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PubMed1989

Androgen modulation of prostate cancer cell androgen receptor content is cell line specific.

Using methods for cell lysis and fractionation which yield essentially quantitative recovery of rat prostate cancer cell cytosolic and nuclear androgen receptors, we examined androgen modulation of androgen receptor content of clonally derived prostate cancer cell lines. We showed that testosterone elicited a concentration-dependent 2.3-fold increase in T5 cell androgen receptor content which was maximum after 48 h and was maintained through at least 72 h of culture. Testosterone caused only a 1.4-fold elevation in D2 cell androgen receptor content which was maximum between 6 and 12 h of culture and was maintained through at least 72 h culture. In contrast, testosterone did not cause a change in C3 cell androgen receptor content. Cycloheximide inhibition showed that both the testosterone-mediated increase in and maintenance of basal prostate cancer cell androgen receptor content required protein synthesis. Because testosterone and the nonmetabolizable androgen R1881 were essentially equipotent as effectors of the increase in T5 cell androgen receptor content, findings using testosterone appear to represent maximum effects. RU 23908 antagonized both R1881 and testosterone promoted elevations of prostate cancer cell androgen receptor content. Effectiveness of RU 23908 was comparable to the relative binding affinity of R1881, testosterone and RU 23908 for androgen receptors. This implies that at least part of the androgen-promoted increase in prostate cancer cell androgen receptor content is mediated through the action of androgen receptors and suggests that androgen receptors may act as both cis and trans regulatory elements. The mechanisms which determine basal or androgen-modulated prostate cancer cell androgen receptor content remain to be elucidated.

Androgens↗
PubMed1990

Synergistic effect of glucocorticoids and androgens on the hormonal induction of tissue plasminogen activator activity and messenger ribonucleic acid levels in granulosa cells.

Tissue-type plasminogen activator (tPA) is secreted by rat granulosa cells in response to treatment with activators of protein kinase A (follitropin, FSH), protein kinase C (gonadotropin-releasing hormone, GnRH) and tyrosine kinase (epidermal growth factor, EGF). Because steroid hormones have been shown to enhance the gonadotropin stimulation of ovarian differentiation, we investigated the effects of steroid hormones, alone or together with various kinase activators, on tPA activities and mRNA levels in cultured rat granulosa cells. Treatment of cells with dexamethasone (DEX; a glucocorticoid agonist) or R1881 (an androgen agonist) caused an increase in tPA secretion and mRNA levels. In addition, the stimulation of tPA activity and mRNA levels by FSH (50 ng/ml) was synergistically enhanced by cotreatment with DEX or R1881 in a time-dependent manner with 2.8- and 1.6-fold increase at 9 h after incubation as compared to cells treated with FSH alone. In contrast, treatment with diethylstilbestrol had no effect on tPA levels. Furthermore, tPA activity and mRNA levels induced by GnRH and EGF were also increased by cotreatment with DEX or R1881 as compared with cells treated with GnRH or EGF alone. Likewise, the stimulation of tPA mRNA levels by dibutyryl cAMP, a protein kinase A activator, and phorbol myristate acetate (PMA), a protein kinase C activator, was enhanced by cotreatment with DEX or R1881. These results demonstrate that glucocorticoid and androgen enhance tPA secretion and mRNA levels stimulated by FSH, GnRH and EGF in granulosa cells. The rat granulosa cells provide a useful model for studying the mechanism of regulation of tPA gene expression by steroid hormones.

Animals↗
PubMed1991

Androgen increases androgen receptor protein while decreasing receptor mRNA in LNCaP cells.

We have examined the effect of androgen treatment on androgen receptor mRNA and protein expression in the LNCaP human prostate carcinoma cell line. Incubation with androgen caused a decrease in cellular androgen receptor mRNA content that was concentration and time dependent. Maximal suppression to approximately 35% of control level was observed after 49 h of exposure to androgen. By contrast, incubation of LNCaP cells with androgen resulted in a 2-fold increase in the cellular content of androgen receptor protein at 24 h. At 49 h androgen receptor protein increased 30% as assayed by immunoblots and 79% as assayed by ligand binding. These results suggest that ligand-induced changes in androgen receptor stability and/or the translational efficiency of androgen receptor mRNA account for the phenomenon of androgen receptor upregulation observed in cultured LNCaP cells. Furthermore, the suppression of androgen mRNA and protein that is caused by prolonged incubation with androgen is incomplete and is reversible upon removal of ligand.

Androgens↗
PubMed1995

Androgen and glucocorticoid regulation of androgen receptor cDNA expression.

Androgen receptor (AR) levels are regulated by androgens, other steroids and non-steroidal hormones via complex, tissue-specific processes. Since alterations in receptor levels may influence cellular sensitivity to androgens, understanding AR regulation is of fundamental and potentially therapeutic significance. In most target tissues and AR-containing cell lines, AR mRNA is down-regulated in response to androgens. We have reconstituted this androgen-mediated down-regulation of AR mRNA in COS 1 cells transfected with a human AR cDNA under the control of the cytomegalovirus (CMV) promoter. The sequences mediating receptor mRNA down-regulation are represented within the AR cDNA and not within the CMV promoter. Androgenic down-regulation of AR cDNA expression was time- and dose-dependent, resembling native AR mRNA down-regulation. In addition, androgenic regulation of the receptor cDNA was not dependent on protein synthesis suggesting that AR and/or another pre-existing protein(s) is involved in this process. In COS 1 cells co-transfected with androgen and glucocorticoid receptor cDNAs, dexamethasone mimicked the action of androgen in down-regulating AR mRNA. This response depended on glucocorticoid receptors. Androgen had little effect on steady-state levels of AR protein consistent with reports that androgen down-regulates AR mRNA but increases AR protein half-life (Kemppainen et al. (1992) J. Biol. Chem. 267, 968-974; Zhou et al. (1995) Mol. Endocrinol. 9, 208-218). However, glucocorticoids decreased AR protein levels in cells that co-expressed androgen and glucocorticoid receptors. These results indicate that sequences represented in the AR cDNA mediate AR mRNA down-regulation by both androgens and glucocorticoids. Inhibition of AR mRNA and protein by glucocorticoids suggests that these steroids may modulate androgen action in tissues, such as mammary gland and prostate, which express both androgen and glucocorticoid receptors.

Cell Line↗
PubMed1996

Activation of androgen receptor in epidermal growth factor modulation of fetal mouse sexual differentiation.

Previous studies from this laboratory indicated a role for epidermal growth factor (EGF) in androgen-dependent male sexual differentiation. The mechanism by which EGF modulates male sexual differentiation has not been determined and investigation has been made to assess the role for androgen receptor (AR) in mediating the EGF-induced effect. We report that EGF, like androgen, stabilized the Wolffian duct in the 13-day female specimen, grown in organ culture. Anti-AR, flutamide and cyproterone acetate blocked the Wolffian duct-stabilizing effect of EGF. EGF also induced cell proliferation of the fetal reproductive tract in a dose-dependent manner and a combination of physiological dosages of EGF and androgen-induced cell proliferation synergistically, suggesting an interactive effect of these two drugs. Cyproterone acetate blocked both EGF-induced normal cell proliferation and the synergistic cell proliferation induced by combination of EGF and androgen suggesting a role of AR in the effects of EGF. The role of AR was further assessed by determining the effect of EGF on AR binding directly. It was shown that EGF stimulated androgen binding activity of the male fetal reproductive tract cells significantly by increasing the number of binding sites by 3-fold with slight decrease in binding affinity. Thus, it appears that AR plays a role in mediating EGF-modulation of sexual differentiation.

Animals↗
PubMed1979

Partial characterization of [3H]methyltrienolone binding in rat prostate cytosol.

3H-labelled R 1881 (methyltrienolone) was bound with high affinity (Kd, 2 . 10(-9) M) and low capacity (11--15 fmol/mg protein)in prostate cytosol from rats castrated 18 h earlier. The binding was inhibited by 5alpha-dihydrotestosterone, testosterone, cyproterone acetate and LEO 1727, but not by estradiol-17beta, R 5020 or corticosterone. The 3H-labelled R 1881-receptor complex was excluded from a Sephadex G=200 column, had a sedimentation coefficient of 3.5 S, was eluted from a DEAE-cellulose column at 0.2 M KCl concentration and precipitated between 20--40% of saturation of ammonium sulfate. 20% of specifically bound 3H-labelled R 1881 was retained by DNA-cellulose at low ionic strength. The fraction which was not bound to DNA-cellulose did not bind either, after rechromatography, not even following heating at 20 degrees C for 20 min or following fractionation with ammonium sulphate. In summary, the results indicate that the 3H-labelled R 1881-receptor complex in rat prostate cytosol has characteristics similar to those of the 5alpha-[3H]dihydrotestosterone-receptor complex.

Animals↗
PubMed1984

Binding of [3H]methyltrienolone to androgen receptor in rat liver.

The synthetic androgen methyltrienolone is superior to testosterone and androstenedione for the measurement of androgen receptor in tissues where the native ligands are metabolized into inactive derivatives. [3H]Methyltrienolone binds with a high affinity to androgen receptor in cytosol prepared from male rat livers, as the Scatchard analysis revealed that the Kd value was 3.3 X 10(-8) M and the number of binding sites was 35.5 fmol/mg protein. Since methyltrienolone also binds glucocorticoid receptor which exists in rat liver, the apparent binding of androgen receptor is faulty when measured in the presence of glucocorticoid receptor. The binding of methyltrienolone to glucocorticoid receptor can be blocked by the presence of a 100-fold molar excess of unlabeled synthetic glucocorticoid, triamcinolone acetonide, without interfering in its binding to androgen receptor, because triamcinolone does not bind to androgen receptor. Triamcinolone-blocked cytosol exhibited that the Kd value was 2.5 X 10(-8) M and the number of binding sites was 26.3 fmol/mg protein, indicating a reduction to 3/4 of that in the untreated cytosol. The profile of glycerol gradient centrifugation indicated that [3H]methyltrienolone-bound receptor migrated in the 8-9 S region in both untreated and triamcinolone-blocked cytosols, but the 8-9 S peak in triamcinolone-blocked cytosol was reduced to about 3/4 of that of untreated cytosol.

Animals↗
PubMed1991

Anabolic/androgenic steroid abuse and thrombosis: is there a connection?

Anabolic/androgenic steroid abuse is an increasing medical and public health problem. The uncontrolled use of these agents has been associated with numerous toxic side-effects including deleterious cardiovascular changes. The most widely reported to these latter changes include the development of adverse lipid profiles and hypertension. Acute thrombosis has only recently been linked to androgen abuse. Such a causative link has been proposed in reports of acute myocardial infarction and stroke in several athletes using androgens. Unfortunately, there exists no direct evidence that androgens are thrombogenic in humans. However, indirect experimental data suggests that androgens affect platelet aggregation, coagulation proteins and the vascular system in ways that facilitate thrombosis. Androgens also increase several anticoagulant and fibrinolytic proteins. However, they have not been shown to protect from thrombosis in high risk patients. Existing data supports a possible thrombogenic effect of exogenous androgens. Further studies are needed to clarify the hemostatic influence associated with androgen abuse in weightlifters. The abuse of these agents may diminish if acute thrombosis becomes clearly and scientifically associated with their uncontrolled use.

Anabolic Agents↗
PubMed1992

Psychological treatment of anabolic-androgenic steroid-dependent individuals.

Anabolic-androgenic steroids (AAS) are synthetic derivatives of the sex hormone testosterone. Anabolic refers to the "growth-promoting" effect while androgenic refers to the "masculinizing" effect. It is becoming more evident that nonathletes as well as athletes are abusing AAS. Although the abuse of alcohol and other drugs contribute significantly to current chemical use problems in American society, AAS abuse is one of the fastest growing "new drug" problems facing secondary and higher education institutes of learning. The purpose of this discussion is to present working hypotheses regarding the psychological treatment of AAS dependent individuals. The treatment approach presented incorporates the approaches used with eating disorders, substance abuse/dependence, and narcissistic personality disorders. This paper considers some of the preliminary considerations for the first phase of treatment, some pitfalls to avoid, and therapist characteristics, as well as treatment modalities that might be helpful in the treatment of AAS-dependent individuals.

Adult↗
PubMed1994

MDA-MB-453, an androgen-responsive human breast carcinoma cell line with high level androgen receptor expression.

The role of androgens and the androgen receptor (AR) in the development and progression of breast cancer is poorly understood. To further define a potential model for androgen action in breast cancer, MDA-MB-453 cells, which express AR in the absence of oestrogen receptors and progesterone receptors, were further characterised in terms of AR expression and androgen responsiveness. High level expression of AR was confirmed by northern blot analysis, radioligand binding and immunocytochemistry, and could not be accounted for by AR gene amplification. Three endogenous androgen-responsive genes (fatty acid synthetase, gross cystic disease fluid protein of 15 kDa and prolactin receptor) and a transfected reporter gene, containing an androgen-responsive element, were induced following androgen administration. A synthetic androgen, mibolerone, induced moderate (27% above control) stimulation of MDA-MB-453 cell proliferation, which was abrogated by the simultaneous administration of the synthetic androgen antagonist, anandron, demonstrating that the effect was AR-mediated. In summary, MDA-MB-453 cells express high levels of functional AR, and thus provide a valuable in vitro model for further studies on androgen regulation of gene expression, and perhaps cell proliferation in breast cancer.

Blotting, Southern↗
PubMed1995

Androgens inhibit the proliferation of a variant of the human prostate cancer cell line LNCaP.

UNLABELLED: The paradoxical androgen response of R2, a subline of the human prostate cancer cell line LNCaP, is described here. Two androgens (DHT and R1881) decreased, in a dose-dependent manner, R2 cell proliferation and [3H]thymidine incorporation. These ligand and cell specific effects were accompanied by an increase in the metabolism of the vital dye MTT and in cell protein content. Both androgens increased the doubling time and the percentage of G0-G1 cells. No evidence of androgen-induced apoptosis was found. Cloning allowed the selection of two cell populations on the basis of the response to 10 nM of R1881. Long term culture of uncloned R2 cells with R1881 modified reversibly the pattern of androgen response. R2 was compared to the androgen-stimulated LNCaP-FGC subline to investigate the causes of their different androgen responsiveness. The androgen receptor (number, affinity for hormones and antihormones, sedimentation constant and molecular weight) and androgen receptor genes (exon size and exon 8 sequence) were found to be identical in the two sublines. EGF stimulated LNCaP-FGC but not R2. Both cells were slightly stimulated by basic FGF but were insensitive to IGF-I and TGF beta 1. IN CONCLUSION: (1) androgens inhibit the proliferation of R2 cells possibly by introducing a G0-G1 block; (2) this inhibition is incomplete because, at least in part, the R2 cell population is heterogeneous; (3) chronic androgen treatment induces reversible cell adaptation; and (4) there is no evidence that the loss of the classical stimulatory effect of androgen on cell proliferation and the gain of inhibitory effect are due to androgen receptor alteration or to a specific action of one of the four growth factors tested.

Amino Acid Sequence↗
PubMed1996

Hormone-binding and solubility properties of fusion proteins containing the ligand-binding domain of the human androgen receptor.

The ligand-binding properties of the human androgen receptor (AR) reside in the carboxy terminus of the receptor and are retained in fusion proteins encoding this domain. Despite a wealth of information pertaining to the importance of specific amino acid residues in the binding of ligands, the precise amino terminal boundary of this domain has not been determined for the androgen receptor. The current studies focused on the expression of a series of AR fusion proteins in bacteria. These experiments demonstrate that specific androgen binding is detected in a fusion protein encoding amino acid residues 675-917, although this binding is of lower affinity than that observed for the native AR. Inclusion of an additional segment (residues 622-675) restores the capacity of the hormone-binding domain to bind mibolerone with high affinity. Detailed studies of the ligand-binding properties and solubility of one AR fusion protein (625-917) indicate that although the levels of ligand binding and soluble receptor fusion protein usually vary in parallel, this is not true at all time points and the proportion of soluble AR fusion that is able to bind hormone is highest when the levels of soluble AR fusion protein are lowest. This observation, coupled with the changes in the quantity of soluble and insoluble fusion protein occurring at different times following induction at 12 degrees C, 22 degrees C, and 37 degrees C, suggests that the saturation of one or more steps is required for folding of the AR hormone-binding domain to a conformation that is both soluble and competent to bind hormone under conditions of high-level expression. Analysis of the solubility of six different fusion proteins containing different portions of the AR hormone-binding domain suggests that a discrete segment of this domain is not responsible for its synthesis as predominantly insoluble aggregates in bacteria when expressed at high levels.

Base Sequence↗
PubMed2006

Performance-enhancing drug use in young athletes.

This article explores the issue of performance-enhancing drug use in adolescent athletes. The article describes current substances that are being used by adolescent athletes, explains their positive and negative effects, examines factors contributing to their increased use in adolescent athletes, and discusses approaches to educating adolescents about alternate means of enhancing their athletic performance. It is hoped that this information will be useful toward encouraging young athletes to pursue, safe, healthy, and natural means of performance enhancement, such as practice and strength training, to improve sports performance in a safe, effective manner.

Adolescent↗
PubMed2006

Sex- and age-specific effects of anabolic androgenic steroids on reproductive behaviors and on GABAergic transmission in neuroendocrine control regions.

Illicit use of anabolic androgenic steroids (AAS) has become a prevalent health concern not only among male professional athletes, but, disturbingly, among a growing number of women and adolescent girls. Despite the increasing use of AAS among women and adolescents, few studies have focused on the effects of these steroids in females, and female adolescent subjects are particularly underrepresented. Among the hallmarks of AAS abuse are changes in reproductive behaviors. Here, we discuss work from our laboratories on the actions of AAS on the onset of puberty and sexual behaviors in female rodents, AAS interactions and sex- and age-specific effects of these steroids on neural transmission mediated by gamma-aminobutyric acid receptors within forebrain neuroendocrine control regions that may underlie AAS-induced changes in these behaviors.

Age Factors↗
PubMed2006

Open-label pilot study of testosterone patch therapy in men with opioid-induced androgen deficiency.

UNLABELLED: We conducted a 24-week open-label pilot study of testosterone (T) patch therapy in 23 men with opioid-induced androgen deficiency (OPIAD). The T dosage was 5 mg/day for the first 12 weeks and 7.5 mg/day for the second 12 weeks. Seven subjects discontinued prematurely: 4 for noncompliance, 2 for skin irritation and 1 for hepatitis C treatment. In the "completers" population (n = 16), mean (SD) free T levels (normal range 52 to 280 pg/mL) were 28.5 (18.6) pg/mL at baseline, 72.8 (29.6) pg/mL on 5 mg/day (P < .001 vs. baseline), and 120.2 (69.5) pg/mL on 7.5 mg/day (P < .001 vs. baseline and P < .01 vs. 5 mg/day). Total T, dihydrotestosterone, and estradiol showed parallel changes. Sex hormone-binding globulin levels were elevated at baseline and decreased modestly with treatment (P < .05 vs. baseline at 5 mg/day; P < .01 vs. baseline at 7.5 mg/day). Luteinizing hormone levels were in the low-normal range at baseline and suppressed markedly with treatment (P < .001 vs. baseline at both doses). Androgen deficiency symptoms (ADSQ), sexual function (Watts SFQ), mood (PGWB), depression (BDI-II), and hematocrit levels showed improvement during treatment, generally more so at the 7.5 mg/day dosage (P < .001 vs. baseline for most parameters). Pain scores (BPI-SF) decreased slightly on 7.5 mg/day (interference score: P < .05 vs. baseline and 5 mg/day); the use of opioids did not change appreciably. The testosterone patches were generally well tolerated. PERSPECTIVE: Long-acting opioid preparations suppress the hypothalamic-pituitary-gonadal axis in men and produce a symptomatic state of opioid-induced androgen deficiency (OPIAD). Testosterone patch therapy at a dose of 7.5 mg/day normalizes hormone levels and appears to improve a number of quality of life parameters (eg, sexual function, well-being, mood) in men with OPIAD.

Administration, Cutaneous↗