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PubMed1975

The pharmacology and metabolism of testosterone undecanoate (TU), a new orally active androgen.

Testosterone undecanoate (TU), either dissolved in arachis oil or as micro-crystal suspension, displays androgenic activity on oral administration to rats in the Hershberger test. The solution in arachis oil is more active than the crystal suspension. When [3H]TU is administered orally to rats, most of it is metabolized in the intestinal wall. The majority of the metabolites probably lose their undecanoate group and are absorbed via the portal vein. The non-metabolized [3H]TU and at least two metabolites are absorbed exclusively via the lymphatic system. One of these metabolites has been identified as 5alpha-dihydrotestosterone undecanoate (5alpha-DHTU). TU has no harmful effects on the liver of the rabbits on oral administration.

Animals↗
PubMed1999

Intramuscular injection of testosterone undecanoate for the treatment of male hypogonadism: phase I studies.

OBJECTIVE: In the search for long-acting testosterone preparations suited for substitution therapy of hypogonadal men, testosterone undecanoate (TU) dissolved in either tea seed oil or castor oil was investigated. DESIGN: In study I, 1000 mg TU in tea seed oil (125 mg/ml) were injected in equal parts into the gluteal muscles of seven hypogonadal men. In study II, 1000 mg TU in castor oil (250 mg/ml) were injected into one gluteal muscle of 14 patients. RESULTS: In comparison with published data on testosterone enanthate, most widely used for i.m. injections, the kinetic profiles of both TU preparations showed extended half-lives and serum levels not exceeding the upper limit of normal. The castor oil preparation had a longer half-life than TU in tea seed oil (33.9+/-4.9 vs 20.9+/-6.0 days (mean pm S.E.M.)). CONCLUSION: The longer half-life and the smaller injection volume make TU in castor oil a strong candidate for further applications in substitution therapy and in trials for male contraception.

Adult↗
PubMed1978

Androgenic effects of the antiprogestagen RMI 12,936.

RMI 12,936 (7alpha-methyl-17beta-hydroxy-androst-5-en-one) was tested for androgenic activity in mouse kidney and for antiprogestational activity in guinea-pig uterus. RMI 12,936 stimulated an increase in kidney weight and in the activity of the androgen-responsive renal enzymes, beta-glucuronidase, alcohol dehydrogenase and arginase. RMI 12,936 was bound by the renal androgen receptor with a relative affinity approximately one-third that of testosterone. Although RMI 12,936 did not stimulate glycogen accumulation in guinea-pig endometrium in vivo, it was active in endometrial organ culture. When RMI 12,936 was combined with progesterone, glycogen accumulation in vitro was partly inhibited. RMI 12,936 was bound by the guinea-pig uterine progesterone receptor with a relative affinity of less than 1%. It is concluded that RMI 12,936 is an androgenic steroid with antifertility actions and in-vitro antiglycogenic activity.

Androstenols↗
PubMed1978

Further investigation of the antifertility effects in the rat of the antiprogestational steroid, RMI 12,936, and related compounds.

The antifertility activities of RMI 12,936 and 7alpha-methyltestosterone may be reversed by progesterone implants in ovariectomized, but not in intact, rats on Day 8 of pregnancy. The presence of the ovary for 48 h after administration of RMI 12,936 is necessary for irreversible antifertility activity to be developed, and it is concluded that this activity is due to a metabolite other than 7alpha-methyltestosterone. 7alpha-Methylandrostenedione was significantly less potent than RMI 12,936 in antifertility tests, while the uterotrophic activity of RMI 12,936 was not inhibited by aromatization inhibitors, suggesting that the active metabolite is not produced by dehydrogenation or aromatization of 7alpha-methyltestosterone.

Androstenedione↗
PubMed1978

Effects of RMI 12,936, a synthetic antiprogestational steroid, on the oestrous cycle and ovulation in the rat.

RMI 12,936 inhibited the vaginal cycle and ovulation in the rat. This effect was not mimicked by oestrogen and was partly reversed by progesterone. Ovulation was restored by injection of hCG and the inhibition was associated with reduced cyclic and tonic LH secretion while hypophysial LH levels were generally unaffected. Hypophysial sensitivity to LH-RH was reduced compared with that when ovulation was blocked with sodium pentobarbitone. It is concluded that RMI 12,936 blocks ovulation by causing a reduction in hypophysial sensitivity to LH-RH and that this is probably an antiprogestational effect.

Androstenols↗
PubMed1997

Beneficial effects of testosterone undecanoate on the lipoprotein profiles in healthy elderly men. A placebo controlled study.

BACKGROUND AND METHODS: In order to assess the effects of testosterone undecanoate (TU; 120 mg/d orally for 2 months) on serum lipid, lipoprotein, and apolipoprotein levels in healthy elderly men, the placebo (PL) controlled study was performed on 37 elderly men, aged between 53 and 89 years. In all subjects venous blood samples were taken after an overnight (10 hours) fast and sera were stored -70 degrees C until analysis. RESULTS: In PL group, neither hormonal data nor lipid, lipoprotein, and apolipoprotein levels showed significant changes. After TU supplementation, serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and estradiol (E2) levels decreased from 198 +/- 30.7 mg/dl to 174 +/- 41.9 mg/dl (p < 0.05), from 111 +/- 18.14 mg/dl to 87.9 +/- 29.4 mg/dl (p < 0.01), and from 86.2 +/- 16.9 pmol/l to 70.5 +/- 18 pmol/l (p < 0.01), respectively. Statistically significant differences were not observed in the serum triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and apolipoprotein (apo) A-1 and apo B levels after TU treatment. The mean ratios TC/HDL-C and LDL-C/HDL-C as coronary risk factor criteria decreased significantly in the TU but not in the PL group. No obvious side effect was observed in those who took TU except for reported pyrosis in 2 of 17 elderly men. CONCLUSIONS: These data indicate that the increased serum levels of total testosterone (TT) produced by administration of TU, 120 mg/d orally for 2 months lead to suppressed levels of TC and LDL-C and E2 but not significantly changed levels of TC, HDL-C, apo A-1 and apo B. Thus, we conclude that TU may be an effective drug for protecting coronary heart disease in healthy elderly men with lowered TT and FT levels. It may also have beneficial effects for sexual function and behavior.

Aged↗
PubMed2004

The TRPS1 transcription factor: androgenic regulation in prostate cancer and high expression in breast cancer.

TRPS1 mRNA is more highly expressed in androgen-dependent lymph node carcinoma of prostate-fast growing colony (LNCaP-FGC) compared with androgen-independent lymph node carcinoma of prostate-lymph node original (LNCaP-LNO) prostate cancer cell lines. Furthermore, TRPS1 mRNA expression is down-regulated by androgens in LNCaP-FGC cells, a process mediated by the androgen receptor (AR). Here, we present TRPS1 protein expression in human prostate cancer material derived from a panel of six androgen-dependent and eight androgen-independent human prostate cancer xenografts. TRPS1 protein is expressed in all androgen-dependent xenografts, which also express AR and prostate-specific antigen (PSA). Androgen withdrawal by castration resulted in an increase in TRPS1 protein in two androgen-dependent xenografts, indicating relieved repression by action of AR. TRPS1 protein is expressed in four androgen-independent xenografts and is low or absent in the other four androgen-independent xenografts. Androgen withdrawal by castration demonstrates that TRPS1 protein levels remain the same in 1 androgen-independent xenograft, most likely due to the lack of AR expression. These data show that TRPS1 protein expression is regulated by androgens via the AR in human prostate cancer xenografts. Analysis of TRPS1 mRNA expression in normal and tumour tissue of the prostate and 18 other human tissues, showed that TRPS1 had the highest mRNA expression levels in normal and tumour tissues of breast. In addition, high TRPS1 mRNA and protein expression levels were observed in four out of five human breast cancer cell lines. In conclusion, TRPS1 protein expression is down-regulated by androgens in human prostate cancer, and analysis of TRPS1 mRNA expression levels in several human tissues showed that the highest levels were observed in normal and tumour breast tissue.

Animals↗
PubMed1995

Characterization of normal and point-mutated human androgen receptors expressed in the baculovirus system.

The baculovirus system is able to generate large amounts of a protein, permitting detailed analysis of structure-function relations. We have used this system to overexpress and characterize normal human androgen receptors (hAR) and mutant hARs from humans with complete or partial androgen insensitivity. Maximum specific binding of [3H]mibolerone (MB) in recombinant baculovirus-infected Spodoptera frugiperda (Sf9) cells varied from 15 to 40 pmol/mg protein, about 1000-fold higher than in genital skin fibroblasts, and peaked 48-72 h after infection. In contrast, Coomassie blue staining and Western blotting revealed maximum accumulation of 100-120 kDa hAR proteins 96 h post-infection. Normal and mutant hARs were specifically photo-affinity-labeled with [3H]methyltrienolone (MT), and had normal steroid-binding selectivity: the order of competition was androgen > estrogen > progestin > glucocorticoid. Normal hAR was phosphorylated in Sf9 cells, reacted with antibodies against phosphoserine and phosphothreonine after purification using testosterone-biotin, and transactivated a transfected androgen response element-luciferase reporter in infected Sf9 cells. Two mutant hARs had increased rates of dissociation from MB and MT that were in accord with the associated degree of clinical androgen insensitivity: complete, Pro903Ser > partial, Leu820Val; the third, Ile663Asn, was not abnormal. Our data extend the characterization of normal hAR produced by baculovirus-infected Sf9 cells, and demonstrate, for the first time, that point-mutated hARs so produced can display distinctive biochemical phenotypes.

Amino Acid Sequence↗
PubMed1977

Binding of methyltrienolone (R1881) to a progesterone receptor-like component of human prostatic cytosol.

The synthetic steroid methyltrienolone (R1881, 17beta-hydroxy-17alpha-methyl-estra-4,9,11-trien-3-one) binds with high affinity to protein in cytosols prepared from human hyperplastic prostate. R1881 also binds to the androgen receptor of rat prostate and the progesterone receptor of rabbit uterus. Other steroids compete with R1881 for unoccupied binding sites in the human prostatic cytosols in a manner similar to that observed with the rabbit uterine progesterone receptor, rather than the rat prostatic androgen receptor. The progesterone receptor-like binding sites are a feature of the prostatic stroma rather than the epithelium.

Animals↗
PubMed1982

Effects of gonadal steroid hormones on the hypothalamo-pituitary-liver axis in the control of sex differences in hepatic steroid metabolism in the rat.

The site of action of gonadal hormones in the regulation of hepatic steroid metabolism was investigated by measuring the effects of (i) implantation of estradiol into the pituitary gland or anterior hypothalamus of males and (ii) subcutaneous injection of a synthetic androgen in differentiated male and female rats. The hepatic responses measured in vitro were 5 alpha-reduction, and 6 beta- and 16 alpha-hydroxylation of androstenedione. After intrapituitary or intrahypothalamic implantation of oestradiol, 5 alpha-reductase activity increased and 6 beta- and 16 alpha-hydroxylase activity decreased in males relative to the enzyme activities of cholesterol-implanted animals, indicating a feminizing effect of the oestrogen. This effect could not be accomplished by subcutaneous injection of the same oestrogen preparation. Deafferentation had no effect on hepatic steroid metabolism in females, but caused a feminization in males. In addition, subcutaneous treatment of intact females with the synthetic androgen caused masculinization of hepatic steroid metabolism, but was without effect in differentiated animals. Treatment with synthetic androgens had no effect on the hepatic steroid metabolism in differentiated male animals. Subcutaneous injection of a potent synthetic progestagen had little effect on hepatic steroid metabolism in intact females. It is concluded that oestrogen feminizes hepatic steroid metabolism by an action at the hypothalamic-pituitary level and that an intact hypothalamic-pituitary axis is required for the masculinizing action of the synthetic androgen on hepatic steroid metabolism. It is possible that the site of action of androgens is in the anterior hypothalamus or in adjacent areas of the brain.

Androstenedione↗
PubMed1983

Effects of 17 beta-hydroxy-17 alpha-methyl-estra-4,9,11-triene-3-one (R 1881): evidence for direct involvement of androgens in the defeminization of behaviour in rats.

The synthetic androgen 17 beta-hydroxy-17 alpha-methyl-estra-4,9,11-triene-3-one (methyltrienolone, R 1881) binds specifically and with high affinity to androgen receptors and is presumably not metabolized into either the less potent androgens or into oestrogens. Because of these intrinsic properties, R 1881 can be used to investigate the possibility of a direct androgen involvement in the development of sexual behaviour. Females, at birth, were implanted with silicone elastomer capsules containing R 1881, testosterone, dihydrotestosterone or cholesterol for 10 days, or given daily injections of 100 micrograms hormone for 5 days. Neonatal treatment with R 1881 inhibited the capacity of female rats to show female mating behaviour when given ovarian hormones in adulthood; both implants and injections caused a similar reduction in receptive and proceptive behaviours. Testosterone, given as implants, caused almost complete defeminization, while injecting the hormone had a partial inhibition on mating responses. Dihydrotestosterone had no appreciable effect upon the development of behaviour. Thus, an androgen, R 1881, which is presumed not to be aromatized to oestrogens, has the potential to cause defeminization of mating and proceptive behaviour in female rats.

Androgens↗
PubMed1984

Sex differences in behavioural androgen sensitivity: possible role of androgen metabolism.

Masculine sexual behaviour was induced in castrated sexually inactive but experienced male rats by testosterone-filled constant-release implants or daily injections of the synthetic androgen 17 beta-hydroxy-17 alpha-methyl-estra-4,9,11-triene-3-one (methyltrienolone, R 1881), which resists metabolism by target organs. Feminization of the hepatic androgen metabolism by subcutaneous implantation of osmotic minipumps, which delivered a constant amount of human GH, did not affect the behavioural response of castrated rats to testosterone. Testosterone implants were only minimally effective in inducing male behaviour in ovariectomized female rats, but R 1881 was as effective in stimulating male behaviour in females as in males. Testosterone-treated but not R 1881-treated females showed pronounced female sexual behaviour in response to progesterone treatment despite the absence of measureable amounts of oestradiol-17 beta in peripheral blood. The results provide evidence that masculine sexual behaviour can be activated by an androgen in the absence of oestrogenic stimulation and suggest that the sex difference in the behavioural response to testosterone may be due to a sex difference in the metabolism of androgens by the brain.

Androgens↗
PubMed1986

Sex difference in the cytosolic and nuclear distribution of androgen receptor in mouse submandibular gland.

Cytosol and nuclear androgen receptors in submandibular glands of male and female mice were measured by an exchange assay at 0 degree C. The binding of [3H]methyltrienolone to cytosol receptors in females was mostly saturated within a short period of incubation (3 h), whereas the saturation was much slower in males; suggesting that almost all of the cytosol receptors were unoccupied in females and the receptors were partially occupied in males. Nuclear receptors were extracted with pyridoxal 5'-phosphate (5 mmol/l) from nuclear fractions with 93-95% efficiency. The exchange of the bound steroids occurred by 24-48 h at 0 degree C, suggesting that most of the nuclear androgen receptor was occupied. The binding was low at higher temperatures, probably due to inactivation of the receptor. Scatchard analysis showed that the apparent dissociation constants of cytosol and nuclear receptors were similar (0.8 and 0.9 nmol/l respectively) in both sexes. On the other hand, the number of androgen-binding sites in the nucleus was much higher in males than in females (1052 fmol/mg DNA and 32 fmol/mg DNA respectively), while the number in the cytosol was higher in females than in males (512 fmol/mg DNA and 368 fmol/mg DNA respectively). These observations show that androgen receptors exist mainly (74%) in the nuclei of males, while they exist mostly (94%) in the cytosol of females.

Animals↗
PubMed1986

Androgen regulation of the androgen receptor of the quail uropygial gland: application of a [3H]mibolerone exchange assay.

An exchange assay for androgen receptors in the quail uropygial gland using [3H]mibolerone was established. The most efficient exchange conditions were 3 days of incubation at 15 degrees C. Under these conditions, androgen receptors were stable in the presence of sodium molybdate, and the exchange of [3H]mibolerone with endogenous testosterone bound to cytosolic or nuclear androgen receptors was maximal. Less than 5% of [3H]mibolerone-binding sites occurred in the extracted nuclear pellets. Using this exchange technique, it was shown that androgen receptors in the uropygial gland of photostimulated male quail or castrated quail treated with testosterone were activated and that their concentrations in both cytosolic and nuclear fractions were increased. These results confirm the androgen dependency of the quail uropygial gland, and show that it is an organ which can be used as a model for the study of androgen action in sebaceous glands.

Animals↗
PubMed1986

Minimal effects of 17 beta-hydroxy-17 alpha-methyl-estra-4,9,11-triene-3-one (R1881) on sexual behaviour in prepubertally castrated rams.

Ten adult prepubertally castrated rams were injected with 5 alpha-dihydrotestosterone propionate (DHTP; 20 mg/day) for 3 weeks to stimulate genital development. Thereafter, half of the sheep were injected with testosterone (100 mg/day) for a further 4 weeks, while the remainder received the same dose of 17 beta-hydroxy-17 alpha-methyl-estra-4,9,11-triene-3-one (methyltrienolone; R1881). All the animals were tested for sexual behaviour on 15 occasions with ovariectomized ewes in which oestrous behaviour was induced by injections of 50 micrograms oestradiol-17 beta benzoate at 4- to 5-day intervals. Behavioural tests were of 10 min duration and were carried out thrice weekly over a 5-week period, starting in the final week of DHTP treatment. Animals treated with testosterone showed a highly significant increase in courtship behaviour (tongue-flicks; lunges and nudges) after only four daily injections and this level of activity was maintained to the end of the experiment. However, the incidence of courtship activity in sheep treated with R1881 was similar to that recorded during the period of DHTP treatment. All animals given testosterone displayed mounts with pelvic thrusts and erections, and achieved intromission with ejaculation. These activities remained significantly more frequent than in sheep treated with R1881, starting from tests 9, 8 and 12 respectively. Four of the five individuals in the group given R1881 showed occasional mounts with thrusts, three showed sporadic erections and one sheep intromitted in the final test. These results indicate that, in contrast to the rat, R1881 has only very weak effects on sexual behaviour in the castrated ram.

Animals↗
PubMed1986

Olfactory recognition in the male hamster: effect of non-aromatizable androgens, 17 beta-hydroxy-17 alpha-methyl-estra-4,9,11-triene-3-one (R 1881) and 5 alpha-dihydrotestosterone, in combination with oestrogen.

Intact male hamsters show olfactory behaviour (sniffing and licking) to novel females. After exposure to female vaginal secretions, they show less sniffing towards a novel female if she does not match previously encountered odours (Steel, 1984). Male hamsters, castrated and injected s.c. with various steroids, were tested for the amount of sniffing they directed towards novel and mismatching females. 5 alpha-Dihydrotestosterone propionate (DHTP), 17 beta-hydroxy-17 alpha-methyl-estra-4,9,11-triene-3-one (methyltrienolone, R1881) and oestradiol benzoate alone did not influence olfactory behaviour, while testosterone propionate (TP), DHTP plus oestradiol and R1881 plus oestradiol all increased sniffing to a novel female over the levels shown by saline-treated, castrated controls. Our results also indicated that only the aromatizable androgen (TP) or non-aromatizable androgens DHTP and R1881, in combination with oestradiol, reduced sniffing directed to a mismatching female after exposure to vaginal odour. We conclude that both androgenic and oestrogenic actions are required not only for olfactory behaviour, but also for olfactory recognition as indicated by a reduction in sniffing directed towards mismatching females. This suggests that aromatization of testosterone may be involved in the control of olfactory processes associated with reproductive behaviour.

Animals↗
PubMed1987

Failure of the synthetic androgen 17 beta-hydroxy-17 alpha-methyl-estra-4,9,11-triene-3-one (methyltrienolone, R1881) to duplicate the activational effect of testosterone on mating in castrated male rats.

Administration of the synthetic steroid, 17 beta-hydroxy-17 alpha-methyl-estra-4,9,11-triene-3-one (methyltrienolone, R1881), which is an androgen receptor agonist not metabolized in vivo, at doses of 400, 800 or 2400 micrograms/kg s.c. in propylene glycol stimulated mounting and ejaculation only slightly in sexually experienced castrated rats. A similar low level of mating was observed in a group of castrated rats given testosterone at doses of 400 followed by 800 micrograms/kg. However, when treated with a higher dose of testosterone (2400 micrograms/kg) these castrated rats displayed significantly higher levels of mounting and ejaculation than rats treated with any of the doses of R1881. Also, when this higher dosage of testosterone was substituted for each dose of R1881, significant increments in mounting and ejaculation occurred in all groups. These findings show that R1881 is only marginally effective in restoring sexual behaviour in castrated rats, suggesting that the activation of neural androgen receptors cannot by itself account for the activational effect of testosterone on mating behaviour in gonadally intact male rats.

Animals↗