Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “ANDROGENS”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 667 records · Page 37Linked to original sources
PubMed2005

Indole-3-carbinol inhibition of androgen receptor expression and downregulation of androgen responsiveness in human prostate cancer cells.

Indole-3-carbinol (I3C), a naturally occurring compound found in vegetables of the Brassica genus, such as broccoli and cabbage, is a promising anticancer agent previously shown to induce a G(1) cell-cycle arrest in the cells of human lymph node carcinoma of prostate (LNCaP) through regulation of specific G(1)-acting cell-cycle components. Since the androgen receptor (AR) mediates proliferation and differentiation in the prostate and is expressed in nearly all human prostate cancers, the effects of I3C on AR expression and function were examined in LNCaP cells. Immunoblot and quantitative RT-PCR assays revealed that I3C inhibited the expression of AR protein and mRNA levels within 12 h of indole treatment. I3C downregulated the reporter activity of LNCaP cells transiently transfected with an AR promoter-luciferase plasmid, demonstrating that a unique response to I3C is the inhibition of AR promoter activity. In contrast to I3C, the natural I3C dimerization product 3,3'-diindolylmethane, which acts as an androgen antagonist, had no effect on AR expression. To determine the functional significance of the I3C-inhibited expression of AR, the AR-regulated prostate specific antigen (PSA) was utilized as a downstream indicator. I3C downregulated the expression of PSA transcripts and protein levels and inhibited PSA promoter activity, as well as that of a minimal androgen responsive element containing reporter plasmid. Expression of exogenous AR prevented the I3C disruption of androgen-induced PSA expression. Taken together, our results demonstrate that I3C represses AR expression and responsiveness in LNCaP cells as a part of its antiproliferative mechanism.

Anticarcinogenic Agents↗
PubMed1993

A single-base substitution in exon 6 of the androgen receptor gene causing complete androgen insensitivity: the mutated receptor fails to transactivate but binds to DNA in vitro.

A single-base substitution in the coding region of the androgen receptor (AR) gene caused complete androgen insensitivity in a patient with 46,XY karyotype. The mutation was a T-to-G transition in exon 6 and changed the codon 807 from ATG (methionine) to AGG (arginine) in the hormone-binding domain of the protein. The mutation was inserted into the wild-type human AR cDNA and the resulting cDNA expressed in CV-1 cells. Native and mutated AR proteins synthesized in recipient cells had identical molecular masses. Ligand-binding activity of the mutant receptor was less than 5% of that of the wild-type AR. The mutant's interaction with an androgen-response element in vitro was identical to that of the native aporeceptor; however, it did not transactivate a reporter gene construct in transfected CV-1 cells. Androgen insensitivity in our patient was thus due to altered structure of the receptor's steroid-binding region, which prevented the mutated AR from gaining a transcriptionally active form in vivo.

Adult↗
PubMed1999

Identification of two nuclear androgen receptors in kelp bass (Paralabrax clathratus) and their binding affinities for xenobiotics: comparison with Atlantic croaker (Micropogonias undulatus) androgen receptors.

Two distinct nuclear androgen receptors (ARs) were identified in brain and ovarian tissues of kelp bass, Paralabrax clathratus, termed kbAR1 and kbAR2, which correspond to the two nuclear ARs we have previously characterized in Atlantic croaker, Micropogonias undulatus, termed acAR1 and acAR2. Scatchard analysis of nuclear fractions of whole brain tissue demonstrated that kbAR1 had a single class of high-affinity binding sites for testosterone (T; K(d) of 1. 8 nM and B(max) of 1.0 pmol/g tissue), whereas cytosolic fractions of kbAR2 ovarian tissue had a single class of high-affinity binding sites for dihydrotestosterone (DHT; K(d) of 0.1 nM and B(max) of 0.5 pmol/g tissue). Competition studies showed that both kbAR1 and kbAR2 were specific for androgens. However, kbAR1 bound only T with high affinity, whereas kbAR2 bound DHT, mibolerone, 17alpha-methyl-testosterone, T, and 11-ketotestosterone with high affinity. In addition, we examined the binding affinities of dichlorodiphenyltrichloroethane and its derivatives, several hydroxylated polychlorinated biphenyl (PCB) congeners, PCB mixtures, and the fungicide vinclozolin and its two metabolites M1 and M2 for the two ARs in Atlantic croaker ovarian, testicular, and brain tissues and in kelp bass ovarian and brain tissues. Only 4, 4'-PCB-3-OH and 2',5'-PCB-3-OH demonstrated greater than 50% displacement of [(3)H]testosterone from either acAR1 or kbAR1. In contrast, with the exception of vinclozolin, all of the xenobiotics examined demonstrated binding to acAR2 in testicular and ovarian tissues. The binding affinities were highest in the testicular tissue with M2, 2,2'5'-PCB-4-OH, and o,p'-DDD all binding with EC(50)s less than 10 microM. The binding affinities of xenobiotics to kbAR2 in ovarian tissue were similar to their binding affinities for ovarian acAR2. The finding that AR1 and AR2 possess different binding affinities for natural androgens and synthetic steroids, as well as for xenobiotics, suggests that the activities of androgens and of certain xenobiotics will depend upon the type of AR present within the target tissue.

Animals↗
PubMed1993

The impact of a pure anti-androgen (flutamide) on LH, FSH, androgens and clinical status in idiopathic hirsutism.

OBJECTIVES: We assessed in women the effects of androgen suppression on gonadotrophin secretion and the therapeutic efficacy of the pure anti-androgen flutamide (2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide). DESIGN AND SUBJECTS: Ten women, aged 28-35 years, using an intrauterine device for contraception, were selected for this study. All women had idiopathic hirsutism with or without acne and seborrhoea. Flutamide was administered orally in a dose of 250 mg twice daily for 1 year. Basal body temperature was recorded and pelvic ultrasonography performed before and every 3 months during treatment. LH pulse frequency and amplitude (Cluster analysis) and basal and GnRH-stimulated plasma LH and FSH levels were determined on day 5 of the cycle prior to flutamide treatment, and after 6 and 12 months of therapy. Plasma total testosterone (T), non-SHBG bound T, androstenedione (A), dehydroepiandrosterone sulphate (DHEAS), androstanediol glucuronide (3 alpha-diol G) and sex hormone binding globulin (SHBG) levels were measured before and every 3 months during therapy, on day 5 of the cycle. Plasma oestradiol and progesterone levels were determined on day 22 of the studied cycles. RESULTS: Disappearance of acne and seborrhoea occurred after 2 months with a marked improvement of hirsutism at 6 months. At 12 months, hirsutism had disappeared with a Ferriman and Gallwey score < 7. No adverse side-effects, apart from transient diarrhoea in two patients, were reported with this flutamide dose. None of the patients had any disturbance of menstrual cycles which remained ovulatory. The pure anti-androgen flutamide induced no significant change in LH pulsatile profile, nor in LH and FSH responsiveness to GnRH. Plasma concentrations of steroids were not altered. Plasma SHBG and 3 alpha-diol G levels did not change during flutamide treatment. CONCLUSION: Flutamide, which interacts only with the androgen receptor, is effective for hirsutism, acne and seborrhoea, and does not disturb menstrual cyclicity or ovulation. It may represent a treatment of choice for essential hirsutism in women using safe contraceptive methods.

Acne Vulgaris↗
PubMed1976

Binding of methyltrienolone to various androgen-dependent and androgen-responsive tissues in four animal species.

Comparative sucrose gradient studies of the in vitro binding of dihydrotestosterone (DHT) and of a synthetic androgen, methyltrienolone (R 1881), have been done with the cytosols of various tissues of the rat, mouse, cock and man. With rat prostate cytosol, the amount of R 1881 and DHT binding in the 8-9S region of the gradient was found to be comparable. Specific 8-9S peaks of R 1881 were also found in rat levator ani/bulbocavernosus and skeletal muscles and in the mouse kidney. Only 4-5S peaks could be demonstrated in the cock's comb while DHT under the same conditions showed both 8-9S and 4-5S binding. Binding of R 1881 to the cytosol of the hyperplastic prostate was polydispersed, and showed evidence of the presence of aggregates. Evidence was also found that R 1881 could bind to the progesterone receptor in rat uterus. Our study supports the theory that in a given species the androgen receptors are similar if not identical in all the tissues. The synthetic androgen R 1881 appears to be a useful tool for androgen receptor studies in various animal species provided that the tissue under study contains no progesterone receptor.

Animals↗
PubMed1978

Rat adrenal androgen receptor: a possible mediator of androgen-induced decreased in rat adrenal weight.

Many previous studies have demonstrated effects of gonadal steroids on adrenal weight in the rat. Most of these effects are indirect, depending upon alterations in the pituitary-adrenal axis for their expression. In this study we have attempted to examine the direct effects of gonadal steroids on adrenal weight in the rat. This was done using hypophysectomized, castrated male rats receiving ACTH replacement, a model which excludes pituitary-adrenal feedback effects. Estradiol-treated rats did not differ from controls, whereas testosterone-treated rats exhibited a small but statistically significant decrease in adrenal weight. As a first step in exploring the mechanism of this androgen effect, we have identified a specific dihydrotestosterone-binding protein in the rat adrenal gland. A single class of high affinity (Kd = 0.6-2.0 x 10(-8) M), saturable (28 fmol/mg cytosol protein), cytoplasmic binding sites was found using both protamine sulfate precipitation and dextran-coated charcoal assays. The specificity, sedimentation coefficient on sucrose gradient, and sensitivity to sulfhydryl reagents and heat of this dihydrotestosterone-binding protein are typical of the cytoplasmic androgen receptor from other androgen target tissues such as prostrate. We conclude that testosterone can decrease rat adrenal weight directly, and that the mechanism may involve a high affinity binding protein, as has been shown in other androgen-responsive systems.

Adrenal Glands↗
PubMed1996

Transforming growth factor-beta1 is a mediator of androgen-regulated growth arrest in an androgen-responsive prostatic cancer cell line, LNCaP.

LNCaP is an androgen-responsive prostatic cancer cell line that exhibits a bell-shaped growth response to increasing doses of dihydrotestosterone (DHT) in culture. Although the precise mechanism responsible for this growth response to androgen stimulation remains unclear, many studies have suggested that androgen modulates the level of various growth factors. In the present study, the role of transforming growth factor-beta (TGF-beta) in mediating the androgen-regulated growth arrest of LNCaP cells was investigated. The following concentrations of DHT were used: 0, 10(-12), 10(-10), and 10 (-7) M. These concentrations were selected because they represent the zero DHT control, the low-proliferative dose, the high-proliferative dose, and the growth arrest dose, respectively. Results of RT-PCR showed that LNCaP cells express TGF-beta1 but not -beta2 and -beta3 messenger RNA. Competitive quantitative RT-PCR demonstrated that the level of TGF-beta1 messenger RNA increased approximately 7-fold when cells were treated with 10(-7) M DHT. Results of Western blot analysis showed a dramatic increase in the level of latent TGF-beta1 protein in cell lysates with increasing concentrations of DHT. In addition, results of enzyme-linked immunoadsorbent assay for TGF-beta1 indicated that treatment of LNCaP cells with DHT led to a dose-dependent increase in both total and biologically active TGF-beta1 in the conditioned media. To determine the role of TGF-beta1 in regulating LNCaP proliferation, the action of TGF-beta1 was blocked by two different but complementary approaches. First, TGF-beta1 neutralizing antibody was added to the culture medium with varying concentrations of DHT. Second, mannose-6-phosphate, which has been demonstrated to inhibit the activation of latent TGF-beta1, was added in a similar manner to the culture. Results demonstrated that the characteristic bell- shaped growth response following treatment with increasing doses of DHT was converted to a linear dose-response curve as the growth of inhibition seen at the high dose by DHT was abolished. These observations, taken together, indicate that TGF-beta1 mediates at least in part the growth arrest observed at the high concentration of DHT in LNCaP cells.

Androgens↗
PubMed1997

Autocrine effect of androgen on proliferation of an androgen responsive prostatic carcinoma cell line, LNCAP: role of interleukin-6.

LNCaP is an androgen-responsive prostatic carcinoma cell line that exhibits a bell-shaped growth response curve to increasing doses of dihydrotestosterone (DHT) in culture. Although the precise mechanism responsible for this unique growth response to androgen stimulation remains unclear, many studies have suggested that androgen modulates the level of various growth factors. In an early study, we demonstrated that LNCaP proliferation was stimulated by interleukin (IL)-6 in a paracrine manner, because these cells did not express a significant amount of IL-6. In the present study, the role of IL-6 in mediating androgen regulated proliferation in LNCaP cells was investigated. DHT, at increasing doses up to 10(-8) M, resulted in a release of IL-6 from LNCaP cells. This dose-dependent effect of DHT on LNCaP proliferation could be partially inhibited by the addition of antibody against IL-6 into the culture medium. These results indicate that the DHT-induced expression of IL-6 stimulates proliferation of LNCaP cells in culture in an autocrine manner.

Androgens↗
PubMed2000

An aged rat model of partial androgen deficiency: prevention of both loss of bone and lean body mass by low-dose androgen replacement.

The aim of this study was to evaluate the effects of different doses of androgen replacement, both on body composition and bone, in an aged male orchidectomized rat model. Testosterone was administered by 0.5, 1, and 2.5-cm sc SILASTIC implants (release of, respectively, 11.5, 23, and 55 microg/day) to aged (12 months old, +/- 550 g) male orchidectomized Wistar rats during a 15-week experimental period. T 0.5 only partially prevented decrease of ventral prostate and seminal vesicle weight, compared with an intact group that received an empty implant (Intact). The 1-cm implant (T 1) completely prevented decrease of both seminal vesicles and ventral prostate weight. The 2.5-cm implant (T 2.5) was clearly supraphysiological, as demonstrated by significant hypertrophy of both androgen-sensitive organs. Serum testosterone was lower in T 0.5 and T 1 (0.38 +/- 0.06 ng/ml and 0.92 +/- 0.06 ng/ml, respectively) and higher in T 2.5 (2.4 +/- 0.28. ng/ml), compared with both Intact (1.6 +/- 0.23 ng/ml) and the baseline group(1.6 +/- 0.11 ng/ml). As expected, orchidectomized rats that received an empty SILASTIC implant had significantly lower bone mineral content (-7.9%), apparent density (-5.7%), and lean body mass (-10.8%), as measured by dual-energy x-ray absorptiometry, without significant changes in body weight and fat mass, compared with Intact. Also, cancellous (-50.3%) and cortical (-1.8%) volumetric density, as measured by peripheral quantitative computed tomography, were decreased in the tibia. Bone turnover, as measured by serum osteocalcin and urinary deoxypyridinoline excretion, was increased in orchidectomized rats that received an empty SILASTIC implant. T 0.5 prevented all changes, not only in bone mineral content, density, and turnover but also in lean body mass. Moreover, there were no significant differences, for all these parameters, between the different doses of testosterone replacement. In conclusion, low-dose androgen replacement does not lead to lower bone mineral density, higher bone turnover, and lower lean body mass in aged male rats, whereas complete androgen deficiency does. Therefore, the threshold concentration of testosterone necessary for prevention of both bone and lean body mass loss in aged male rats is clearly lower than for prostate and seminal vesicles.

Aging↗
PubMed2004

Androgen receptor in human skeletal muscle and cultured muscle satellite cells: up-regulation by androgen treatment.

Androgens stimulate myogenesis, but we do not know what cell types within human skeletal muscle express the androgen receptor (AR) protein and are the target of androgen action. Because testosterone promotes the commitment of pluripotent, mesenchymal cells into myogenic lineage, we hypothesized that AR would be expressed in mesenchymal precursor cells in the skeletal muscle. AR expression was evaluated by immunohistochemical staining, confocal immunofluorescence, and immunoelectron microscopy in sections of vastus lateralis from healthy men before and after treatment with a supraphysiological dose of testosterone enanthate. Satellite cell cultures from human skeletal muscle were also tested for AR expression. AR protein was expressed predominantly in satellite cells, identified by their location outside sarcolemma and inside basal lamina, and by CD34 and C-met staining. Many myonuclei in muscle fibers also demonstrated AR immunostaining. Additionally, CD34+ stem cells in the interstitium, fibroblasts, and mast cells expressed AR immunoreactivity. AR expression was also observed in vascular endothelial and smooth muscle cells. Immunoelectron microscopy revealed aggregation of immunogold particles in nucleoli of satellite cells and myonuclei; testosterone treatment increased nucleolar AR density. In enriched cultures of human satellite cells, more than 95% of cells stained for CD34 and C-met, confirming their identity as satellite cells, and expressed AR protein. AR mRNA and protein expression in satellite cell cultures was confirmed by RT-PCR, reverse transcription and real-time PCR, sequencing of RT-PCR product, and Western blot analysis. Incubation of satellite cell cultures with supraphysiological testosterone and dihydrotestosterone concentrations (100 nm testosterone and 30 nm dihydrotestosterone) modestly increased AR protein levels. We conclude that AR is expressed in several cell types in human skeletal muscle, including satellite cells, fibroblasts, CD34+ precursor cells, vascular endothelial, smooth muscle cells, and mast cells. Satellite cells are the predominant site of AR expression. These observations support the hypothesis that androgens increase muscle mass in part by acting on several cell types to regulate the differentiation of mesenchymal precursor cells in the skeletal muscle.

Adult↗
PubMed2006

SHBG gene promoter polymorphisms in men are associated with serum sex hormone-binding globulin, androgen and androgen metabolite levels, and hip bone mineral density.

CONTEXT: SHBG regulates free sex steroid levels, which in turn regulate skeletal homeostasis. Twin studies have demonstrated that genetic factors largely account for interindividual variation in SHBG levels. Glucuronidated androgen metabolites have been proposed as markers of androgenic activity. OBJECTIVE: Our objective was to investigate whether polymorphisms in the SHBG gene promoter [(TAAAA)(n) microsatellite and rs1799941 single-nucleotide polymorphism] are associated with serum levels of SHBG, sex steroids, or bone mineral density (BMD) in men. DESIGN AND STUDY SUBJECTS: We conducted a population-based study of two cohorts of Swedish men: elderly men (MrOS Sweden; n congruent with 3000; average age, 75.4 yr) and young adult men (GOOD study; n = 1068; average age, 18.9 yr). MAIN OUTCOME MEASURES: We measured serum levels of SHBG, testosterone, estradiol, dihydrotestosterone, 5alpha-androstane-3alpha,17beta-diol glucuronides, androsterone glucuronide, and BMD determined by dual-energy x-ray absorptiometry. RESULTS: In both cohorts, (TAAAA)(n) and rs1799941 genotypes were associated with serum levels of SHBG (P < 0.001), dihydrotestosterone (P < 0.05), and 5alpha-androstane-3alpha,17beta-diol glucuronides (P < 0.05). In the elderly men, they were also associated with testosterone and BMD at all hip bone sites. The genotype associated with high levels of SHBG was also associated with high BMD. Interestingly, male mice overexpressing human SHBG had increased cortical bone mineral content in the femur, suggesting that elevated SHBG levels may cause increased bone mass. CONCLUSIONS: Our findings demonstrate that polymorphisms in the SHBG promoter predict serum levels of SHBG, androgens, and glucuronidated androgen metabolites, and hip BMD in men.

Adolescent↗
PubMed1997

Assessment of androgen receptor function in genital skin fibroblasts using a recombinant adenovirus to deliver an androgen-responsive reporter gene.

Mutations of the androgen receptor (AR) cause defects in virilization and can result in a spectrum of phenotypic abnormalities of male sexual development that includes patients with a completely female phenotype (complete testicular feminization) and individuals with less severe defects of virilization, such as Reifenstein syndrome. These phenotypes are not specific for mutations of the AR gene, however, and defects in other genes can also result in similar abnormalities of male development. For this reason, the diagnosis of an AR defect is laborious and requires data from endocrine studies, the family history, and in vitro binding experiments. To assist in the evaluation of patients with possible AR defects, we previously employed the use of a recombinant adenovirus to deliver an androgen-responsive gene into fibroblast cultures to assay AR function in normal subjects and patients with complete forms of androgen resistance. Although these studies demonstrated measurable differences between these two groups of subjects, we did not assay samples from patients with partial defects of androgen action. In the current study, we have modified this method to examine AR function in three groups of patients with known or suspected defects of AR function: patients with Reifenstein syndrome, patients with spinobulbar muscular atrophy, and patients with severe forms of isolated hypospadias. When assayed using this method, the AR function of patients with Reifenstein syndrome was intermediate between that of normal control subjects and that of patients with complete testicular feminization. Using the parameters established by the aforementioned experiments, we found that defective AR function can be detected in fibroblasts established from patients with spinobulbar muscular atrophy and in some patients with severe forms of isolated hypospadias, including two with a normal AR gene sequence. These results suggest that this method may have some utility in screening samples to detect defects of AR function, particularly when viewed in the context of other AR assays results.

Adenoviridae↗
PubMed1999

Leptin and androgens in male obesity: evidence for leptin contribution to reduced androgen levels.

Leptin circulates in plasma at concentrations that parallel the amount of fat reserves. In obese males, androgen levels decline in proportion to the degree of obesity. Recently, we have shown that in rodent Leydig cells leptin inhibits hCG-stimulated testosterone (T) production via a functional leptin receptor isoform; others have found that leptin inhibits basal and hCG-induced T secretion by testis from adult rats. In this study, we further investigated the relationship linking leptin and androgens in men. Basal and hCG-stimulated leptin and sex hormone levels were studied in a large group of men ranging from normal weight to very obese (body mass index, 21.8-55.7). Initial cross-sectional studies showed that circulating leptin and fat mass (FM) were inversely related with total and free T (r = -0.51 and r = -0.38, P < 0.01 and P < 0.05, respectively). Multiple regression analysis indicated that the correlation between leptin or FM and T was not lost after controlling for SHBG and/or LH and/or estradiol (E2) levels and that leptin was the best hormonal predictor of the lower androgen levels in obesity. Dynamic studies showed that in obese men the area under the curve of T and free T to LH/hCG stimulation (5000 IU i.m.) was 30-40% lower than in controls and inversely correlated with leptin levels (r = -0.45 and r = -0.40, P < 0.01 and P < 0.05, respectively). Also, LH/hCG-stimulation caused higher increases in 17-OH-progesterone to T ratio in obese men than in controls, whereas no differences were observed between groups either in stimulated E2 levels or in the E2/T ratio. In all subjects, the percentage increases from baseline in the 17-OH-progesterone to T ratio were directly correlated with leptin levels or FM (r = 0.40 and r = 0.45, P < 0.01), but not with E2 or other hormonal variables. In conclusion, our studies, together with previous in vitro findings, indicate that excess of circulating leptin may be an important contributor to the development of reduced androgens in male obesity.

17-alpha-Hydroxyprogesterone↗
PubMed2000

Preserved male fertility despite decreased androgen sensitivity caused by a mutation in the ligand-binding domain of the androgen receptor gene.

Mutations in the androgen receptor gene are considered as incompatible with preservation of fertility and have been suggested as a cause of male infertility. Two adult brothers, referred because of gynecomastia and hormonal levels in serum indicating androgen insensitivity (high sex hormone-binding globulin, and LH levels, despite extremely high testosterone concentration), turned out to be relatives to a third young man, referred independently of the two others and exhibiting identical clinical and hormonal stigmata. In all three men, we found a C-->A substitution at position 2470 (exon 7) in the androgen receptor gene, leading to a Gln824Lys mutation in the ligand-binding domain of the receptor. Exploring the family history revealed that their grandfathers, on their mothers' side, were brothers; and the Gln824Lys mutation was also found in the one of them who was still alive. Binding studies with the mutant receptor in transfected COS-7 cells, with mibolerone as ligand, exhibited equal Kd (0.7 vs. 1.0 nmol/ L), IC50 (0.8 vs. 1.1 nmol/L), and maximum binding (7.1 vs. 8.9 fmol/ 10(6) cells), as compared with the wild-type (WT) receptor. In a chloramphenicol acetyl transferase trans-activation assay, the activity of the mutant receptor was identical to that of the WT, when the synthetic androgen R1881 was'used as a ligand; but with dihydrotestosterone, in concentrations up to 10 nmol/L, the activity of Gln824Lys mutated receptor was 10-62% of the WT variant. Thus, Gln824Lys mutation was found, both in vivo and in vitro, to cause slight impairment of receptor function but was compatible with preservation of male fertility. The patients inherited the mutation from their grandfathers through their mothers, and one of the young men possessing the mutation has fathered a daughter.

Adult↗
PubMed2002

Synergistic action of prolactin (PRL) and androgen on PRL-inducible protein gene expression in human breast cancer cells: a unique model for functional cooperation between signal transducer and activator of transcription-5 and androgen receptor.

The signal transducer and activator of transcription 5 (Stat5) has been shown to cooperate with some nuclear receptors. However, an interaction has never been demonstrated with the androgen receptor (AR). Given that the PRL-inducible protein/gross cystic disease fluid-15 (PIP/GCDFP-15) is both a PRL-controlled and an androgen-controlled protein, we used its promoter region to investigate the potential interaction between Stat5 and androgen receptor. Dihydrotestosterone or PRL alone slightly modulated or did not modulate the luciferase activity of all reporter gene constructs. In contrast, a maximal increase was observed using the -1477+42 reporter gene construct after exposure to both dihydrotestosterone and PRL. The requirement of half-site androgen-responsive elements and two consensus Stat5-binding elements, Stat5#1 and Stat5#2, was determined by site-directed mutagenesis. Activated Stat5B binds with a higher affinity to Stat5#2 than to Stat5#1. Stat5ADelta749 and Stat5BDelta754 mutants demonstrated that the Stat5 trans-activation domain is involved in the hormonal cooperation. The cooperation depends on the PRL-induced phosphorylation on Tyr(694) in Stat5A and Tyr(699) in Stat5B, as demonstrated using the Stat5AY694F and Stat5BY699F proteins. The use of AR Q798E, C619Y, and C784Y mutants showed that trans-activation, DNA-binding, and ligand-binding domains of AR are essential. Our study thus suggests a functional cooperation between AR and Stat5.

5' Flanking Region↗
PubMed1981

[Studies of androgen binding protein. 1st report: Androgen binding protein in testis and epididymis of rabbit and human (author's transl)].

Androgen-binding protein (ABP) appears to originate in the Sertoli cells, which are stimulated by FSH and androgens, and serves to transport androgen into the lumen of the seminiferous tubules. Androgen may be more readily available for the process of spermatogenesis and sperm maturation. ABP was measured in rabbit and human testes using the method of polyacrylamide gel electrophoresis described by Ritzen et al. (1974). The values of ABP were as follows: rabbit testes (n=6) 0.44 +/- 0.05 pmoles/mg protein, rabbit caput epididymides (n=5) 5.52 +/- 1.4 pmoles/mg protein, rabbit corpus epididymides (n=5) 1.35 +/- 0.43 pmoles/mg protein, rabbit cauda epididymides (n=5) 0.39 +/- 0.12 pmoles/mg protein, rabbit efferent duct fluid (n=2) 62.4 +/- 24.6 pmoles/mg protein and human testes (obtained from untreated patients with prostatic cancer)(n=3) 0.30 +/- 0.22 pmoles/mg protein. Since we could not distinguish ABP from testosterone-estrogen binding globulin (TeBG) with the assay, the values were corrected at first by Hb concentration, but it was not satisfactory, and other methods are now being studied.

Aged↗
PubMed1984

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

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

Androgens↗
PubMed2001

Familial resemblance for free androgens and androgen glucuronides in sedentary black and white individuals: the HERITAGE Family Study. Health, Risk Factors, Exercise Training and Genetics.

Familial correlation analyses were used to evaluate the familial aggregation of plasma androgens and androgen glucuronides (testosterone (TESTO), dihydrotestosterone (DHT), androstane-3 alpha,17 beta-diol glucuronide (3 alpha-DIOL-G), and androsterone glucuronide (ADT-G)) in 505 members of 99 white families and 296 members of 111 black families participating in the Health, Risk Factors, Exercise Training and Genetics (HERITAGE) Family Study. Each of these four measures was determined by RIA after separation of conjugated and unconjugated steroid using C18 column chromatography. All participants were sedentary prior to being including in this study. Significant spouse correlations, as well as parent-offspring and sibling correlations, were found for TESTO, DHT, 3 alpha-DIOL-G, and ADT-G in the white sample, suggesting that common familial environments and genes contribute to the familial resemblance. In the black sample, significant sibling and parent-offspring correlations were found for all four phenotypes, while the spouse correlation was marginally significant for 3 alpha-DIOL-G and not significant for TESTO, DHT, and ADT-G. The non-significance of spouse correlations in the black individuals may be due to the small number of spouse pairs. The maximal heritability estimates of TESTO, DHT, 3 alpha-DIOL-G, and ADT-G were 69%, 87%, 74%, and 56% for white individuals and 70%, 73%, 62%, and 48% for black individuals respectively. Sex differences in heritability estimates were found in the white individuals, but they were less dramatic in the black individuals. In conclusion, plasma levels of androgens and androgen glucuronides are highly heritable in both white individuals and black individuals. There are notable sex differences in the white individuals.

Adolescent↗