Pup-killing behavior in mice: suppression by early androgen exposure.
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Binding of [3H] methyltrienolone (R 1881) in rat prostate and human benign prostatic hypertrophy (BPH).
Methyltrienolone (R 1881 - 17beta-hydroxy-17alpha-methyl-estra-4, 9, 11-trien-3-one) binding to rat ventral prostate cytosol has a specificity typical of an androgen receptor. In human benign prostatic hypertrophy (BPH) tissue, the specificity of [3H] R 1881 binding is different from that measured in rat prostate: progesterone and R 5020 (17, 21-dimethyl-19-nor-4, 9-pregnadiene-3, 20-dione) being more potent while 19-nortestosterone is less potent competitor. Moreover, the synthetic progestin [3H] R 5020 binds to BPH tissue with a similar specificity. These data suggest the presence of progestin binding components or of an atypical androgen receptor in human BPH cytosol.
Animals↗
Assay of androgen binding sites by exchange with methyltrienolone (R 1881).
Methyltrienolone (R 1881 - 17beta-hydroxy-17alpha-methyl-estra-4,9,11-trien-3-one) binds specifically to androgen receptor in rat prostate cytosol where, unlike androstanolone, it is not metabolized. By exchanging bound endogenous hormone in rat prostate cytosol with labelled R 1881, it is possible to measure total (free anc occupied) binding sites. This assay method has also been applied to the measurement of androgen receptor sites in human benign prostatic hypertrophy where R 1881 has the added advantage of not being bound by any contaminating plasma protein (sex hormone binding protein).
Animals↗
A new class of long-acting hormonal steroid preparation: synthesis of dimeric androgenes coupled at C3-C3 and C17-C3 and of an androgen-progestogen combination.
3beta-Hydroxy-4-androsten-17-one was prepared from 4-androsten-3,17-dione according to the method of Klimstra and Colton (1) and dimerized by means of esterification with succinic acid. The reduction with lithium-tri-t-butoxyaluminium hydride gave a testosterone derivative coupled between C3-C3 which showed after a single injection of 10 mg a protracted but relatively weak androgenic effect in castrated male rats. The direct esterification of testosterone hemisuccinate with 4-androsten-3beta, 17beta-diol gave the testosterone derivative coupled between C17-C3 which showed a more even and more protracted time response curve than testosterone enanthate. The testosterone-ethynodiol succinate also coupled between C17-C3, showed an androgenic depot-effect similar to that of the dimeric C17-C3 testosterone derivative.
Animals↗
Characteristics of androgen binding in rat adrenal tissue using [3H]methyltrienolone (R1881) as tracer.
A high level of binding of [3H]methyltrienolone (R1881 = 17beta-hydroxy-17alpha-methyl-estra-4, 9, 11-trien-3-one) was found in cytosol prepared from adrenals of castrated male rats. Binding of [3H]R1881 was of high affinity (DK = 6.2 nM) and highly specific for androgens. The [3H]R1881 complex migrates at 7-9S on sucrose gradients in low ionic strength buffer and at 4-5S in buffer containing 0.4M KC1. All binding studies have been performed in parallel with rat ventral prostate and adrenal cytosol. The present data suggest the presence of an androgen binding component in rat adrenal tissue.
Adrenal Glands↗
A microassay for the measurement of androgen receptors in human prostatic tissue.
A microassay utilizing R 1881 (methyltrienolone) has been developed for the measurement of androgen receptor sites in the cytosol and nuclear extract of human prostatic tissue. Binding of R 1881 to the progesterone binding molecule in cytosol was eliminated by the addition of triamcinolone acetonide. Utilizing a six tube, single point assay, the number of binding sites estimated in nuclear extract averaged 95% of the number measured by a full 7 point Scatchard analysis; the number estimated by the microassay in cytosol averaged 91%. When the single point assay was applied to needle biopsy specimens (200 mg of tissue), the estimated number of binding sites in nuclei averageed 83% of the number measured in bulk tissue (2 grams) utilizing a 7 point Scatchard analysis; the number in cytosol estimated by the microassay on needle biopsy specimens averaged 73%. It is hoped that this technique may be useful in correlating receptor content with hormonal responsiveness in men with metastatic carcinoma of the prostate.
Binding, Competitive↗
Synthesis and some reactions of 6-bromoandrogens: potential affinity ligand and inactivator of estrogen synthetase.
The synthesis of epimeric 6-bromo-4-androstene-3,17-dione (1a and 1b), 6-bromotestosterone (2a and 2b) and its acetate (3a and 3b), and 6-bromo-16 alpha-acetoxy-4-androstene-3,17-dione (5a and 5b), and 6 beta-bromo-16 alpha-hydroxy-4-androstene-3,17-dione (4) is described. The interconversions among compounds 1, 2, and 3 are also studied. The 6 beta-isomer (1b, 2b, and 3b) was epimerized to the 6 alpha-isomer (1a, 2a and 3a) in carbon tetrachloride or chloroform-methanol (9:1) and the 6 alpha-isomer was isolated by fractional crystallization from the epimeric mixture. 6 alpha-Bromo isomer 1a was also epimerized back to 6 beta-bromo isomer 1b in chloroform-methanol (9:1). Two polymorphic forms of 6 beta-bromotestosterone acetate (3b) were isolated (mp. 114--117 degrees and 138--141 degrees). The 6 beta-bromo isomers were found to be unstable in methanol and decomposed to give 5 alpha-androstane-3,6-dione derivative (6). The results of irreversible inactivation of human placental androgen aromatase with some of these 6-bromoandrogens are discussed.
Methods↗
Effect of ionic strength on the interaction of androgens with Sertoli cell nuclei.
Only 35-50% of the label accumulated after incubation of cultured Sertoli cells with 3H-testosterone was readily extractable with 0.4 M KCl during a 1 h exposure. The degree of extractability was relatively constant over the pH range 7.0-8.5 but could be increased by prolonged (15 h) exposure. While 0.1 M KCl extracted a measurable amount of label, 0.4 M KCl was significantly more efficient. Furthermore, a higher proportion of the material extracted with 0.4 M KCl was associated with macromolecular species. After a 45 min exposure to 3H-testosterone, the nuclear fraction contained primarily labeled testosterone and its 5 alpha-reduced metabolites. The relative distribution of these metabolites between salt-resistant and readily extractable forms varied between experiments. In contrast, 3H-R1881 (17 beta-hydroxy-17-methylestra-4,9,11-trien-3-one) remained essentially intact in the nuclear fraction but also was only 35% extractable with 0.4 M KCl. In conclusion, although the quantitative aspects of salt extractability appear to depend to some extent upon the extraction conditions, it is apparent that the Sertoli cell nuclear fraction accumulates a significant amount of androgen in a form which is relatively resistant to removal with 0.4 M KCl. The biological significance of this phenomenon remains to be established.
Animals↗
Synthesis of 2-carboxy-11 beta, 17 beta-dihydroxy-17-methyl-1, 4-androstadien-3-one and related compounds.
A series of 2-carboxy-1, 4-androstadien-3-one derivatives and their alkyl esters, were prepared by high-yield syntheses. The compounds were structurally identified by physical methods. All these steroids are characterized by a marked antiglucocorticoid activity that proved long-acting in the case of the ester derivatives. 2-Carboxy-11 beta, 17 beta-dihydroxy-17-methyl-1, 4-androstadien-3-one or roxibolone, and its n-decylester or decylroxibolone, are the most promising derivatives in consideration of their pharmacological properties.
Androstadienes↗
Steroids and related products. LIV. The synthesis of 11-oxa steroids. VI. The synthesis of 11-oxatestosterone.
The synthesis of 11-oxatestosterone from 11-oxa-5 alpha-androstane-3,17-dione, which is available from hecogenin, is described. The product shows, in comparison with the natural hormone, diminished androgenic and anabolic activities.
Anabolic Agents↗
Unusually high rates of metabolism of DHT in cytosols of the quail uropygial gland.
The metabolism of DHT in the cytosol of the quail uropygial gland was found to be so high that the steroid was almost completely inactivated within 2 hours of incubation at 0 C. In these conditions, DHT cannot be used for the characterization of androgen receptors. By contrast, R 1881 and mibolerone, which are not metabolized, can be used as alternative ligands. Moreover, the extremely high metabolism of DHT questions the physiologic role of this steroid in the quail uropygial gland.
Animals↗
Synthesis and testing of 17a beta-hydroxy-7 alpha-methyl-D-homoestra-4,16-dien-3-one: a highly potent orally active androgen.
The title compound, 17a beta-hydroxy-7 alpha-methyl-D-homoestra-4,16-dien-3-one (3), was synthesized in five steps (17% overall yield) from 7 alpha-methylestrone methyl ether (5) and was found to possess oral androgenic activity, in excess of other known androgens, without using 17 alpha-alkyl substitution.
Animals↗
Androgen receptor binding activity in meningiomas.
Analyses of androgen receptor binding activity in 54 intracranial, intraspinal, and metastatic meningiomas were performed with a specific radioligand binding technique using [3H]R 1881 as radioligand. [3H]R 5020 was used for the concurrent determination of progesterone receptor binding activity. Moderate concentrations of androgen receptors (33.4 +/- 5.4 fmol/mg protein) were detected in 35 (65%), whereas high levels of progesterone binding components (236 +/- 35 fmol/mg protein) were demonstrated in 48 (89%) tumors. The androgen receptor binding activity was positively correlated with the progesterone receptor binding activity (rs = 0.38, p less than 0.05). This relationship is suggestive of an androgen regulation of the progesterone receptor via the androgen receptor system. The presence of androgen and progesterone receptors in a large proportion of meningiomas, and the tendency for a dependence of androgen receptor and progesterone receptor binding activity on the histological subtype could have implications for tumor therapy.
Estrenes↗
Androgens are specifically implicated in female rat sexual motivation. The influence of methyltrienelone (R1881) on sexual orientation.
The present experiment was designed to investigate whether androgens are specifically involved in the induction of a male-directed orientation in adult female rats. Ovariectomized female rats were either treated with the non-aromatizable androgen methyltrienelone (R1881), with testosterone propionate (TP), with estradiol benzoate (EB) or with an equal volume of the solvent. Sexual orientation of these females towards either sexually active males or estrous females was then investigated and related to levels of receptive and mounting behavior. Compared to the solvent-treated females, females treated with R1881, TP or EB spent more time near sexually active males. Mounting behavior was stimulated in the R1881- and TP-treated females, but EB-treated females mounted as often as females treated with the solvent only. Lordosis behavior was only observed in TP-treated or EB-treated females. Mount frequency of the females of the different treatment groups was positively correlated with time spent near males. These correlations reached statistical significance in the TP-treated and EB-treated females. In the TP-treated females, the lordosis quotient was negatively correlated with time spent near males. The results of the present experiment suggest that androgens need not be converted into estrogens in order to facilitate a male-directed orientation in ovariectomized female rats.
Androgens↗
Biological activity of hormonally active and non-active androgen derivatives.
Androgen derivatives appeared to have different biological activities in vivo and in vitro. Testosterone-17-isobutyrate given in three doses of 50 or 200 microgram increased significantly the weight of seminal vesicles and reduced thymus weight in castrated males, whereas testosterone-17-hemisuccinate, testosterone-D-beta-glucoside and testosterone-3-(O-carboxymethyl)-oxime had no such effects. Similarly, ten 1-mg doses of testosterone-17-isobutyrate, unlike testosterone-17-hemisuccinate, resulted in a marked reduction of thymus weight in non-castrated males and in a significant inhibitory effect on the activity of spermatogenesis. On the other hand, all three androgen derivatives, which had appeared inactive in vivo, had similar effects in vitro (as had active testosterone) as demonstrated by inhibition of Concanavalin A-induced lymphocyte activation expressed by 14C thymidine incorporation and inhibition of cell agglutination. These results seem to suggest that as for the regulation of androgen-dependent organs and functions (such as the size of seminal vesicles, activity of spermatogenesis, thymus size), hormonally active androgens are also involved in certain immunosuppressive effects in vivo. On the other hand, in vitro immunological effects are produced by both hormonally active and non-active androgen derivatives as well as by other steroid hormones, the common denominator being the steroid structure.
Animals↗
Binding of [3H]-methyltrienolone (R1881) by human breast cancers.
The synthetic radioligand [3H]-R1881 binds to both androgen and progestogen receptors; these two types of receptor activity can be separated by competition experiments with radioinert steroids of defined biological activity. Using two standard tissues, rat prostate and human uterus, which are sources of androgen and progestogen receptors respectively, the optimal conditions for the determination of each type of activity were established. For the purposes of routine assay, androgen receptors were quantified after saturation of progestogen receptor sites with 125 nM radioinert R5020 using [3H]-R1881 and increasing concentrations of radioinert R1881. Progestogen receptor activity could be identified using the same radioligand and competition with radioinert progesterone or R5020, though for routine purposes, progestogen receptors were quantified using the more specific radioligand, [3H]-R5020. The binding of [3H]-R1881 to tumour cytosol was examined in 122 human breast cancers. Seventy-two tumours (59%) showed binding. Androgen receptor activity alone was present in 16 tumours, progestogen receptor activity alone in 30 tumours and both types in 26 tumours. Tumours containing progestogen receptor activity also showed binding to the progestogen [3H]-R5020, whilst those containing androgen receptors alone did not. Androgen receptor concentration varied from 17 to 210 fmol binding sites/mg cytosol protein (mean value 68) and the mean Kd was 2.15 X 10(-9) M. Progestogen receptor concentration varied from 25 to 1350 fmol binding sites/mg cytosol protein (mean value 410) and the mean Kd was 1.35 X 10(-9) M. The biological significance of the presence of these types of receptor in human breast cancers is currently being assessed from clinical follow-up.
Animals↗
Hormonal regulation in two rat mammary cancer cell lines: glucocorticoid and androgen receptors.
We have studied the hormonal control of two continuous cell lines derived from rat-mammary tumors induced by two different carcinogens (dimethylbenzanthracene and N-nitrosomethylurea). The steroid receptors were assayed using charcoal or hydroxyapatite and the effect of different hormones on cell growth was evaluated by measuring total DNA and following the growth of transplanted cells in nude mice. Similar results were found for the two cell lines; they were unresponsive to estrogen since they did not contain appreciable amounts of estradiol receptor. Conversely, these two cell lines contained high concentrations of androgen and glucocorticoid receptors, which were both transferable to the nucleus. While dexamethasone stimulated, directly or indirectly, the growth of RBA and NMU cells, the effect of androgens on cell growth is still questioned. These two cell lines offer a potential model to study the mechanism of action of androgens and glucocorticoids in mammary cancer.
9,10-Dimethyl-1,2-benzanthracene↗
The human androgen receptor is a 110 kDa protein.
The androgen receptor in human prostate carcinoma cells (LNCaP) has been studied after in situ photolabeling with [3H]R1881. Sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis of whole cell extracts revealed the presence of two specifically labeled proteins of 110 kDa and 43 kDa. Both photolabeled proteins were stable in cell homogenates and generated different chymotryptic maps, suggesting that the two proteins were different. From ligand binding specificity studies could be concluded that the 110 kDa protein represents the androgen receptor. The 43 kDa protein showed binding specificity only for R1881. Both photolabeled proteins were recovered from LNCaP nuclei, but the 43 kDa protein showed a relatively higher affinity for nuclei than the 110 kDa protein. The function of this protein is unknown. It is concluded that the human androgen receptor is a protein with a molecular mass of 110 kDa.
Cell Line↗