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PubMed1991

[Androgen receptor gene polymorphism analysis: application to screening of heterozygote and to prenatal diagnosis of androgen insensitivity syndrome].

Androgen insensitivity syndromes are X-linked disorders. Restriction fragment length polymorphism analysis of the androgen receptor gene showed that deletions were infrequent. Some mutations have been described. In these conditions, in high-risk family, carrier diagnosis is impossible unless identification of mutations is made. It is thus necessary to detect androgen receptor gene polymorphism in order to differentiate the two maternal X chromosomes. Two androgen receptor gene polymorphisms have been reported (Hind III and exon 1). In this study we analyzed these two gene polymorphisms to detect carriers in at-risk families. The combined results of the two analyses allowed us to detect carriers in 45% of the studied families. In two families the prenatal diagnosis of androgen insensitivity syndrome was performed.

Deoxyribonuclease HindIII↗

PubMed1990

Lipoprotein lipids in women with androgen excess: independent associations with increased insulin and androgen.

Concentrations of triglycerides are increased and concentrations of high-density lipoprotein (HDL) cholesterol are low in women with hyperandrogenism. These alterations could be related to excessive androgen or estrogen, to hyperinsulinism, or to a combination of these abnormalities. We examined their independent influences on lipids in 21 women with hyperandrogenism, subgrouped according to apparent source of androgen excess. Results for lipid, androgen, and insulin did not differ among subgroups, so these data were pooled. Free plus albumin-bound testosterone (uT) was correlated with triglycerides (r = 0.69, P less than 0.01) and HDL cholesterol (r = -0.56, P less than 0.01). Both triglycerides (r = 0.66, P less than 0.01) and HDL cholesterol (r = -0.48, P less than 0.05) were also correlated with insulin measured during fasting. Partial correlation revealed that, after adjusting for insulin, lipids were associated with uT. This suggests that androgen excess is independently related to lipid excess. Insulin also was correlated with lipids when adjusted for uT. Free plus albumin-bound estradiol was not associated with any of the lipids. We conclude that altered lipids in women with hyperandrogenism result from the independent effects of androgen and insulin.

Adult↗

PubMed1998

Apoptosis and other mechanisms in androgen ablation treatment and androgen independent progression of prostate cancer: a review.

Patients with advanced prostate cancer commonly present with disseminated disease. For these patients, androgen ablation is a first-line treatment. This mode of therapy usually has an initially palliative effect on tumor-related symptoms and slows growth, although virtually all tumors eventually relapse to an androgen-independent, more aggressively growing phenotype. However, surprisingly little is known about the actions mediating the initial palliative effect as well as the initiation of androgen-independent tumor growth. In this review, some current concepts on mechanisms of androgen ablation treatment and androgen-independent progression of prostate cancer is highlighted. Special attention is given to the involvement of apoptosis in these processes.

Androgen Antagonists↗

PubMed2003

Extreme androgen resistance in a kindred with a novel insertion/deletion mutation in exon 5 of the androgen receptor gene.

Androgen insensitivy syndrome (AIS) is the most frequent cause of male pseudohermaphroditism resulting from target-organ resistance to androgen action. Individuals bearing the complete form of the disease (CAIS) present a female phenotype and a lack of pubic and axillary hair. In the present study, four 46,XY patients born in two generations from a kindred with a history of AIS were examined for genetic abnormalities in the androgen receptor gene (AR). All eight exons encoding the AR protein were individually amplified from genomic DNA followed by a mutation screening with single-strand conformation polymorphism analysis. Sequencing of the mutant AR revealed a novel insertion/deletion mutation in exon 5. A deletion of 7 bp is replaced by an insertion of 11 nucleotides, which represents a duplication of the adjacent downstream sequence. The mutation g.2640_2646delAGGATGC/2652_2662insTTCGCCCCTGA, results in a frameshift that introduces a premature termination signal TGA, nine codons downstream. Such a rearrangement predicts a truncation of the AR, thereby deleting a large portion of the ligand-binding domain (amino acid position 768-919). Furthermore, although this mutation breaks the translational reading frame starting from codon 760, examination of the complementary DNA suggested that it does not disturb mRNA splicing. These changes have been found in all the patients and appear to account for the observed absence of detectable androgen binding to the AR in cultured fibroblasts and for the CAIS phenotype in the kindred. This disorder represents the first insertion/deletion mutation of the AR that probably arose by a slipped-strand mispairing mechanism.

Adult↗

PubMed1998

Partial androgen insensitivity and correlations with the predicted three dimensional structure of the androgen receptor ligand-binding domain.

Genetic defects of the human androgen receptor (AR) can cause a wide spectrum of androgen insensitivity syndromes (AIS) ranging from phenotypic females in those with complete AIS; ambiguous genitalia in partial AIS; to male infertility in minimal AIS. The majority of these defects are due to point mutations resulting in amino acid substitutions. It is however unclear why certain mutations result in partial AIS, whereas others in the same exon cause the complete syndrome. We present a case of partial AIS due to a point mutation affecting codon 758 of the AR ligand-binding domain (LBD) that changed the sense of the codon from asparagine to threonine (N758T). The mutant receptor displayed normal binding affinity to DHT but abnormal dissociation kinetics in both patient's fibroblasts and transfected COS-7 cells. The mutant AR was thermolabile, and resulted in approximately 50% reduction in receptor transactivation capacity when examined with a reporter gene incorporating an androgen-response-element. Although the 3-D structure of AR LBD is not known, the homologous region in a member of the steroid receptor superfamily, retinoid-X receptor (RXR-alpha), has been crystallized, allowing comparison of aligned amino-acid sequences of RXR-alpha and AR. The mutation, N758T, lies in a predicted linker region between the fifth alpha-helix (H5) and the first beta-strand (S1). Generally, mutations leading to partial AIS tend to cluster in the predicted linker regions located between the structural helices of the AR LBD. Most strikingly, the predicted linker regions contain over 70% of the mutant ARs associated with prostate cancer in the LBD. The occurrence of mutations associated with both partial AIS and prostate cancer in the same predicted linker regions, suggest that this clustering is not coincidental and that the predicted linker regions are likely to have important, but subtle, roles in defining androgen binding and ligand specificity.

Adult↗

PubMed1997

Interaction of androgen receptors with androgen response element in intact cells. Roles of amino- and carboxyl-terminal regions and the ligand.

Promoter interference assay was employed to examine in intact cells the roles of the functional domains of androgen receptor (AR) and the ligand for specific DNA interactions using a cytomegalovirus-(androgen response element)-chloramphenicol acetyltransferase reporter (pCMV-ARE2-CAT). Native rat and human ARs interfered with pCMV-ARE2-CAT expression in a hormone-dependent fashion. Low steroid-independent interference seemed to occur because of the ligand binding domain (LBD), which was transcriptionally inhibitory also in a heterologous context. AR devoid of LBD (rARDelta641-902) decreased pCMV-ARE2-CAT activity by 50%. The rARDelta46-408 mutant devoid of the NH2-terminal transcription activation region exhibited ligand-dependent promoter interference of a similar magnitude. Ligand and DNA binding-deficient mutants (hARM807R and rARC562G, respectively) did not influence pCMV-ARE2-CAT expression, although hARM807R binds to ARE in vitro. Non-steroidal anti-androgens casodex and hydroxyflutamide antagonized agonist-dependent promoter interference, whereas cyproterone acetate, RU 56187, RU 57073, and RU 59063 were partial agonists/antagonists. Collectively, interaction of ARs with ARE in intact cells does not require the presence of the COOH-terminal or NH2-terminal domain and/or their interaction. In the context of native AR, however, the androgen-induced conformational change in LBD is mandatory for generation of a transcriptionally competent receptor that binds to DNA in intact cells.

Androgen Antagonists↗

PubMed2003

Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1/2 pluripotent cells through an androgen receptor-mediated pathway.

Testosterone supplementation increases skeletal muscle mass and decreases fat mass; however, the underlying mechanisms are unknown. We hypothesized that testosterone regulates body composition by promoting the commitment of mesenchymal pluripotent cells into myogenic lineage and inhibiting their differentiation into adipogenic lineage. Mouse C3H 10T1/2 pluripotent cells were treated with testosterone (0-300 nM) or dihydrotestosterone (DHT, 0-30 nM) for 0-14 d, and myogenic conversion was evaluated by immunocytochemical staining for early (MyoD) and late (myosin heavy chain II; MHC) myogenic markers and by measurements of MyoD and MHC mRNA and protein. Adipogenic differentiation was assessed by adipocyte counting and by measurements of peroxisomal proliferator-activated receptor gamma 2 (PPAR gamma 2) mRNA and PPAR gamma 2 protein and CCAAT/enhancer binding protein alpha. The number of MyoD+ myogenic cells and MHC+ myotubes and MyoD and MHC mRNA and protein levels increased dose dependently in response to testosterone and DHT treatment. Both testosterone and DHT decreased the number of adipocytes and down-regulated the expression of PPAR gamma 2 mRNA and PPAR gamma 2 protein and CCAAT/enhancer binding protein alpha. Androgen receptor mRNA and protein levels were low at baseline but increased after testosterone or DHT treatment. The effects of testosterone and DHT on myogenesis and adipogenesis were blocked by bicalutamide. Therefore, testosterone and DHT regulate lineage determination in mesenchymal pluripotent cells by promoting their commitment to the myogenic lineage and inhibiting their differentiation into the adipogenic lineage through an androgen receptor-mediated pathway. The observation that differentiation of pluripotent cells is androgen dependent provides a unifying explanation for the reciprocal effects of androgens on muscle and fat mass in men.

Adipocytes↗

PubMed2002

Pathophysiology of androgen insensitivity syndromes: molecular and structural approaches of natural and engineered androgen receptor mutations at amino acid 743.

To decipher the clues of genotype-phenotype mapping in androgen insensitivity syndromes (AIS), we integrated clinical, molecular, and structural data in an investigation into the characteristics of androgen receptor (AR) ligand binding and activation. We looked for residues substituted in AIS that are conserved among the different AR species but that diverge in the other steroid receptors, thus suggesting a role in androgen binding specificity. Of the residues fitting these characteristics, we focused on the glycine at position 743, for which natural substitutions (glutamic acid and valine) have been associated with different androgen resistance phenotypes. The consequences of both substitutions were evaluated along with the minimal glycine to alanine mutation. The gradual impairment of binding and trans-activation efficiencies in AR mutants ranging from alanine to valine and subsequently glutamic acid were highlighted by in vitro experiments. Structural analyses showed the consequences of these substitutions at the atomic level and suggested a difference in local organization among the nuclear receptor superfamily. Overall, this integrative approach provides a useful tool for further investigations into the AR structure-function relationship in AIS.

Amino Acid Sequence↗

PubMed1980

Changes in the cytoplasmic androgen receptor of rat ventral prostate after administration of androgens, antiandrogens and anabolic steroids.

The effect of the administration of androgens (testosterone and dihydrotestosterone(, antiandrogens (progesterone and cyproterone acetate) and anabolic steroids (Bolandiol, Nandrolone, Furazabol and Methenolone) on depletion and replenishment of the androgen receptor in the cytosol of ventral prostate from castrated rats was examined using 3H-R1881 as the ligand. Administration of androgens lead to a rapid fall in the level of the receptor and the receptor in the cytosol was replenished in the period following treatment. Length of the period of receptor depletion was dependent on the dose of androgen administered. Administration of antiandrogens did not cause any depletion of the receptor and concomitant administration of testosterone induced a pattern similar to that of the depletion observed following administration of testosterone alone. Effect of pretreatment of animals with ethidium bromide, an intercalating dye which has been shown to prevent the in vitro nuclear binding of steroid hormone-receptor complexes, on the depletion of receptor induced by testosterone administration was also insignificant. Anabolic steroids depleted the receptor but the degree of depletion was relatively low. The rate of inhibition of in vitro 3H-R1881 binding by these anabolic steroids was not correlated to the rate of in vivo depletion of the receptor. The significance of these observations is discussed.

Anabolic Agents↗

PubMed2002

Nerve growth factor induces the re-expression of functional androgen receptors and p75(NGFR) in the androgen-insensitive prostate cancer cell line DU145.

BACKGROUND: One of the paracrine/autocrine factors regulating prostate growth and differentiation is nerve growth factor (NGF). The role of NGF and its receptors in the prostate, however, remains controversial. We have shown that NGF treatment of human prostate cancer cell lines reduced their tumorigenicity, both in vitro and in vivo. OBJECTIVE: To investigate the involvement of NGF as a differentiation factor in prostate cancer cells. DESIGN: We exposed the androgen-independent/androgen receptor (AR)-negative prostate cancer cell line DU145 to NGF to study whether this neurotrophin could revert DU145 cells to a less malignant phenotype. METHODS: DU145 cells were treated with NGF, then ARs and NGF receptor p75(NGFR) expression and telomerase activity were studied. Finally, we investigated whether re-expression of ARs could restore the androgen sensitivity in this cell line. RESULTS AND CONCLUSIONS: NGF treatment induced a reversion of DU145 cells to a less malignant phenotype, characterized by the re-expression of ARs and p75(NGFR) NGF receptors. Re-expression of ARs restored the androgen sensitivity, as suggested by the fact that exposure to dihydrotestosterone stimulated the growth of NGF-treated DU145 cells. This effect was blocked by androgen antagonist drugs, such as hydroxyflutamide and cyproterone acetate, which also induced apoptotic death of NGF-treated cells. The hypothesis that a differentiation pathway is activated by exogenous NGF in DU145 cells is also supported by findings indicating that NGF-treated DU145 cells expressed a low telomerase activity, as a result of a decrease in human telomerase reverse transcriptase transcription.

Androgen Antagonists↗

PubMed1992

An androgen-dependent subclone derived from a mouse mammary tumor, Shionogi carcinoma 115, secretes a heparin-binding growth factor having an apparent molecular weight of 31,000 in response to androgen.

An androgen-dependent cell line denoted SC2G is a clone of an androgen-dependent mouse mammary tumor, Shionogi Carcinoma 115. Fibroblast growth factors (FGFs), epidermal growth factor (EGF) and transforming growth factor-alpha (TGF alpha) are stimulatory for the growth of SC2G cells in the absence of androgen. This clone was found to secrete an androgen-induced growth factor mostly eluting at 1.8 M NaCl on a heparin-Sepharose column. This factor was partially purified by chromatography on two consecutive heparin-Sepharose columns followed by cation-exchanging chromatography on an S-Sepharose column from the chemically defined serum-free medium conditioned by SC2G cells in the presence of androgen. The factor was a heat- and acid-labile cationic protein that was inactivated by reduction with dithiothreitol. On sodium dodecyl sulfate polyacrylamide gel electrophoresis, most of the growth-promoting activity of this factor was found at approx. 31 kDa under non-reduced conditions. Neither neutralizing antibody against basic-FGF nor that against EGF inhibited the growth-promoting activity of this factor in cell culture, suggesting the factor was distinct from basic FGF or EGF. However, the possibility that the factor was another FGF- or EGF-like growth factor was not excluded.

Animals↗

PubMed1998

Epidermal growth factor receptor activation in androgen-independent but not androgen-stimulated growth of human prostatic carcinoma cells.

These studies were undertaken to assess the relative expression and autocrine activation of the epidermal growth factor receptor (EGFR) in normal and transformed prostatic epithelial cells and to determine whether EGFR activation plays a functional role in androgen-stimulated growth of prostate cancer cells in vitro. EGFR expression was determined by Western blot analysis and ELISA immunoassays. Immunoprecipitation of radiophosphorylated EGFR and evaluation of tyrosine phosphorylation was used to assess EGFR activation. The human androgen-independent prostate cancer cell lines PC3 and DU145 exhibited higher levels of EGFR expression and autocrine phosphorylation than normal human prostatic epithelial cells or the human androgen-responsive prostate cancer cell line LNCaP. PC3 and DU145 cells also showed higher levels of autonomous growth under serum-free defined conditions. Normal prostatic epithelial cells expressed EGFR but did not exhibit detectable levels of EGFR phosphorylation when cultured in the absence of exogenous EGF. Addition of EGF stimulated EGFR phosphorylation and induced proliferation of normal cells. LNCaP cells exhibited autocrine phosphorylation of EGFR but did not undergo significant proliferation when cultured in the absence of exogenous growth factors. A biphasic growth curve was observed when LNCaP cells were cultured with dihydrotestosterone (DHT). Maximum proliferation occurred at 1 nM DHT with regression of the growth response at DHT concentrations greater than 1 nM. However, neither EGFR expression nor phosphorylation was altered in LNCaP cells after androgen stimulation. In addition, DHT-stimulated growth of LNCaP cells was not inhibited by anti-EGFR. These studies show that autocrine activation of EGFR is a common feature of prostatic carcinoma cells in contrast to normal epithelial cells. However, EGFR activation does not appear to play a functional role in androgen-stimulated growth of LNCaP cells in vitro.

Adult↗

PubMed1991

Biological effects of sex hormone-binding globulin on androgen-induced proliferation and androgen metabolism in LNCaP prostate cells.

The effects of purified human sex hormone-binding globulin (SHBG) on androgen-sensitive cell proliferation were examined using a human prostatic cell line (LNCaP-FGC). Cells were grown for 5 days in medium supplemented with 10% charcoal-dextran-stripped human serum (10% CDHuS) and various concentrations of 5 alpha-dihydrotestosterone (DHT). In 10% CDHuS, without SHBG, the proliferative response of these cells to androgens was typically biphasic. At low androgen concentrations, cell yields were increased in a dose-dependent manner, reaching maximal levels at 0.3 nM DHT. However, at high androgen concentrations, cell proliferation was inhibited. Addition of purified human SHBG to the medium reduced the effectiveness of DHT on both phases of the proliferative response in a dose-dependent manner. These effects of SHBG appeared to be due primarily to the high affinity binding of DHT by SHBG. Proliferative responses induced by the synthetic androgen methyltrienolone (R1881), which binds poorly to SHBG, were not affected by added SHBG. Furthermore, analysis of the protein binding of DHT revealed that cell proliferation correlated best with the concentration of DHT not bound to SHBG. The presence of SHBG in the medium also altered the uptake and metabolism of DHT. LNCaP-FGC cells rapidly metabolized DHT to a polar glucuronidase-sensitive conjugate of DHT. In 10% CDHuS, LNCaP-FGC cells conjugated virtually all of the added DHT during the 5-day experiment. However, in medium containing SHBG, the SHBG-bound DHT remained unconjugated; more than 90% of the DHT initially bound to SHBG was present in the medium at the end of the experiment as unconjugated DHT. Uptake of radiolabeled DHT by cells was also inhibited by SHBG. In summary, these experiments provide evidence that 1) SHBG-bound DHT is not a signal for DHT-induced cell proliferation and 2) SHBG inhibits the uptake and metabolism of DHT by LNCaP-FGC cells.

Cell Division↗

PubMed1978

Age difference in the response to synthetic luteinizing hormone-releasing hormone (LHRH) in androgenized rats with special reference to the dose of testosterone propionate for androgenization.

Five-day-old female rats were androgenized with 1,000 or 100 microgram testosterone propionate and were examined regarding the response to LHRH at 4, 7 and 12 weeks of age by measuring peripheral LH concentrations. The order of magnitude in LH release was 7 greater than 4 greater than 12 weeks old, whereas in normal rats, 4 greater than 12 greater than 7 weeks old. LH release in 4- and 7-week-old rats was higher than that in normal controls at the respective age, but was much lower than that in normal controls 12 weeks old. The LH release by Des-Gly10-(D-Ala6)-LHRH-ethylamide (TAP127) was greater than that by natural LHRH both in normal and androgenized rats at 7 or 12 weeks old. The results indicate that the pituitary gland in androgenized rats responds to LHRH to a much larger extent during the premature period and its responsiveness declines during the course of maturation. A marked hypersensitivity was observed in 7-week-old rats androgenized with 100 microgram testosterone propionate. The process of androgenization may include the induction of alterations in the sensitivity of the pituitary to LHRH and probably in the LH synthesizing ability of the pituitary.

Aging↗

PubMed1975

The physicochemical properties of the cytoplasmic androgen receptor in the kidneys of normal, carrier female (tfm/+) and androgen-insensitive (tfm/y) mice.

The physicochemical properties of the androgen-receptor complex in mouse kidney were determined. The sedimentation coefficient, 7.9S and Stokes radius of 82A, are compatible with an asymmetric protein [frictional ratio f/fo 1.98; axial ratio, assuming a prolate ellipsoid, 20] having a molecular weight of 270,000 daltons. The kidney receptor is a relatively acidic protein of esoelectric point (pI) 4.8 and readily precipitable with protamine sulfate or ammonium sulfate. Studies with protein-specific reagents suggest that both cysteine and tryptophan residues may be necessary for maintaining the functional configuration associated with androgen binding. The kidney receptor can promote the association of testosterone with purified DNA. These properties of the androgen receptor in mouse kidney are remarkably similar to those of male accessory sexual tissue. The receptor detected in carrier female mice (tfm/+ heterozygous for the gene for testicular feminization (tfm), has the same physical properties as that of normal mice. However, due to a decrease in receptor concentration, binding activity is only 69% that of normal. In cytosol from androgen-insensitive mice (tfm/+), a specific androgen receptor cannot be demonstrated by 5 different techniques.

Animals↗

PubMed1988

Mechanism of induction of mouse kidney alcohol dehydrogenase by androgen. Androgen-induced stimulation of transcription of the Adh-1 gene.

The three alcohol dehydrogenase genes in the mouse are subject to developmental, hormonal, and genetic control as revealed by variation in expression among inbred strains. The primary purpose of this study was to determine the mechanism by which androgen regulates the expression of the Adh-1 gene in kidney. In addition, the fold-induction in several inbred strains was examined in a search for possible genetic variation in the induction process, and Adh-1 expression in several tissues was studied. Testosterone treatment of female mice results in a 10-12-fold increase in alcohol dehydrogenase activity and a corresponding increase in the rate of enzyme synthesis accounts for this induction. The induction of Adh-1 mRNA after androgen treatment is sufficient to account for the induction in enzyme synthesis. An increase in Adh-1 transcription accounts for a substantial part of the increase in Adh-1 mRNA level following androgen simulation. This conclusion was reached using nuclear "run-on" assays, in vivo labeling, and a kinetic analysis of Adh-1 mRNA accumulation and loss in response to hormone. This induction requires androgen receptor. The fold induction by androgen of Adh-1 mRNA is similar in eight inbred mouse strains. There is almost a 100-fold variation in Adh-1 mRNA concentrations among various mouse tissues. Tissues with lowest level of expression are brain and heart, while liver and adrenals have the highest content of Adh-1 mRNA.

Alcohol Dehydrogenase↗

PubMed1997

Effects of Ca++ mobilization on expression of androgen-regulated genes: interference with androgen receptor-mediated transactivation by AP-I proteins.

BACKGROUND: The adult prostate is maintained through an equilibrium between cell growth and death rates. Androgen deprivation induces an increase in intracellular Ca++, AP-1 gene expression of androgen-inducible genes. METHODS: Northern blot analysis, band-shift assays, and transient cotransfection assays were used to study the effects of Ca++ mobilizer A23187 on gene expression in human prostate cancer cells. RESULTS: A23187 repressed androgen-upregulated mRNAs for prostate-specific antigen (PSA) and hKLK2, and rapidly induced mRNA levels for c-fos and c-jun. AP-1 protein-DNA binding activities were elevated after A23187 treatments. Androgen receptor (AR)-mediated induction of chloramphenicol acetyltransferase (CAT) reporter was repressed by AP-1 proteins. CONCLUSIONS: The repression of AR-mediated induction of PSA and hKLK2 genes by Ca++ mobilizers is due to the interference of AR transactivation activity by AP-1 proteins.

Androgens↗

PubMed2006

Play fighting in androgen-insensitive tfm rats: evidence that androgen receptors are necessary for the development of adult playful attack and defense.

The frequency of playful attack and the style of playful defense, are modifiable by gonadal steroids and change after puberty in male and female rats. The present study examined the play behavior exhibited by testicular feminized mutation (tfm)-affected males, who are insensitive to androgens but can bind estrogens aromatized from androgens, to determine the relative contributions of androgens and estrogens to the age-related changes in play behavior. tfm males did not exhibit a decrease in playful attack with age and were more likely to maintain the use of complete rotations, a juvenile form of playful defense, into adulthood. tfm males did however, show age related changes in the use of partial rotations and upright postures, two other forms of playful defense, that were similar to normal males. These data suggest that the development of play fighting and defense in males is dependent on both androgen- and estrogen-receptor-mediated effects.

Age Factors↗