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PubMed1987

Relative binding affinity at metribolone androgenic binding sites of various antiandrogenic agents.

Sebaceous glands are androgen sensitive structures with activity reduced by antiandrogens. We characterized the relative binding affinity of cyproterone acetate, 17 alpha-propyl-mesterolone, spironolactone (canrenoic acid), ethisterone and dexamethasone by means of the competitive binding analysis at metribolone (R1881) androgen binding sites. Using the DCC-assay (dextran-coated charcoal absorption) with the Scatchard plot and saturation analysis we quantified R1881 androgen binding sites from sebaceous glands situated in the ventral side of the pinna of the Syrian hamster. As parameters for ligand affinity at these binding sites served the ligand concentration for 50% displacement of 3H-labelled synthetic steroid R1881 in constant concentrations. The in vitro measurements of the used steroids were compared to the biologic sebosuppressive effect in vivo. 17 alpha-Propylmesterolone showed the highest affinity at the androgenic binding site followed by ethisterone, cyproterone acetate and spironolactone. The results, however, do not admit an interpretation about the mode of action of the given substances, which display their biologic activity either after systemic or topic administration. In vivo distribution problems and metabolizing procedures might be due to this discrepancy.

Androgen Antagonists↗

PubMedDate not supplied

The effects of steroid hormones on a human colon cancer cell line in vitro.

Estrogen analogues, moxestrol (10(-8)-10(-5) M) and ethinyl estradiol (10(-8)-10(-6) M), produced a 30% and 15% inhibition of LoVo cell growth, respectively, in serum-free Ham's F-10 medium. Under the same conditions, no growth effects were observed on these cells following the addition of progesterone or testosterone (10(-8)-10(-6) M); however, metribolone (10(-8)-10(-6) M), a synthetic androgen with glucocorticoid receptor-binding properties, moderately stimulated cell growth (18%). The synthetic antiandrogen, RU 23908 (10(-6) M), did not reduce metribolone effects, and hydrocortisone (10(-9)-10(-7) M) stimulated LoVo cell growth by 31% in serum-free medium. In medium containing 10% charcoal-treated fetal bovine serum, the inhibitory effects of estrogens were not observed, and the lower concentrations (10(-11) M) of moxestrol and ethinyl estradiol facilitated cell growth (10 to 15%). The other steroid hormones produced the same results as observed with serum-free medium. These data suggest that estrogen and glucocorticoid hormones may play an important role in the growth of colon carcinoma cells. Androgen and progesterone hormones appear to be less significant in this regard. Serum factors alter the effects of estrogen, but not of glucocorticoids.

Androgens↗

PubMed1986

Binding of glucocorticoid antagonists to androgen and glucocorticoid hormone receptors in rat skeletal muscle.

The binding of ten steroids possessing antiglucocorticoid activity has been studied in rat skeletal muscle cytosol. The affinity of these steroids for both the androgen and the glucocorticoid receptors was determined by competition with radioactive R1881 (methyltrienolone, metribolone) and dexamethasone, respectively. The antiglucocorticoid activity of these compounds was assessed in rat hepatoma (HTC) cells by measuring their inhibitory effect on the glucocorticoid-induced tyrosine aminotransferase activity. This led to identification of five novel in vitro glucocorticoid antagonists. All the steroids tested bound to both the glucocorticoid and the androgen receptors in muscle. Four steroids had an affinity for the glucocorticoid receptor higher than for the androgen receptor. The assumption is made that the steroids tested also behave as antagonists when binding to the glucocorticoid receptor in muscle and behave as agonists when binding to the androgen receptor. On this basis, the data allow one to compute a potential anticatabolic (PAG) and a potential anabolic (PAA) index for each compound. These indices might be of predictive value to determine whether these steroids exert their anabolic action in muscle through the glucocorticoid receptor or through the androgen receptor. The data also make it unlikely that satellite cells are a preferential target for anabolic steroids in muscle.

Androgens↗

PubMed1992

Synthesis of high affinity fluorine-substituted ligands for the androgen receptor. Potential agents for imaging prostatic cancer by positron emission tomography.

We have prepared nine androgens substituted with fluorine at C-16 or C-20 to evaluate their potential, as positron emission tomographic (PET) imaging agents for prostatic cancer when labeled with the positron emitting radionuclide fluorine-18 (t1/2 = 110 min). These compounds represent members from the following classes of androgens: testosterone (T), 5 alpha-dihydrotestosterone (DHT), 7 alpha-methyl-19-nortestosterone (MNT), mibolerone (Mib), and metribolone (R1881). All of these compounds were prepared by functionalization of suitable androgen precursors, and the synthetic routes were developed to allow the introduction of fluorine by a fluoride ion displacement reaction late in the synthesis, as is required for the preparation of these compounds in fluorine-18 labeled form. We have also prepared four androgens in which the C-3 carbonyl or 17 beta-hydroxyl groups are replaced by fluorine. Most of the fluorine-substituted androgens show high affinity for the androgen receptor (AR), although fluorine substitution lowers their affinity by a small factor. None of the androgens where fluorine replaces oxygen functions at C-3 or C-17 have substantial affinity for AR. Derivatives of the natural androgens (T and DHT) as well as MNT have little affinity for other steroid hormone receptors (progesterone and mineralocorticoid receptors), whereas the Mib and R1881 derivatives have somewhat greater heterologous binding. With sex steroid binding protein, a human serum binding protein, the pattern of binding affinities is nearly the reverse, with derivatives of Mib, R1881 and MNT having low affinity, and DHT and T, high affinity. From these fluorine-substituted compounds, we can select several whose preparation in fluorine-18 labeled form for further tissue distribution studies is merited.

Androgens↗

PubMed2000

Structural evidence for ligand specificity in the binding domain of the human androgen receptor. Implications for pathogenic gene mutations.

The crystal structures of the human androgen receptor (hAR) and human progesterone receptor ligand-binding domains in complex with the same ligand metribolone (R1881) have been determined. Both three-dimensional structures show the typical nuclear receptor fold. The change of two residues in the ligand-binding pocket between the human progesterone receptor and hAR is most likely the source for the specificity of R1881 to the hAR. The structural implications of the 14 known mutations in the ligand-binding pocket of the hAR ligand-binding domains associated with either prostate cancer or the partial or complete androgen receptor insensitivity syndrome were analyzed. The effects of most of these mutants could be explained on the basis of the crystal structure.

Amino Acid Sequence↗

PubMed1988

Androgen receptors in boys with isolated bilateral cryptorchidism.

A study was conducted in boys with bilateral cryptorchidism, who were to undergo surgical orchiopexy, to determine if target-organ androgen insensitivity might play a role in the failure of the testes to descend into the scrotum. Nine boys older than 1 year in whom bilateral undescended testes was the only genitourinary abnormality were evaluated. Each subject was administered a six-week course of human chorionic gonadotropin (hCG), 3000 U/m2 of body surface area, intramuscularly injected daily for five days and then twice per week. Basal and hCG-stimulated levels of testosterone were normal. However, hCG administration failed to induce testicular descent in all cases. At the time of surgery, scrotal skin and testicular biopsy specimens were obtained for propagation of cells in tissue culture. Androgen receptor levels and binding affinity were normal for the androgen-specific ligands dihydrotestosterone and metribolone in both skin fibroblasts and testicular cells. In addition, 5 alpha-reductase activity was normal in scrotal skin fibroblasts. Nine boys with bilateral cryptorchidism and normal testicular androgen biosynthesis had normal androgen receptor-binding activity and 5 alpha-reductase activity in cultured scrotal skin fibroblasts and testicular cells. Therefore, bilateral maldescent of the testes in these boys with cryptorchidism was not due to androgen insensitivity.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed1992

Fluorine-18-labeled androgens: radiochemical synthesis and tissue distribution studies on six fluorine-substituted androgens, potential imaging agents for prostatic cancer.

We have synthesized six androgens labeled with 18F as potential imaging agents for prostatic cancer. These include 16 beta-fluorine-substituted testosterone, dihydrotestosterone and mibolerone, 16 alpha- and 16 beta-fluorine substituted 7 alpha-methyl-19-nortestosterone, and 20-fluoro-R1881 (metribolone). All of the radiochemical preparations proceeded in satisfactory yield, giving material with adequately high effective specific activity for the in vivo studies. In the tissue distribution studies in diethylstilbestrol-treated male rats, high selective uptake by the prostate was observed that ranged from 0.39% to 1.21% injected dose (ID)/g at 1 hr and 0.20 to 0.47 at 4 hr, with prostate-to-blood and prostate-to-muscle ratios ranging from 3.28 to 9.45, respectively, at 1 hr and 4.06 to 35.0, respectively, at 4 hr. Those compounds that are likely to be metabolized rapidly showed lower prostate uptake but higher uptake selectivity at 4 hr; at earlier times, uptake selectivities were more comparable. Compounds with a 16 beta-fluorine substituent showed extensive metabolic defluorination, resulting in ca. 50% of the dose being deposited in bone at 4 hr. This is consistent with a 16 alpha-hydroxylation process that may proceed rapidly with these compounds, but would be retarded by a 17 alpha-methylation, blocked by inversion of stereochemistry at C-16, and would not affect fluorine at the C-20 position. These fluoroandrogens, together with 20-fluoromibolerone described previously, are the first positron-emitting androgens to show high affinity and selective uptake by androgen target tissues in vivo, and they may be useful as in vivo prostate imaging agents in man.

Animals↗

PubMed1997

Synergistic activation of androgen receptor by androgen and luteinizing hormone-releasing hormone in prostatic carcinoma cells.

BACKGROUND: We investigated modulation of androgen receptor (AR) activity in prostatic tumor cells by luteinizing hormone-releasing hormone (LHRH)-induced increase of the intracellular cyclic adenosine monophosphate (cAMP) level. METHODS: AR transactivation activity was assessed in transiently transfected DU-145 and in LNCaP cells. RESULTS: LHRH and cAMP derivative, respectively, induced reporter gene activity to about 15% of the maximal level in DU-145 cells transfected with an AR expression vector and an androgen-inducible reporter gene. LHRH or the cAMP analogue acted synergistically in combination with low concentrations of androgen thus lowering the androgen concentration required for maximal AR activation by a factor of 100. A similar activation of the AR by cAMP analogue was observed in LNCaP cells when enhancement of androgen-induced secretion of prostate-specific antigen was determined. The two nonsteroidal antiandrogens hydroxyflutamide and Casodex(R) inhibited reporter gene activity. CONCLUSIONS: The AR is synergistically activated by low doses of androgen and LHRH or the second messenger cAMP. This may have implications for the treatment of advanced prostate cancer.

Androgen Antagonists↗

PubMed1999

Mechanistic studies of the effects of the retinoid N-(4-hydroxyphenyl)retinamide on prostate cancer cell growth and apoptosis.

To explore the mechanisms underlying the chemopreventive effects of the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) in prostate cancer, we evaluated the anti-proliferative and apoptosis-inducing effects of 4-HPR in the androgen-sensitive human prostate cancer cell line LNCaP. 4-HPR decreased the number of viable LNCaP cells (as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay) in a dose-dependent manner. Although 4-HPR exerted a modest G1 cell-cycle block (as determined by flow cytometry), its effect on reduced cell number appeared to result primarily from induction of apoptosis (as measured by an enzyme-linked immunosorbent assay and flow-cytometric assays). The mitogenic effects of R1881, a non-metabolizable androgen that potently induces LNCaP cell proliferation, was completely blocked by greater than 0.5 microM 4-HPR. Furthermore, increasing the R1881 concentration in the presence of 2.0 microM 4-HPR increased apoptotic cell death. 4-HPR decreased prostate-specific antigen (PSA) protein levels in conditioned medium and decreased PSA mRNA expression. 4-HPR also decreased the ratio of bcl-2 to bax mRNA expression in LNCaP cells by approximately 45%, indicating that the apoptotic effects of 4-HPR may be mediated, at least in part, by alterations in the bcl-2/bax-regulated apoptotic pathway. N-acetylcysteine (4 mM) completely blocked the anti-proliferative and apoptotic-inducing effects of 4-HPR, suggesting that an oxidative mechanism may be involved. We concluded that (i) 4-HPR exerts growth-suppressive and apoptotic effects on LNCaP cells, (ii) 4-HPR can interact with androgen to suppress proliferation and induce apoptosis, (iii) the apoptotic effects of 4-HPR may be mediated in part by the bcl-2/bax pathway, and (iv) a pro-oxidant mechanism may contribute to the anti-proliferative and apoptotic-inducing effects of 4-HPR.

Androgens↗

PubMed2000

Phenotypic characterization of immortalized normal and primary tumor-derived human prostate epithelial cell cultures.

BACKGROUND: Cell lines can provide powerful model systems for the study of human tumorigenesis. However, the human prostate cancer cell lines studied most intensively by investigators (PC3, DU145, and LNCaP) were established from metastatic lesions, and it is unlikely that they accurately recapitulate the genetic composition or biological behavior of primary prostate tumors. Cell lines more appropriate for the study of human prostate primary tumors would be those derived from spontaneously immortalized cells; unfortunately, explanted prostate cells survive only short-term in culture, and rarely immortalize spontaneously. Therefore, we examined whether cell lines developed through viral gene-mediated immortalization of human normal or primary tumor prostate epithelium express aspects of the normal or malignant phenotypes, and could serve as appropriate models for normal or transformed human prostatic epithelium. METHODS: To accomplish these goals, we assessed the phenotypic expression of cell cultures established through the immortalization of normal (1532N, 1535N, 1542N, and PrEC-T) or malignant (1532T, 1535T, and 1542T) human prostate epithelium with the E6 and E7 genes of HPV-16, or the large T antigen gene of SV40. RESULTS: Examination of these cell lines for their proliferative rates and their abilities to grow with or without serum or androgen stimulation, to form colonies in soft agar, or to form tumors in vivo, suggests that they may serve as valid, useful tools for the elucidation of prostate tumorigenesis. Moreover, the observation of structural alterations involving chromosome 8, including gain of 8q in 3 of the 4 cell lines expressing aspects of the malignant phenotype, implies that these cell lines accurately recapitulate the genetic composition of primary prostate tumors. CONCLUSIONS: Taken together, these data suggest that cell lines generated from immortalized normal or primary tumor epithelium may be useful for the elucidation of early transforming events in the prostate.

Animals↗

PubMed1985

Androgen receptor binding activity in human prostate cancer.

Androgen binding (cytosol and nucleus) was measured in tissue obtained from 223 untreated patients with proven prostate cancer (199 primary tumor, 24 malignant lymph nodes), 19 patients with hormone refractory cancer, and 46 patients with benign prostatic hyperplasia (BPH). The mean binding in both the cytosol and nucleus was significantly higher for patients with cancer than for those with BPH. Binding appeared to correlate with tumor stage. Androgen binding in malignant nodes can differ from that in the primary tissue and can vary from node to node in the same patient. Results obtained from an assay using a single saturating concentration of R1881 correlated well with those calculated from a full six-point Scatchard analysis when an adequate amount (500 mg) of tissue was available. However, binding results obtained from a single-point analysis performed on needle biopsy specimens (about 50 mg) obtained before complete surgical removal of the prostate correlated poorly with those derived from a full six-point analysis performed on tissue (500-1000 mg) removed from the center of the malignancy. Androgen binding in nuclear extracts of histologically benign tissue adjacent to the malignancy was significantly higher than in nuclear extracts of BPH tissue. Cytosolic androgen binding in tissue removed from patients who were refractory to hormonal therapy was higher than in tissue from untreated cancer patients. The binding of estradiol by extracts of benign and malignant prostate tissue was low or absent and, thus, did not appear to be a significant phenomenon.

Androgens↗

PubMed1984

Familial external genital ambiguity due to a transformation defect of androgen-receptor complexes that is expressed with 5 alpha-dihydrotestosterone and the synthetic androgen methyltrienolone.

We have studied various properties of the binding of 5 alpha-dihydrotestosterone (DHT) or the synthetic, nonmetabolizable androgen methyltrienolone (R1881; 17 beta-hydroxy-17 alpha-methylestra-4,9,11-trien-3-one) to the androgen receptor of genital skin fibroblasts (GSF) from controls and a subject with familial, receptor-positive, partial androgen insensitivity. The mutant cells form R1881-receptor complexes that dissociate 7 times more rapidly than normal at 30 degrees C, and they do not increase their specific R1881-receptor activity in response to a 72-hr period of incubation with R1881, whereas the cells from normal individuals do so two- to three-fold. As previously reported [Pinsky et al, 1981; Kaufman et al, 1981], the mutant cells have similar abnormalities with DHT as with R1881. When the patient's cells are incubated for 120 min with varying concentrations (0.05-3 nM) of R1881 or DHT, Scatchard analysis shows that their androgen-receptor activity has an apparent equilibrium dissociation constant (Kd) for each ligand that is six-fold greater than that of normal cells (approximately 0.2 nM). Normal GSF have higher, more variable values of Kd (0.3-1.8 nM) for either ligand after 30 compared to 120 min of incubation, and the 60-min values are intermediate. This explains why we previously reported that the patient's cells had a 30-min Kd for DHT in the normal range [Pinsky et al, 1981]. Sucrose gradient centrifugation of mutant GSF cytosol incubated with DHT in the presence of 10 mM sodium molybdate yields a normal 6.5-8S peak of DHT-receptor complexes. From these data we conclude that normal GSF form initial, low-affinity androgen-receptor complexes that are transformed into one (or more) higher-affinity (? activated) states by a process that depends on time and initial concentration of androgen; the subject's GSF can form low-affinity androgen-receptor complexes but cannot generate the normal high-affinity state of the complexes, and this lack precludes augmentation of their androgen-receptor activity in response to prolonged incubation with either androgen; and failure of molybdate to stabilize the androgen-receptor activity in GSF cytosol is not a more sensitive indicator of structurally altered androgen-receptor proteins than are other qualities described heretofore.

Adolescent↗

PubMed2001

Quantitative expression profile of androgen-regulated genes in prostate cancer cells and identification of prostate-specific genes.

Quantitative expression profile of androgen-regulated genes (ARGs) was evaluated in the hormone-responsive prostate cancer cell line LNCaP by serial analysis of gene expression (SAGE). A total of 83,489 SAGE tags representing 23,448 known genes or expressed sequence tags (ESTs) and 1,655 potentially novel sequences have unraveled the transcriptome of LNCaP cells, the most common cell line used in prostate cancer research. Comparison of transcripts between control and R1881-treated LNCaP cells revealed the induction of 136 genes and repression of 215 genes in response to androgen (p < 0.05). Strikingly, a high fraction ( approximately 90%) of ARGs identified in our study has not been described as ARGs previously. A number of prostate-specific transcription factors were among the ARGs identified here. Classification of the ARGs on the basis of biochemical functions revealed that a great majority of ARGs identified in our experimental system appear to be involved in regulation of transcription, splicing, ribosomal biogenesis, mitogenesis, bioenergetics and redox processes. One of the novel aspects of androgen signaling included androgen regulation of genes involved in DNA repair/recombination process. By comparing our LNCaP-C and LNCaP-T SAGE libraries with SAGE tag libraries available at the NCBI-SAGE website, we have identified >200 potential prostate specific/abundant transcripts. The discovery of new prostate-specific genes and ARGs provides a unique opportunity to determine the role of these genes in prostate cell growth, differentiation and tumorigenesis.

Androgens↗

PubMed1988

Regulation of growth and epidermal growth factor receptor levels of LNCaP prostate tumor cells by different steroids.

The growth of LNCaP cells, derived from a lymph-node carcinoma of the human prostate, was stimulated by different hormones. Optimal growth (3- to 4-fold increase in DNA content per culture versus controls) was observed at 0.1 nM R1881 (a synthetic androgen), 1 nM progesterone or 10 nM estradiol. Triamcinolone acetonide had no effect. Dihydrotestosterone maximally stimulated cell growth at 10 nM. When the culture medium was changed 4 times in 6 days instead of twice, optimal growth was observed at 1 nM dihydrotestosterone. This indicates that a rapid metabolism of dihydrotestosterone influenced growth response. LNCaP cells contained considerable amounts of androgen receptors (920 fmol/mg cytosol protein) while progestagen, estrogen and glucocorticoid receptors were absent. The affinity of steroids for the androgen receptor decreased in the order of: R1881 (relative binding affinity: 100.0) greater than dihydrotestosterone (67.7) greater than progesterone (29.4) greater than testosterone (23.8) greater than estradiol (4.3) greater than triamcinolone acetonide (less than 0.1). Effects on cell growth of these steroids paralleled their affinity for the androgen receptor. The number of EGF receptors per cell increased in a dose-dependent manner upon treatment with various hormones. Again the amount of steroid needed for maximal effects reflected the affinity of the steroid for the androgen receptor. An approximately 2-fold increase in EGF receptor number was observed within 24 hr and before an increase in growth could be detected. Actinomycin-D and cycloheximide inhibited the hormonally induced increase in EGF receptor numbers.

ErbB Receptors↗

PubMedDate not supplied

Evidence for the presence of androgen receptors in purified rat Leydig cells.

Leydig cells, purified on two sequential Percoll gradients to purities of 89 +/- 1%, were used to study the binding of 17-beta-hydroxy-17 alpha-methyl-estra-4,9,11-triene-3-one(3H-R1881). The accumulation of 3H-R1881 in the nuclear fraction of these cells was time- and temperature-dependent. Specific binding was saturable with an apparent Ka of 0.14 nM-1 and a single class of binding sites at a concentration of 721 fmol/mg DNA. A fraction of the bound radioactivity in the nuclear pellet could be extracted with 0.4 M KCl, and a portion of this extracted steroid was associated with macromolecular species. The nuclear accumulation was androgen-specific. These data are consistent with the presence of androgen receptors in rat Leydig cells.

Animals↗

PubMedDate not supplied

Androgen receptor levels and androgen contents in the prostate lobes of intact and testosterone-treated Noble rats.

Plasma testosterone (T) levels were correlated with androgen receptors, tissue content of T, and 5 alpha-dihydrotestosterone (DHT) in the three anatomically-discrete prostate lobes of intact and castrated Noble (Nb) rats bearing T-filled silastic capsules. Differences in androgen receptor content and tissue androgen levels were observed among the three prostatic lobes of intact Nb rats. Total (cytosolic and nuclear) androgen receptor levels were highest in the ventral prostate followed by the dorsolateral and anterior prostate lobes. In the ventral and anterior prostate, androgen receptors were found to be equally distributed between cytosols and nuclear extracts, whereas in the dorsolateral prostate, androgen receptors were predominantly nuclear (cytosolic: nuclear = 1.5). The ventral prostate had the highest total androgen content and DHT was the major tissue androgen in all three lobes. The ratio of tissue DHT:T varied among the lobes; the highest value was observed in the dorsolateral prostate. The higher proportions of nuclear androgen receptor, as well as the elevated tissue DHT:T found in the dorsolateral prostate compared to other lobes, suggest that differences in the androgen activation process may exist between the dorsolateral prostate and other prostatic lobes. Despite lower plasma and tissue T levels, the DHT content, weight and cytodifferentiation in all lobes of T-treated castrated rats closely approximated the situation found in intact animals. Total androgen receptor levels were, however, elevated in all prostatic lobes of T-treated, castrated rats as compared to intact controls. These increases were primarily attributed to the augmented levels of androgen receptor in the nuclear extracts of the three prostate lobes. Exposure of the prostate to a constant level of T, produced by silastic implantation, might be responsible for the higher total androgen receptor levels and enhanced nuclear androgen receptor retention found in the prostates of T-treated, castrated rats.

Androgens↗

PubMedDate not supplied

Whole cell and nuclear androgen uptake in skin fibroblasts from infertile men.

In order to reexamine the hypothesis that a high percentage of infertile men with oligo/azoospermia have androgen resistance due to androgen receptor abnormalities, both whole cell and nuclear uptake of [3H]R1881 (a synthetic, nonmetabolizable androgen) were measured in intact, dispersed fibroblasts cultured from pubic skin biopsy specimens of 15 men selected because of infertility associated with varying degrees of oligozoospermia. Eight men had sperm densities less than or equal to 2 X 10(6)/ml; 7 were greater than 2 X 10(6)/ml. Serum levels of FSH and LH were elevated in the severely oligo/azoospermic group, but normal in the other infertile men; concentrations of testosterone, estradiol, and prolactin were normal in both groups. The controls were six normal, age-matched, fertile males. There was no difference in binding capacity or dissociation constant for androgen uptake either into whole cells (3940 +/- 940 [mean +/- SE] sites/cell vs. 4700 +/- 1120 sites/cell, P = NS) or into nuclei (1360 +/- 340 sites/cell vs. 1460 +/- 340 sites/cell, P = NS) of the fibroblasts from the patients vs. the controls, respectively. Furthermore, there was no correlation between patient sperm densities and fibroblast whole cell or nuclear uptake binding capacities. Finally, there was no difference in any androgen binding parameter when only the fibroblasts from the men with severe oligozoospermia or azoospermia were compared with the controls. The authors conclude that the infertility of men with severe testicular germ cell depletion cannot be accounted for by a quantitative androgen receptor abnormality in their pubic skin fibroblasts.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMedDate not supplied

Suppression of steroid receptor-chromatin interaction by inhibitors present in ammonium sulfate-fractionated rat testicular androgen receptor preparations.

Tritiated androgen receptor complex was partially purified by ammonium sulfate precipitation at 15 to 37% saturation from rat testicular or prostatic cytosols. A greater amount of prostatic tritiated androgen receptor complex bound to rat Sertoli cell chromatin than tritiated testicular androgen receptor complex. However, the testicular androgen receptor complex was more potent in competing for binding of either tritiated androgen receptor complex preparation to the Sertoli cell chromatin. Combining equal amounts of tritiated testicular and prostatic androgen receptor complexes resulted in lower binding than that observed with tritiated prostatic androgen receptor complex alone, while doubling the concentration of tritiated prostatic androgen receptor complex led to a 2-fold increase in binding. It is conceivable that the partially purified testicular androgen receptor complex preparations contain factor(s) that inhibit the binding interaction of tritiated androgen receptor complex with chromatin, while there is no evidence for the presence of such inhibitors in tritiated prostatic androgen receptor complex preparations. Fractionation of testicular cytosol on DEAE-cellulose yielded a flow-through fraction with inhibitory activity and a bound fraction containing tritiated androgen receptor complex that was eluted with 0.3 M KCl and also showed inhibitory activity. These factors also inhibited the binding of tritiated estradiol receptor complex to chromatin. They were non-dialyzable and their inhibitory effect was abolished after heating at 60 C for 30 minutes. It is concluded that ammonium sulfate-fractionated rat testicular androgen receptor complex preparations contain inhibitors of steroid receptor-chromatin interaction. The inhibitory factors can be fractionated into two distinct fractions by DEAE-cellulose column chromatography. They are nondialyzable and heat-labile. The precise chemical nature of the postulated inhibitor(s) remains to be determined.

Ammonium Sulfate↗