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At least 811 records · Page 45Linked to original sources
PubMed1990

A novel, nonsteroidal inhibitor of androgen binding to the rat androgen binding protein: diethyl [[[3-(2,6-dimethyl-4-pyridinyl)-4-fluorophenyl]amino]methylene] propanedioate.

In vitro binding studies demonstrate the binding specificity of a series of 4-aryl-2,6-dimethylpyridines for the rat epididymal androgen binding protein (rABP). The compounds bound competitively to rABP but have very weak or no demonstrable affinity for rat ventral prostate androgen receptor and human sex hormone binding globulin. In particular, compound 11, diethyl [[[3-(2,6-dimethyl-4-pyridinyl)-4-fluorphenyl]amino]methylene] propanedioate, bound with high affinity to rABP (binding affinity about 1/3 that of the endogenous ligand 5 alpha-dihydrotestosterone). However, additional in vitro binding studies indicated that 11 did not bind to testicular or epididymal ABP from rabbit, rhesus monkey, and human. Nevertheless, the specificity and relatively high affinity of these nonsteroidal compounds make them unique and potentially ideal agents for the study of the role of ABP in spermatogenesis and sperm maturation in the rat.

Androgen-Binding Protein↗
PubMed2002

Methoxyacetic acid disregulation of androgen receptor and androgen-binding protein expression in adult rat testis.

Chemical agents can disrupt the balance between survival and apoptosis during spermatogenesis and thus give rise to reduced counts of spermatozoa (oligospermia). One such agent that produces significant germ cell apoptosis at specific stages of the cycle of the seminiferous epithelium is methoxy acetic acid (MAA), the active metabolite of a commonly used solvent, methoxyethanol. Although MAA gives rise to apoptosis of pachytene spermatocytes, it is not known whether MAA exerts a direct effect on germ cells or whether it also affects other testicular cell types such as the Sertoli cells. In the present investigation, we tested the hypothesis that MAA has direct effects on Sertoli cells in vivo. In MAA-treated rats, stage-specific expression of androgen receptor (AR) protein in Sertoli cells was significantly altered, as determined by AR immunohistochemistry. In MAA-treated animals, high AR expression was found in Sertoli cells coincident with the MAA-induced apoptosis of late-stage pachytene spermatocytes. The altered expression of AR in MAA-treated animals was also seen in seminiferous tubules harvested by laser capture microdissection. In addition to effects on AR expression, androgen-binding protein (ABP) mRNA levels were also altered in a stage-specific manner. Using a different system for mouse Sertoli cell lines TM4 and MSC-1, positive for either AR or ABP, respectively, we found a direct effect of MAA on ABP protein and mRNA expression in the MSC-1 cell but did not detect an effect on AR protein or mRNA expression in TM4 cells. Mouse fibroblasts that express endogenous AR were stably transfected with two AR promoter/reporter systems (MMTV-CAT and probasin-luciferase, respectively). We used these fibroblasts to examine the ability of MAA to potentiate dihydrotestosterone (DHT) activation of AR. Although MAA did not activate AR directly, it did potentiate DHT activation of the AR by 2- to 4-fold. MAA altered the expression level of AR and ABP in vivo and increased AR transcriptional activity in tissue culture cells. The abnormal spermatogenesis generated by MAA is at least partly due to direct effects on Sertoli cells. It is still unclear whether MAA elicits a proapoptotic signal from Sertoli cells or diminishes a prosurvival signal required by germ cells downstream to altering AR and ABP expression in a stage-specific fashion.

Acetates↗
PubMed2004

An examination of how different mutations at arginine 855 of the androgen receptor result in different androgen insensitivity phenotypes.

Two substitutions at an identical location in the ligand-binding domain (LBD) of the human androgen receptor (AR), R855C and R855H, are associated with complete androgen insensitivity syndrome (AIS) and partial AIS, respectively. Kinetic analysis of the mutant receptors in genital skin fibroblasts and in transfected cells revealed very low total binding (Bmax) and increased rate constants of dissociation (k) for the R855C mutant; and normal Bmax and k, with slightly elevated equilibrium affinity constants (Kd), but decreased transactivational capacity for the R855H mutant. Further analysis of the R855H mutant revealed both thermolability and decreased N/C-terminal inter-actions in the presence and absence of the co-activator transcriptional intermediary factor 2. To establish the nature of these functional differences we have used molecular dynamic modeling to create four-dimensional models of each of the mutant receptors. Molecular dynamic modeling produced profoundly different models for each of the mutants: in modeling of R855C a surprisingly significant distant alteration in the position of helix 12 of the helix 12 positioning of the AR ligand binding domain (AR-LBD) occurs, which would predict severe ligand binding abnormalities and complete AIS; in modeling of R855H, no dramatic effect on the position of helix 12 was seen; thus, binding properties of the receptor are not compromised. Molecular dynamics four-dimensional modeling clearly supports the biochemical and kinetic studies of both mutants. Such novel computational modeling may lead to a better understanding of the structure-function relationships and the molecular mechanics of ligand binding not only of the AR-LBD but also of other nuclear receptors.

Adult↗
PubMed2004

Co-localization with DJ-1 is essential for the androgen receptor to exert its transcription activity that has been impaired by androgen antagonists.

DJ-1 was first identified as a novel candidate of an oncogene product in cooperation with an activated ras, and DJ-1 was later found to be a positive regulator of the androgen receptor (AR) transcription activity that was repressed by PIASxalpha. DJ-1 was also found to be an infertility-related protein that was reduced in rat sperm treated with sperm toxicants that cause infertility in rats. To determine the roles of DJ-1 in the AR function, the effects of several androgen antagonists, some of which had been identified as endocrine-disrupting chemicals, on AR transcription activity and localization of AR and DJ-1 in Cos7 cells were examined. Co-localization of DJ-1 with the AR as dot-like spots in the nucleus was first found in cells that had not been treated with chemicals. Although all of the chemicals tested inhibited AR transcription activity to an average of 25% of that without chemicals, there were two classes affecting the localization of the two proteins; one changes the AR from dot-like spots to diffuse spaces in the nucleus and the other still keeps the AR in the dot-like spots. The localization of DJ-1, on the other hand, was found to be dramatically changed by all of the chemicals, resulting in loss of co-localization with the AR. These results indicate that DJ-1 is an essential factor for the AR to exert its full activity.

Androgen Antagonists↗
PubMed2003

A novel point mutation in the hormone binding domain of the androgen receptor associated with partial and minimal androgen insensitivity syndrome.

Mutations in the coding sequence of the androgen receptor (AR) gene result in a wide range of androgen insensitivity syndromes (AIS). We report an extended family in which at least five male individuals in different generations suffer from partial AIS. The index patient presented at birth with ambiguous genitalia; the karyotype was 46,XY and subsequent sex assignment male. Elevated stimulated testosterone (T) and normal baseline gonadotropins were found. Family history revealed four additional adult males affected with various abnormalities of their external genitalia. Molecular analysis of the coding sequence of the AR gene revealed in all a novel point mutation in exon 6, changing threonine to isoleucine at codon position 800 in the hormone-binding domain. We conclude that phenotypic variations in mild AR defects are striking and can remain undetected even until late in life.

Adult↗
PubMed1998

[Trinucleotide repeats polymorphism of the androgenic receptor gene in the detection of carriers of androgen insensitivity syndrome].

Androgen insensitivity syndrome (AIS) is caused by mutation in androgen receptor (AR) gene. This phenomenon leads to the defect of the virilization of the external genitalia and is one of the causes of human male pseudohermaphroditism. Molecular diagnosis of AR gene mutations is very complex because of heterogeneity of AR mutations. AIS is X-linked recessive trait and therefore the simple diagnosis of AIS carriers is a very important problem. Detection of AIS carriers by using the analysis of CAG repeating sequence polymorphism of exon 1 or AR gene is reported.

Adult↗
PubMed1982

The influence of androgens, anti-androgens, and castration on cell proliferation in the jejunal and colonic crypt epithelia, and in dimethylhydrazine-induced adenocarcinoma of rat colon.

Androgenic hormones have previously been shown to promote cell proliferation in the small intestine of rat and androgen receptors have been demonstrated in carcinomata of the large intestine of rat. In this study the influence of testosterone and of castration on epithelial cell proliferation in the small intestine, the large intestine and in dimethylhydrazine-induced colonic tumours is compared. Cell proliferation in the small intestine and in colonic tumours was accelerated by testosterone treatment, and cell proliferation in colonic tumours, but not in the small intestine, was retarded following castration. Cell proliferation in colonic tumours was also inhibited by the anti-androgenic drug, Flutamide. Testosterone and castration each failed to influence cell proliferation in the colonic crypt epithelium of both normal and carcinogen-treated animals.

Adenocarcinoma↗
PubMed1983

Influence of androgen on the development of sexual behavior in the rat. II. Time and dosage of androgen administration during the neonatal period and masculine and feminine copulatory behavior in females.

The objective of the present study was to delineate the period of sensitivity to a single androgen exposure during the initial neonatal hours on the development of masculine and feminine copulatory behavior in female rats. Female rats were injected once with either 500, 50, or 5 micrograms testosterone propionate (TP) at either 1 or 24 hr after birth. Following castration in adulthood and TP replacement, the females were tested four times at weekly intervals in prolonged sessions for masculine copulatory behavior. One month following the masculine copulatory tests the females were tested for 3 weeks for feminine copulatory behavior with weekly increasing levels of estradiol benzoate (2.5, 10, and 25 micrograms) and progesterone (200 micrograms). The results demonstrate that a single injection of TP administered at either 1 or 24 hr after birth can significantly increase the capacity of female rats to exhibit ejaculation patterns and that the amount of androgen that is administered is critical in determining the levels of ejaculatory responding. Similarly, the females given high doses (50 and 500 micrograms) of TP at either 1 or 24 hr neonatally were almost completely defeminized. In contrast, however, the females treated with 5 micrograms TP at 1 and 24 hr showed different levels of lordotic performance indicating a greater sensitivity to androgen immediately after birth than at 24 hr in female rats as has been shown in male rats.

Age Factors↗
PubMed1991

Non-classical androgenic actions of RU38486 in androgen-responsive Shionogi carcinoma 115 cells in serum-free culture.

Antiglucocorticoid and antiprogestin RU38486 (RU486) stimulated the growth of highly androgen- and moderately glucocorticoid-sensitive SC-3 cells (a cloned cell line from Shionogi mouse mammary carcinoma 115) in a dose-dependent manner. A maximal 8-fold stimulation of growth by RU486 has been observed at 10(-7) M in a serum-free medium and its potency has been found to be almost the same as that of dexamethasone (Dex). The growth rate of SC-3 cells treated by triamcinolone acetonide (TA) or Dex combined with RU486 at 10(-9)-10(-7) M was enhanced compared to cells treated by TA or Dex alone, indicating that RU486 had additive rather than antagonistic effects. Our previous study revealed that RU486 could compete with the specific uptake of [3H]testosterone in intact SC-3 cells at relatively low affinity and the present study showed that the stimulatory effect of RU486 on the growth of SC-3 cells was significantly inhibited by pure antiandrogen flutamine and that half-maximal inhibition by flutamine was achieved at 10(-6) M. Moreover, we demonstrated that the conditioned medium from RU486-stimulated SC-3 cells contained growth-promoting activity which caused a 3.5-fold increase in DNA synthesis by SC-3 cells in the absence of RU486 and which was abolished by treatment with heparin-Sepharose. These results indicate that RU486-induced growth of SC-3 cells may be expressed as an androgenic activity through androgen receptor and mediated by a heparin-binding growth factor.

Animals↗
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↗
PubMed2005

Stimulating effects of androgen on proliferation of cultured ovarian germ cells through androgenic and estrogenic actions in embryonic chickens.

The effect of androgen on germ cell proliferation was evaluated by a chicken ovarian germ-somatic cell co-culture model and the mechanisms were explored. Ovarian cells were dispersed from 18-day-old embryos, cultured in serum-free McCoy's 5A medium and challenged with testosterone (T) alone or in combinations with androgen receptor antagonist Flutamide, estrogen receptor antagonist Tamoxifen or aromatase inhibitor Letrozole for 48 h. Germ cells were identified by c-kit immunocytochemistry. The number of germ cells was counted and the proliferating cells were identified by immunocytochemistry of proliferating cell nuclear antigen (PCNA). The labeling index (LI) was determined for germ cells. Results showed that T (10(-7) to 10(-6)M) significantly increased the number of germ cells (P<0.05) and this stimulating effect was inhibited by Flutamide (10-1000 ng/ml), Tamoxifen (10-1000 ng/ml) or Letrozole (10(-9) to 10(-7)M) in a dose-dependent manner. Furthermore, PCNA-LI of germ cells displayed similar changes with the numbers of germ cells. These results indicated that T-stimulated proliferation of cultured ovarian germ cells through both, androgenic and estrogenic actions in embryonic chickens.

Animals↗
PubMed1997

The kidney androgen-regulated protein promoter confers renal proximal tubule cell-specific and highly androgen-responsive expression on the human angiotensinogen gene in transgenic mice.

Transgenic mice were generated containing a 1542-base pair fragment of the kidney androgen-regulated protein (KAP) promoter fused to the human angiotensinogen (HAGT) gene with the goal of specifically targeting inducible expression of renin-angiotensin system components to the kidney. High level expression of both KAP-HAGT and endogenous KAP mRNA was evident in the kidney of male mice from two independent transgenic lines. Renal expression of the transgene in female mice was undetectable under basal conditions but could be strongly induced by administration of testosterone. Testosterone treatment did not cause a transcriptional induction in any other tissues examined. However, an analysis of six androgen target tissues in males revealed that the transgene was expressed in epididymis. No other extra-renal expression of the transgene was detected. In situ hybridization demonstrated that expression of HAGT (and KAP) mRNA in males and testosterone-treated females was restricted to proximal tubule epithelial cells in the renal cortex. Although there was no detectable human angiotensinogen protein in plasma, it was evident in the urine, consistent with a pathway of synthesis in proximal tubule cells and release into the tubular lumen. These results demonstrate that 1542 base pairs of the KAP promoter is sufficient to drive expression of a heterologous reporter gene in a tissue-specific, cell-specific, and androgen-regulated fashion in transgenic mice.

Angiotensinogen↗
PubMed1995

Survival and quality of life of patients with stage D1 (T1-3 pN1-2 M0) prostate cancer. Radical prostatectomy plus androgen deprivation versus androgen deprivation alone.

A series of 139 patients with histologically proven stage D1 (T1-3 pN1-2 M0) prostate cancer was reviewed in order to determine the influence of radical surgery in addition to hormonal treatment on long-term outcome with respect to survival and quality of life. In all 139 patients a pelvic lymphadenectomy was performed. In 87 patients, lymphadenectomy was followed by androgen deprivation alone (group 1). Fifty-two patients underwent additional radical prostatectomy (group 2). The actuarial 10-year nonprogression rates were 14.6% in group 1 and 35.8% in group 2, respectively (p = 0.0016). The overall and disease-specific 10-year survival rates were found to be 29.7 and 32.1%, respectively, for group 1 and 50.8 and 70.7%, respectively, for group 2. Local progression as the main parameter influencing quality of life occurred in 60 of the 87 patients (69%) not subjected to radical prostatectomy. Transurethral resection of the prostate was required in 29 of these patients. In contrast, following radical prostatectomy, only 4 of the 52 patients (8%) had local progression and only 1 patient (2%) needed a dilatation of the vesicourethral anastomosis for relief of infravesical obstruction. Thus, radical prostatectomy plus androgen deprivation for patients with stage D1 prostate cancer appeared to be superior to androgen deprivation alone with respect to survival expectancy and quality of life. Prospective randomized trials, however, have to be undertaken to verify these results.

Biopsy↗
PubMed1989

Androgens affect the processing of secretory protein precursors in the guinea pig seminal vesicle. I. Evidence for androgen-regulated proteolytic processing.

The guinea pig seminal vesicle epithelium synthesizes and secretes four major secretory proteins (SVP-1-4). Previous work has established that these four proteins are cleaved from two primary translation products in a complex series of protein processing reactions. The present studies suggest that these protein processing reactions are regulated by androgens. In vitro labeling of seminal vesicle proteins revealed significant differences in the patterns of secretory protein intermediates produced by tissue from intact and castrated animals. Seminal vesicle tissue explants from castrated animals secreted a subset of the processing intermediates secreted by tissue from intact animals. The changes in the patterns of secretory protein intermediates became more pronounced with increasing time after castration, and were fully reversible by treatment of castrated animals with testosterone, suggesting that androgens were affecting the processing or secretion of secretory protein precursors. Amino-terminal protein sequencing of secretory protein processing intermediates that accumulate in the seminal vesicle lumen after castration suggests that the guinea pig seminal vesicle contains an androgen-regulated proteolytic processing activity.

Animals↗
PubMed2001

[Androgenic alopecia revealing an androgen secreting ovarian tumor].

INTRODUCTION: Androgen-producing tumors of the ovary are rare in postmenopausal women and are revealed by severe virilization. Leydig hilus cell tumors are the most frequent postmenopausal virilizing tumors. In this report, an unusual and rare cause of alopecia due to Leydig cell hyperplasia within the wall of a simple cyst and in the ovarian hilus is described. OBSERVATION: An 80 year-old woman complained of a 10-year history of severe androgenic alopecia associated with very mild facial hirsutism, without others signs of virilization. Hormonal blood levels showed markedly elevated testosterone. Computed tomographic scan of the adrenals and the ovaries revealed an enormous left ovarian cystic mass. Bilateral hystero-ophorectomy was performed. Histological examination demonstrated bilateral Leydig cell hyperplasia within the wall of the cyst and in the right ovarian hilus. Two months postoperative hormonal evaluation demonstrated dramatically decreased plasma levels of testosterone. COMMENTARY: The clinical, X ray and histologic aspects of this case, although rare, show that the presence of virilization should lead to a search for an androgen-secreting ovarian or adrenal tumor.

Aged↗
PubMed1998

Expression of Fusion Protein Containing Androgen Receptor Segment and Preparation of Polyclonal Antibodies to Androgen Receptor.

The cDNA segment (1105-2224) of the androgen receptor was cloned into the pGEX-3X expression vector and expressed in E. coli. The soluble fusion proteins GST-AR were used to immunize rabbits to obtain polyclonal antibodies to androgen receptors. The antibodies were purified by GST-Sepharose 4B and indicated the specificity to androgen receptors. The purified antibodies can be used in study the function of AR.

Journal Article↗
PubMedDate not supplied

Enhancement by androgen of the angiogenic ability of androgen-responsive Shionogi carcinoma 115.

The effects of various steroids on the induction of angiogenesis by androgen-responsive Shionogi carcinoma 115 (SC115) were investigated by implanting a piece of a SC115 tumor tissue into a rabbit cornea together with a pellet containing each steroid (250 micrograms) and by examining neovascularization from the limbus. SC115 tumor tissues induced neovascularization in 42% corneas in the absence of steroids, and in 31, 63, 80 and 4% in the presence of estradiol-17 beta, progesterone, testosterone and dexamethasone, respectively. Only testosterone significantly increased the percentage of corneas with neovascularization, while dexamethasone significantly decreased it. Testosterone itself induced no neovascularization, and dexamethasone also inhibited neovascularization induced by acidic fibroblast growth factor. The present results suggest that androgen increases the secretion of an angiogenic factor(s) by an androgen-responsive SC115 tumor, while dexamethasone inhibits angiogenesis induced by the angiogenic factor(s).

Animals↗
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↗