controls; total insulin response 133+/-16 vs. 117+/-15 microU/mL in controls). In spite of this, glucose uptake was reduced from the control study value of 10.96+/-1.11 to 7.3+/-0.70 mg/kg/min by methyltestosterone (P < 0.05). The ratio of glucose uptake per unit of insulin was also significantly reduced from a control study value of 14.3+/-1.4 to 9.4+/-1.3 mg/kg/min per microU/mL x 100 during methyltestosterone administration. In the euglycemic hyperinsulinemic clamp studies, insulin was infused at rates of 0.25 and 1.0 mU/kg/min to achieve insulin levels of approximately 25 and 68 microU/mL, respectively. During low-dose insulin infusion, rates of endogenous hepatic glucose production were equivalently suppressed from basal values of 2.37+/-0.29 and 2.40+/-0.27 mg/kg/min to 0.88+/-0.25 and 0.77+/-0.26 mg/kg/min in the methyltestesterone and control studies respectively. Whole body glucose uptake during low-dose insulin infusion was minimally affected. During the high-dose insulin infusion, endogenous hepatic glucose production was nearly totally suppressed in both groups. However, whole body glucose uptake was reduced from the control value of 6.11+/-0.49 mg/kg/min to 4.93+/-0.44 mg/kg/min during methyltestosterone administration (P < 0.05). Our data demonstrate that androgen excess leads to the development of insulin resistance during both hyperglycemic and euglycemic hyperinsulinemia. These findings provide direct evidence for a relationship between hyperandrogenemia and insulin resistance, and its associated risk factors for cardiovascular disease.

Adult↗
PubMed1995

Metabolism of anabolic steroids in humans: synthesis of 6 beta-hydroxy metabolites of 4-chloro-1,2-dehydro-17 alpha-methyltestosterone, fluoxymesterone, and metandienone.

Hydroxylation at position 6 beta testosterone I (17 beta-hydroxyandrost-4-en-3-one) and the anabolic steroids 17 alpha-methyltestosterone II (17 beta-hydroxy-17 alpha-methylandrost-4-en-3-one), metandienone III (17 beta-hydroxy-17 alpha-methylandrosta-1,4-dien-3-one), 4-chloro-1,2-dehydro-17 alpha-methyltestosterone IV (4-chloro-17 beta-hydroxy-17 alpha-methylandrosta-1,4-dien-3-one), and fluoxymesterone V (9-fluoro-11 beta, 17 beta-dihydroxy-17 alpha-methylandrost-4-en-3-one) was achieved via light-induced autooxidation of the corresponding trimethysilyl 3,5-dienol ethers dissolved in isopropanol or ethanol. The reaction further yielded the 6 alpha-hydroxy isomer in low amounts. The 6 beta-hydroxy isomer of I-V and the 6 alpha-hydroxy isomers of I, III, and IV were isolated and characterized by 1H and 13C NMR, high-performance liquid chromatography, gas chromatography, and mass spectrometry. Human excretion studies with single administered doses of boldenone (17 beta-hydroxyandrosta-1,4-dien-3-one), 4-chloro-1,2-dehydro-17 alpha-methyltestosterone, fluoxymesterone, metandienone, 17 alpha-methyltestosterone, and [16,16,17-2H3] testosterone showed that 6 beta-hydroxylation is the major metabolic pathway in the metabolism of 4-chloro-1,2-dehydro-17 alpha-methyltestosterone, fluoxymesterone, and metandienone, whereas for boldenone, 17 alpha-methyltestosterone, and testosterone, 6 beta-hydroxylation is negligible.

Adult↗
PubMed1989

The glucocorticoid antagonist 17 alpha-methyltestosterone binds to the 10 S glucocorticoid receptor and blocks agonist-mediated dissociation of the 10 S oligomer to the 4 S deoxyribonucleic acid-binding subunit.

The glucocorticoid antagonist 17 alpha-methyltestosterone inhibits binding of the agonist [3H]triamcinolone acetonide ot the glocucorticoid receptor in cytosol prepared from rat pituitary tumor GH1 cells. Competitive binding studies indicate that the dissociation constant for 17 alpha-methyltestosterone is about 1 microM. After incubation of intact GH1 cells with 10 nM [3H]triamcinolone acetonide at 37 C and subsequent cell fractionation at 4 C, three glucocorticoid receptor forms are observed: cytosolic 10 S receptor, cytosolic 4 S receptor, and nuclear receptor. Concurrent incubation with 17 alpha-methyltestosterone reduces the amount of [3H]triamcinolone acetonide bound to each of these receptor forms. Ligand-exchange assays performed at 0 C in intact cells using [3H]triamcinolone acetonide show that the exchangeable antagonist is associated predominantly with cytosolic 10 S receptor. Immunochemical analysis using monoclonal antibody BuGR2 indicates that 17 alpha-methyltestosterone does not cause substantial accumulation of glucocorticoid receptors in GH1 cell nuclei and, when present together with agonist, reduces nuclear accumulation of receptor seen with agonist alone. Results from dense amino acid labeling studies show that unlike [3H]triamcinolone acetonide, 17 alpha-methyltestosterone does not reduce the total amount of cellular glucocorticoid receptor and does not reduce receptor half-life. These results are consistent with a model for glucocorticoid receptor transformation in which binding of agonist promotes the dissociation of an oligomeric 10 S cytosolic receptor protein to its DNA-binding 4 S subunit. The antagonist 17 alpha-methyltestosterone competes with agonist for binding to the 10 S cytosolic receptor but does not appear to promote dissociation of the oligomer, thus inhibiting agonist-mediated nuclear actions of the glucocorticoid receptor.

Animals↗
PubMed2001

Effects of 17alpha-methyltestosterone on seminal vesicle development and semen release response in the African catfish, Clarias gariepinus.

The effects of 17alpha-methyltestosterone on seminal vesicle development in the African catfish, Clarias gariepinus, were investigated in an attempt to improve semen collection from this species. Treatment of larvae with dietary 17alpha-methyltestosterone at 50 mg kg(-1) for days 12-33 or days 12-40 after hatching, or at 20 mg kg(-1) for days 12-26, 12-33, 12-40 or 12-47 after hatching inhibited the development of the seminal vesicle finger-like extensions in male catfish, but did not affect the sex ratio. The minimum effective dose and period of treatment to inhibit seminal vesicle development in all male catfish treated with 17alpha-methyltestosterone was 20 mg kg(-1) for days 12-40 after hatching. Male catfish from this treatment group developed normal testes that, in some cases, contained a few oocytes, which tended to disappear before sexual maturation. After sexual maturation, the semen release response was evaluated in males with incomplete seminal vesicles. Fluid with viable spermatozoa was obtained after two consecutive injections of carp pituitary suspension, from 10 of 19 males that had been fed 20 mg 17alpha-methyltestosterone kg(-1) for days 12-40 or days 12-47 after hatching, but from only 4 of 15 males that did not receive any dietary steroid. Intratesticular semen quality was not affected by 17alpha-methyltestosterone treatment. The results of this study demonstrate that the absence of seminal vesicle extensions induced by treatment with 17alpha-methyltestosterone facilitated the collection of semen by stripping from this species of fish.

Analysis of Variance↗
PubMedDate not supplied

Effects of drugs which influence renal transport systems on the urinary excretion of the beta 2-adrenoceptor agonist clenbuterol and the anabolic steroids ethinylestradiol and methyltestosterone.

The aim of this study was to determine whether the illegal application of clenbuterol, ethinylestradiol and methyltestosterone in cattle as growth promoters can be concealed by co-treatment with drugs that affect urinary excretion. Six male veal calves were fed with 0.8 micrograms clenbuterol kg-1 of body weight (BW), 3.5 micrograms ethinylestradiol kg-1 BW and 35 micrograms methyltestosterone kg-1 BW together twice daily for 28 days. At the eighth day of clenbuterol, ethinylestradiol and methyltestosterone treatment each calf was additionally fed either with probenecid, para-aminohippuric acid, trimethoprim, famotidine or cimetidine at three different doses which were increased in weekly intervals. During the treatment 24 h-urine and blood samples (once daily) were obtained and analysed for clenbuterol, ethinylestradiol and methyltestosterone by specific enzyme immunoassay. By high performance liquid chromatography/enzyme immunoassay it was determined whether these drugs or their metabolites interfered with the immunological detection of the growth promoters. Clenbuterol, ethinylestradiol and methyltestosterone could be detected in plasma and urine throughout the whole experiment. Co-treatment with probenecid led to a five-fold reduction in urinary excretion of ethinylestradiol and co-treatment with trimethoprim led to a three-fold reduction in urinary excretion of clenbuterol. None of the drugs reduced urinary excretion of the growth promoters to concentrations below the limit of detection. The detection of these three growth promoters in urine samples from calves which were co-treated with the drugs tested in this study can thus not be prevented.

Adrenergic beta-Agonists↗
PubMed1989

Methyltestosterone-induced cholestasis. The importance of disproportionately low serum alkaline phosphatase level.

We describe a 64-year-old man who developed cholestatic jaundice after receiving 20 to 40 mg of methyltestosterone daily for 6 months for impotence but failed to mention it as part of his drug history. He underwent endoscopic retrograde and papillotomy before a positive history for methyltestosterone ingestion could be obtained. Since methyltestosterone is most often used for sexual impotence, the patient may be quite reluctant to mention this hormone as part of his medication. A normal or mildly elevated alkaline phosphatase level, disproportionate to the level of hyperbilirubinemia seen in this patient and in all previous reports, appears to be characteristic of this phenomenon. This pattern of liver function abnormality can be a clue to suspect methyltestosterone as the causative agent and spare the patient unneeded expensive noninvasive and potentially harmful invasive procedures.

Alkaline Phosphatase↗
PubMed2003

In vivo biotransformation of 17 alpha-methyltestosterone in the horse revisited: identification of 17-hydroxymethyl metabolites in equine urine by capillary gas chromatography/mass spectrometry.

The in vivo phase I biotransformation of 17 alpha-methyltestosterone in the horse leads to the formation of a complex mixture of regio- and stereoisomeric C(20)O(2), C(20)O(3) and C(20)O(4) metabolites, excreted in urine as glucuronide and sulphate phase II conjugates. The major pathways of in vivo metabolism are the reduction of the A-ring (di- and tetrahydro), epimerisation at C-17 and oxidations mainly at C-6 and C-16. Some phase I metabolites have been identified previously by positive ion electron ionisation capillary gas chromatography/mass spectrometry (GC/EI + MS) mainly from the characteristic fragmentation patterns of their methyloxime-trimethylsilyl ether (MO-TMS), enol-TMS or TMS ether derivatives. Following oral administration of 17 alpha-methyltestosterone to two castrated thoroughbred male horses, the glucuronic acid conjugates excreted in post-administration urine samples were selectively hydrolysed by E. coli beta-glucuronidase enzymes. Unconjugated metabolites and the steroid aglycones obtained after enzymatic deconjugation were isolated from urine by solid-phase extraction, derivatised as MO-TMS ethers and analysed by GC/EI + MS. In addition to some of the known metabolites previously identified from the characteristic mass spectral fragmentation patterns of 17 alpha-methyl steroids, some isobaric compounds exhibiting a diagnostic loss of 103 mass units from the molecular ions with subsequent losses of trimethylsilanol or methoxy groups and an absence of the classical D-ring fragment ion were detected. From an interpretation of their mass spectra, these compounds were identified as 17-hydroxymethyl metabolites, formed in vivo in the horse by oxidation of the 17-methyl moiety of 17 alpha-methyltestosterone. This study reports on the GC/EI + MS identification of these novel 17-hydroxymethyl C(20)O(3) and C(20)O(4) metabolites of 17 alpha-methyltestosterone excreted in thoroughbred horse urine.

Animals↗
PubMed2002

A repeated 28-day oral dose toxicity study of 17alpha-methyltestosterone in rats, based on the 'enhanced OECD Test Guideline 407' for screening the endocrine-disrupting chemicals.

As part of the international validation project to establish the Enhanced OECD Test Guideline 407, we performed a 28-day repeated-dose toxicity study of 17alpha-methyltestosterone, an exogenous androgen agonist. Special attention was paid to the sensitivity of additional parameters for detecting endocrine-related effects of endocrine-disrupting chemicals, based on the existing Test Guideline 407. Seven-week-old Crj:CD(SD)IGS rats were allocated to one of four groups, each consisting of ten males and ten females, and 17alpha-methyltestosterone was administered daily by gavage at doses of 0 (control), 5, 20 and 80 mg/kg body weight per day. Male rats were killed on the day after the 28th administration and females on the day of the diestrus stage during the 4 day period after the 28th administration. Male rats receiving 80 mg/kg 17alpha-methyltestosterone demonstrated decreases in testis and epididymis weights, atrophy of seminiferous tubules and Leydig cells, and degenerated pachytene spermatocytes in the testes and degenerated germ cells in the epididymides as major alterations. Female rats showed abnormal estrous cycles, decreases in ovary and adrenal weights, increase in immature follicles with decreased corpus lutea in the ovaries at doses of 5 mg/kg and higher, as well as atrophy of zona reticularis in the adrenals and increase in mammary gland secretion at 20 mg/kg and above. Dilatation of the lumina and apoptosis of endometrial cells in the uterus, mucinification in the vagina and increase in serum follicle-stimulating hormone were seen with 80 mg/kg. Among the parameters examined in the present experimental system, effects of 17alpha-methyltestosterone on endocrine-related organs were detected in organ weights and histopathological examination of both sexes, and in serum hormones and estrous cycle of females. Based on these results, the no-observed-adverse-effect level (NOAEL) in the present study was estimated to be below 5 mg/kg per day. In particular, effects were most sensitively detected by organ weights and histopathological examination of sexual organs.

Administration, Oral↗
PubMed2003

Comparative effects of oral esterified estrogens with and without methyltestosterone on endocrine profiles and dimensions of sexual function in postmenopausal women with hypoactive sexual desire.

OBJECTIVE: In some women, a decline in sexual interest accompanies a relative androgen insufficiency after menopause. We sought to characterize the hormonal effects of the combination of oral esterified estrogens and methyltestosterone and to investigate whether this regimen improves hypoactive sexual desire. DESIGN: Double-blind randomized trial. SETTING: Healthy volunteers in a multicenter research environment. PATIENT(S): Postmenopausal women taking estrogen therapy who were experiencing hypoactive sexual desire. INTERVENTION(S): 4 months of treatment with 0.625 mg of esterified estrogens (n = 111) or the combination of 0.625 mg of esterified estrogens and 1.25 mg of methyltestosterone (n = 107). MAIN OUTCOME MEASURES: Baseline and end-of-study measurements of total and bioavailable testosterone and sex hormone-binding globulin (SHBG), and mean change in level of sexual interest or desire as rated on the Sexual Interest Questionnaire. RESULT(S): Treatment with the combination of esterified estrogens and methyltestosterone significantly increased the concentration of bioavailable testosterone and suppressed SHBG. Scores measuring sexual interest or desire and frequency of desire increased from baseline with combination treatment and were significantly greater than those achieved with esterified estrogens alone. Treatment with the combination was well tolerated. CONCLUSION(S): Increased circulating levels of unbound testosterone and suppression of SHBG provide a plausible hormonal explanation for the significantly improved sexual functioning in women receiving the combination of esterified estrogen and methyltestosterone.

Administration, Oral↗
PubMed1978

Conservative treatment of endometriosis externa: the effects of methyltestosterone therapy.

Twenty-four women with documented endometriosis externa were treated with methyltestosterone. Twenty-one of these patients desired fertility and three conceived (one after methyltestosterone therapy alone, two after conservative operation followed by methyltestosterone treatment). Ten patients later required surgical therapy for recurrence of pain, although all but one patient had initial relief of pain (3 to 6 months after therapy). These results of therapy are contrasted to those of similar studies in the literature in which methyltestosterone and other agents were used.

Adult↗