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PubMed1986

Androgen receptors and partial androgen insensitivity in male pseudohermaphroditism.

Male pseudohermaphroditism can occur either as a result of inadequate fetal androgen secretion or ineffective androgen action. Partial androgen insensitivity syndrome is related to a decrease in the binding capacity of target cells androgen receptors. However, the biochemical expression of these syndromes is variable: although a low concentration of androgen receptors is observed in 75% of the cases, a normal binding capacity is sometimes reported. If the presence of androgen receptors is necessary for hormonal action, it is not sufficient since the receptor has to conserve its functional integrity. Several qualitative abnormalities of the androgen receptor have been described and could thus explain the disturbance in the androgen mechanism of action. The study of androgen-dependent proteins and other androgen-receptor "markers" should offer the clinician a better management of partial androgen insensitivity and allow, in amniotic or trophoblastic cells, a prenatal diagnosis of androgen resistance in high-risk families.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1996

Activation of two mutant androgen receptors from human prostatic carcinoma by adrenal androgens and metabolic derivatives of testosterone.

The androgen receptor (AR) plays a central regulatory role in prostatic carcinoma and is a target of androgen ablation therapy. Recent detection of mutant receptors in tumor specimens suggest a contribution of AR alterations to progression towards androgen independence. In a specimen derived from metastatic prostate cancer we have reported a point mutation in the AR gene that leads to a single amino acid exchange in the ligand binding domain of the receptor. Another amino acid exchange resulting from a point mutation was also identified 15 amino acids away from our mutation. This mutation was detected in the AR gene isolated from an organ-confined prostatic tumor. Here we report the functional characterization of the two mutant receptors in the presence of adrenal androgens and testosterone metabolites. These studies were performed by cotransfecting androgen-responsive reporter genes and either the wild-type or mutant AR expression vectors into receptor negative DU-145 and CV-1 cells. The indicator genes used consisted of the promoter of the androgen-inducible prostate-specific antigen gene or the C' Delta9 enhancer fragment from the promoter of the mouse sex-limited protein driving the expression of the bacterial chloramphenicol acetyl transferase gene. Cotransfection-transactivation assays revealed that the adrenal androgen androstenedione and two products of testosterone metabolism, androsterone and androstandiol, induced reporter gene activity more efficiently in the presence of the mutant receptors than in the presence of the wild-type receptor. No difference between wild-type and mutant receptors was observed in the presence of the metabolite androstandione. The interaction of receptor-hormone complexes with target DNA was studied in vitro by electrophoretic mobility shift assays (EMSA). Dihydrotestosterone and the synthetic androgen mibolerone induced a faster migrating complex with all receptors, whereas the androgen metabolite androstandione induced this complex only with the two mutant receptors. Androsterone and androstandiol were inactive in the EMSA. These aberrant properties of the mutant receptors in the presence of adrenal androgens and products of androgen metabolism may be of importance in the course of the prostate cancer, especially during androgen ablation therapy.

Androgens↗
PubMed1995

Androgen-directed development of the Xenopus laevis larynx: control of androgen receptor expression and tissue differentiation.

The larynx of adult male Xenopus laevis differs markedly from that of the female; masculinization of the larynx requires androgen secretion during postmetamorphic development. Early in postmetamorphic development, androgen stimulates laryngeal cell proliferation and androgen binding activity is high. Later, androgen induces laryngeal cell differentiation and binding levels decrease. Here we explore the relation between laryngeal differentiation and androgen receptor expression. In untreated females, the larynx expresses high levels of androgen receptor mRNA early in postmetamorphic life; levels decline as females mature. The highest level of androgen receptor message is found in the undifferentiated laryngeal elastic precartilage of both sexes. When juveniles are exposed to androgen, laryngeal cell proliferation is stimulated within 48 hr in both sexes. Short exposures to androgen result in a biphasic response of AR mRNA levels; a marked down-regulation (4 hr) is followed by recovery at 8 hr (males) or 48 hr (females). Following longer periods of androgen treatment (3 weeks), AR mRNA expression is down-regulated and male-typical differentiation of elastic cartilage is induced in both sexes. Thus laryngeal growth responses to androgen are closely related to expression levels of androgen receptor mRNA.

Animals↗
PubMed1992

Three cell lines showing androgen-dependent, -independent, and -suppressed phenotypes, established from a single tumor of androgen-dependent Shionogi carcinoma 115.

We investigated the heterogeneity of cells in terms of androgen responsiveness within a single tumor mass of Shionogi carcinoma SC-115 showing androgen-dependent growth. After cloning of the tumor by the limiting dilution method in the presence of androgen, we isolated 40 clones at random. Twenty-two clones required androgen for growth (androgen-dependent phenotype), 16 did not (androgen-independent phenotype), and the remaining two clones showed growth inhibition when androgen was added (androgen-suppressed phenotype). In addition, 22 androgen-dependent clones showed heterogeneity in growth factor sensitivity in the absence of androgen. All clones were sensitive to both acidic and basic fibroblast growth factor (FGF), 7 of 22 clones were sensitive to epidermal growth factor (EGF) and transforming growth factor (TGF)-alpha, and 2 of 22 clones were sensitive to TGF-beta. This preexisting heterogeneity may be partly responsible for the growth of androgen-dependent tumor under hormone-deprived circumstances. Three typical clones, SC2G, SC1G, and SC4A, were selected from androgen-dependent, -independent, and -suppressed phenotypic groups, respectively. These clones, as well as original solid tumors, were found to produce heparin-binding growth factors of heterogeneous elution positions. The molecular nature of these growth factors is not yet known. Neither anti-basic FGF antibody nor anti-EGF antibody inhibited the cell growth when added in cell culture, suggesting the factors were distinct from basic-FGF and EGF.

Androgens↗
PubMed1996

Intermittent androgen suppression delays progression to androgen-independent regulation of prostate-specific antigen gene in the LNCaP prostate tumour model.

In most patients with prostate cancer, continuous androgen suppression (CAS) therapy causes tumour regression and an accompanying decrease in serum prostate specific antigen (PSA). However, with tumour progression, regulation of both tumour growth and PSA gene expression becomes androgen-independent. Because androgen resistance develops, in part, from adaptive cell survival mechanisms activated by androgen withdrawal, we hypothesize that intermittent re-exposure to androgens may prolong time to androgen-independent progression. The objective of this study was to determine whether intermittent androgen suppression (IAS) could delay the onset of androgen-independent PSA gene regulation in LNCaP prostate tumour model when compared to CAS. Five or six cycles of IAS were possible before progression developed. IAS prolonged time to androgen-independent PSA gene regulation from an average of 26 days in CAS to 77 days in IAS. Serum PSA increased above pre-castrate levels in all mice treated with CAS by 28 days post-castration, but remained below pre-castrate levels in 75% of IAS-treated mice by 60 days post-castration. By 15 weeks post-castration, serum PSA levels increased 7-fold above pre-castrate levels in CAS-treated mice compared to 1.9-fold increase in IAS-treated mice. PSA mRNA expression levels highly correlated with serum PSA levels in both groups. Maintenance of androgen dependency through IAS may be due to androgen-induced differentiation and/or down-regulation of androgen-suppressed gene expression.

Androgens↗
PubMed2006

Dual androgen-response elements mediate androgen regulation of MMP-2 expression in prostate cancer cells.

AIM: To characterize the matrix metalloproteinases (MMP)-2 promoter and to identify androgen response elements (AREs) involved in androgen-induced MMP-2 expression. METHODS: MMP-2 mRNA levels was determined by reverse transcription-polymerase chain reaction (RT-PCR). MMP-2 promoter-driven luciferase assays were used to determine the fragments responsible for androgen-induced activity. Chromatin-immunoprecipitation assay and electrophoretic mobility shift assays (EMSA) were used to verify the identified AREs in the MMP-2 promoter. RESULTS: Androgen significantly induced MMP-2 expression at the mRNA level, which was blocked by the androgen antagonist bicalutamide. Deletion of a region encompassing base pairs -1591 to -1259 (relative to the start codon) of the MMP-2 promoter led to a significant loss of androgen-induced reporter activity. Additional deletion of the 5'-region up to -562 bp further reduced the androgen-induced MMP-2 promoter activity. Sequence analysis of these two regions revealed two putative ARE motifs. Introducing mutations in the putative ARE motifs by site-directed mutagenesis approach resulted in a dramatic loss of androgen-induced MMP-2 promoter activity, indicating that the putative ARE motifs are required for androgen-stimulated MMP-2 expression. Most importantly, the androgen receptor (AR) interacted with both motif-containing promoter regions in vivo in a chromatin immunoprecipitation assay after androgen treatment. Furthermore, the AR specifically bound to the wild-type but not mutated ARE motifs-containing probes in an in vitro EMSA assay. CONCLUSION: Two ARE motifs were identified to be responsible for androgen-induced MMP-2 expression in prostate cancer cells.

Androgens↗
PubMed2005

In vivo effects of the human type I insulin-like growth factor receptor antibody A12 on androgen-dependent and androgen-independent xenograft human prostate tumors.

PURPOSE: The type I insulin-like growth factor receptor (IGF-IR) and its ligands have been shown to play a critical role in prostate carcinoma development, growth, and metastasis. Targeting the IGF-IR may be a potential treatment for prostate cancer. A fully human monoclonal antibody, A12, specific to IGF-IR, has shown potent antitumor effects in breast, colon, and pancreatic cancers in vitro and in vivo. In this study, we tested the in vivo effects of A12 on androgen-dependent and androgen-independent prostate tumor growth. EXPERIMENTAL DESIGN: Androgen-dependent LuCaP 35 and androgen-independent LuCaP 35V prostate tumors were implanted s.c. into intact and castrated severe combined immunodeficient mice, respectively. When tumor volume reached about 150 to 200 mm(3), A12 was injected at 40 mg/kg body weight thrice a week for up to 5 weeks. RESULTS: We find that A12 significantly inhibits growth of androgen-dependent LuCaP 35 and androgen-independent LuCaP 35V prostate xenografts, however, by different mechanisms. In LuCaP 35 xenografts, A12 treatment induces tumor cell apoptosis or G(1) cycle arrest. In LuCaP 35V xenografts, A12 treatment induces tumor cell G(2)-M cycle arrest. Moreover, we find that blocking the function of IGF-IR down-regulates androgen-regulated gene expression in androgen-independent LuCaP 35V tumor cells. CONCLUSIONS: Our findings suggest that A12 is a therapeutic candidate for both androgen-dependent and androgen-independent prostate cancer. Our findings also suggest an IGF-IR-dependent activity of the androgen receptor in androgen-independent prostate cancer cells.

Androgens↗
PubMed2006

Growth inhibitory concentrations of androgens up-regulate insulin-like growth factor binding protein-3 expression via an androgen response element in LNCaP human prostate cancer cells.

IGF binding protein-3 (IGFBP-3), the most abundant circulating IGF binding protein, inhibits cell growth and induces apoptosis by both IGF-I-dependent and -independent pathways. The ability of IGFBP-3 to inhibit tumor growth has been demonstrated in many cancers including prostate cancer (PCa). High concentrations of androgens, which inhibit the growth of the LNCaP human PCa cell line, have been shown to have both positive and negative effects on IGFBP-3 expression by different laboratories. To further explore the relationship between IGFBP-3 and androgens, we examined IGFBP-3 expression in LNCaP cells. We demonstrate that IGFBP-3 expression can be induced by 10 nm of the synthetic androgen R1881 or dihydrotestosterone. Transactivation assays show that the 6-kb IGFBP-3 promoter sequence directly responds to androgen treatment. In silico analysis identified a putative androgen response element (ARE) at -2,879/-2,865 in the IGFBP-3 promoter. A single point mutation in this ARE disrupted transactivation by R1881. Combining the data obtained from EMSA, chromatin immunoprecipitation and mutational analysis, we conclude that a novel functional ARE is present in the IGFBP-3 promoter that directly mediates androgen induction of IGFBP-3 expression. Furthermore, we found that the combination of androgens and calcitriol significantly potentiated the IGFBP-3 promoter activity, suggesting that enhanced induction of the expression of the endogenous IGFBP-3 gene may contribute to the greater inhibition of LNCaP cell growth by combined calcitriol and androgens. Because androgens are well known to stimulate PCa growth and androgen deprivation therapy causes PCa to regress, the stimulation by androgens of this antiproliferative and proapoptotic protein is paradoxical and raises interesting questions about the role of androgen-stimulated IGFBP-3 in PCa.

Androgens↗
PubMed1999

Differential effects of estrogen-androgen and estrogen-only therapy on vasomotor symptoms, gonadotropin secretion, and endogenous androgen bioavailability in postmenopausal women.

OBJECTIVE: To investigate somatic symptom relief, gonadotropin secretion, and endogenous androgen bioavailability (protein-bound and free) during 3 months of estrogen-androgen therapy or matched estrogen-only replacement therapy. DESIGN: Ninety-three naturally menopausal outpatients with 6 or more months of amenorrhea, who were experiencing mild-to-moderate vasomotor symptoms, were randomized to receive one of five treatments: oral esterified estrogens (0.625 mg or 1.25 mg), oral esterified estrogens combined with methyltestosterone (0.625 mg combined with 1.25 mg methyltestosterone or esterified estrogens 1.25 mg combined with 2.5 mg methyltestosterone), or placebo for 12 weeks. All treatments were preceded by a 4-week placebo lead-in period. RESULTS: Patients receiving the lower dose of estrogen-androgen therapy had fewer somatic menopausal symptoms than patients receiving the lower dose estrogen (0.625 mg), and they experienced somatic symptom relief similar to those patients receiving the higher dose of estrogen (1.25 mg). Significantly greater luteinizing hormone suppression (p < or = 0.03) occurred in estrogen-androgen groups compared to estrogen groups, suggesting that added androgen might mediate a more pronounced negative feedback on the hypothalamic-pituitary axis. Sex hormone-binding globulin increased significantly in both estrogen-treated groups (p < or = 0.01), whereas decreases occurred in both estrogen-androgen groups (p < or = 0.006). The higher dose estrogen-only preparation significantly reduced androstenedione (p < or = 0.01) and dehydroepiandrosterone sulfate (p < or = 0.005). CONCLUSION: The extent of relief with lower dose estrogen-androgen therapy was similar to higher dose estrogen-only treatment. The greater efficacy of combination therapy on somatic symptoms could be mediated by the same mechanism responsible for the suppressive effects of estrogen-androgen therapy on luteinizing hormone secretion. The marked differences in circulating levels of sex hormone building globulin, which were increased by estrogen and decreased by estrogen-androgen, and the resulting impact on bioavailable androgens and estrogens could also explain the differential somatic relief with both treatments. Endogenous adrenal androgens were lower in women treated with esterified estrogens 1.25 mg/day, suggesting that estrogen therapy can produce a significant hypoandrogenic state by inhibiting production or accelerating clearance of adrenal androgens.

Administration, Oral↗
PubMedDate not supplied

Androgen deprivation induces selective outgrowth of aggressive hormone-refractory prostate cancer clones expressing distinct cellular and molecular properties not present in parental androgen-dependent cancer cells.

PURPOSE: The mechanism of progression of human prostate cancer (CaP) cells under androgen ablation therapy remains unclear. To study the alternative pathways of CaP cell growth under conditions of androgen deprivation, androgen-independent CaP variants were selected and expanded from an androgen-dependent CaP line via an in vitro androgen deprivation treatment. Cellular and molecular properties of these androgen-independent variants were characterized both in vitro and in vivo and compared with those of their parental androgen-dependent cells. METHODS: Androgen deprivation treatment of an androgen-dependent CaP cell line, LNCaP, was carried out by replacing culture medium with RPMI 1640 medium plus 10% charcoal-stripped serum. Cells that survived through the androgen deprivation treatment were harvested and expanded in the androgen-deficient culture medium and were designated CL-1. The CL-1 cells were also recultured in androgen-containing medium and designated CL-2. The growth (cell cycle analysis, 3H-thymidine incorporation assay, growth expansion, and colonization efficiency), expression of CaP-associated markers (semiquantitative reverse transcriptase polymerase chain reaction), interaction with endothelial and bone marrow stromal cells, sensitivity to anticancer agents and radiation (growth inhibition), and tumorigenicity of CL-1 and CL-2 cells were determined and compared with these characteristics in parental LNCaP cells. RESULTS: CL-1 and CL-2 cells are fast-growing cells when compared with parental LNCaP cells. They were capable of potentiating the growth of endothelial and bone marrow stromal cells in co-culture experiments and acquired significant resistance to radiation and to anticancer cytotoxic agents (Taxol paclitaxel, vinblastine, and etoposide). In contrast to the poorly tumorigenic parental LNCaP cells, CL-1 and CL-2 lines proved highly tumorigenic, exhibiting invasive and metastatic characteristics in intact and castrated mice or in female mice within a short period of 3 to 4 weeks. No growth supplements (e.g., Matrigel) were needed. When transfected with the green fluorescence protein (GFP) gene and transplanted orthotopically in the accessory sex gland, extensive metastatic disease from the primary CL tumor could be identified in bone, lymph nodes, lung, liver, spleen, kidney, and brain. Semiquantitative reverse transcriptase polymerase chain reaction analysis revealed a markedly distinct molecular expression profile in the CL lines: overexpression of basic fibroblast growth factor, interleukin-6, interleukin-8, vascular endothelial growth factor, transforming growth factor-beta, epidermal growth factor receptor, caveolin, and bcl-2 messenger RNAs and marked down-regulation of E-cadherin, p-53, and pentaerythritol tetranitrate. CONCLUSIONS: Early administration of hormonal therapy after failure of first-line treatment is associated with a profound clonal selection of aggressive AI variants, such as CL-1 and CL-2 lines. These tumor lines, with their parental counterparts, can serve as valuable tools for studying the cellular and molecular mechanisms of CaP progression and metastasis under hormonal therapy. CL-1 and CL-2 offer a unique and reproducible model for the evaluation of drug sensitivity and for other therapeutic modalities for advanced prostate cancer.

Androgens↗
PubMed1999

One and the same androgen for all? Towards designer androgens.

The introduction of designer oestrogens as a treatment modality in hormone replacement in women has invited to consider the concept of compounds with selective androgenic effects for male hormone replacement therapy. The full spectrum of the actions of testosterone may not be necessary of even undesired for certain indications for testosterone treatment. To define for what indications certain androgenic properties are desired and undesired more insight in basic androgen (patho)physiology is required. There is convincing evidence that aromatization of androgenic compounds to oestrogens might be an advantage for maintenance of bone mass and it might also mitigate negative effects of androgens on biochemical parameters of cardiovascular risks; the potentially negative effects of oestrogens on prostate pathology in ageing men needs further elucidation. While the role of dihydro-testosterone (DHT) for the male sexual differentiation and for pubertal sexual maturation is evident, its role in mature and ageing males seems less significant or may even be harmful. It is, however, of note that a negative effect of DHT on prostate pathophysiology is certainly not proven. For male contraception a progestational agent with strong androgenic properties might be an asset. For most of the androgenic actions the critical levels of androgens are not well established. The latter is relevant since the large amount of androgen molecules required for its biological actions (as compared to oestrogens) is an impediment in androgen replacement modalities. There may be room for more biopotent androgens since delivery of large amounts of androgen molecules to the circulation poses problems for treatment modalities.

Aging↗
PubMed1999

Direct androgenic regulation of calcitonin gene-related peptide expression in motoneurons of rats with mosaic androgen insensitivity.

The spinal nucleus of the bulbocavernosus (SNB) and its target muscles, bulbocavernosus and levator ani (BC/LA), form a sexually dimorphic neuromuscular circuit whose development and maintenance are androgen-dependent. The mechanisms whereby androgen regulates gene expression in the SNB of adult rats are largely unknown, although a retrograde influence from the BC/LA muscles has been suggested to underlie the suppression of calcitonin gene-related peptide (CGRP) expression observed in SNB motoneurons after systemic androgen treatment. A mosaic paradigm was used to determine the site of action of androgen in the regulation of CGRP expression in SNB motoneurons. As a consequence of random X chromosome inactivation, androgenized female rats heterozygous for the tfm androgen receptor (AR) mutation (XwtXtfm-mosaics) express a mosaic of androgen-sensitive and androgen-insensitive motoneurons in the SNB, whereas the BC/LA target musculature appears to be uniformly sensitive to androgens. In adult mosaics, testosterone administration resulted in a reduction in the proportion of androgen-sensitive cells expressing CGRP, whereas no such reduction was observed in the androgen-insensitive population, indicating that neuronal AR plays an essential role in the neuromuscular regulation of CGRP expression in these motoneurons. This provides the first in vivo demonstration of AR regulation of gene expression unambiguously localized to a neuronal population.

Androgen-Insensitivity Syndrome↗
PubMed1976

Androgen-uterine interaction: nuclear translocation of the estrogen receptor and induction of the synthesis of the uterine-induced protein (IP) by high concentrations of androgens in vitro but not in vivo.

High concentrations of androgens in vitro [10(-6) and 10(-7)M 5alpha-dihydrotestosterone (DHT) and testosterone (T)] translocate the estrogen receptor from cytoplasmic to the nuclear fraction of the immature rat uterus, and the androgen translocated sites are capable of eliciting the synthesis of the specific uterine "induced protein" (IP), formerly attributed to estrogenic compounds only. The magnitude of receptor translocation and IP synthesis induction is related to the concentration of androgen, and, at equal concentrations, DHT is more effective than T. Competitive protein-binding asssays with cell-free uterine cytosol indicate that DHT and T bind with barely detectable affinity to the cytosol estrogen receptor detectable affinity to the cytosol estrogen receptor [relative binding ability ca. 0.001% that of estradiol (E2)], and radioactive E2 uptake into whole uterus after pretreatment with androgens indicates that the androgen-translocated nuclear sites are readily filled by E2. DHT and T translocate the estrogen receptor to the nucleus in vitro, and the salt-extracted nuclear receptor is present as a 5 S ("transformed") receptor; however, concentrations of DHT and T that effect translocation are unable to elicit the heat-activated transformation of the estrogen receptor in cell free cytosol under conditions in which low concentrations of E2 fully transform the receptor. Under in vivo conditions, high levels of androgens (5--2,000 mug DHT or T) do not evoke any detectable translocation of the estrogen receptor and do not elicit any IP synthesis induction although uterine weight is increased (greater than 200 mug androgen) in long-term (2--3 day) assays. The analysis of androgen uptake and metabolism indicates that 500 mug or higher doses of DHT or T in vivo result in uterine concentrations of unmetabolized DHT or T equal to those seen after exposure to 5 X 10(-7) - 1 X 10(-6)M DHT or T in vitro. Hence, under conditions where in vivo and in vitro tissue uptake of androgen is equivalent, in vivo androgens are unable to affect the estrogen receptor system as is seen in vitro. These studies indicate that the in vitro and in vivo effects of androgens on the uterus are clearly different and suggest that the actions of androgens on the uterus in vivo are probably not directly mediated through the estrogen receptor system.

Animals↗
PubMed2000

Use, misuse and abuse of androgens. The Endocrine Society of Australia consensus guidelines for androgen prescribing.

Androgen replacement therapy (ART) is usually life-long, and should only be started after androgen deficiency has been proven by hormone assays. The therapeutic goal is to maintain physiological testosterone levels. Testosterone rather than synthetic androgens should be used. Oral 17 alpha-alkylated androgens are hepatotoxic and should not be used for ART. There is no indication for androgen therapy in male infertility. Although androgen deficiency is an uncommon cause of erectile dysfunction, all men presenting with erectile dysfunction should be evaluated for androgen deficiency. If androgen deficiency is confirmed, investigation for the underlying pathological cause is required. Contraindications to androgen therapy are prostate and breast cancer. Precautions include using lower starting doses for older men and induction of puberty. Intramuscular injections should be avoided in men with bleeding disorders. Androgen-sensitive epilepsy, migraine, sleep apnoea, polycythaemia or fluid overload need to be considered. Competitive athletes should be warned about the risks of disqualification. ART should be initiated with intramuscular injections of testosterone esters, 250 mg every two weeks [corrected]. Maintenance requires tailoring treatment modality to the patient's convenience. Modalities currently available include testosterone injections, implants, or capsules. Choice depends on convenience, cost, availability and familiarity. There is no convincing evidence that, in the absence of proven androgen deficiency, androgen therapy is effective and safe for older men per se, in men with chronic non-gonadal disease, or for treatment of non-specific symptoms. Until further evidence is available, such treatment cannot be recommended.

Anabolic Agents↗
PubMed1993

Up-regulation of androgen receptor immunoreactivity in the rat brain by androgenic-anabolic steroids.

To characterize central nervous system changes that occur with anabolic steroid abuse in humans, immunocytochemical localization of androgen receptors in the brains of 10 intact and 10 castrated male rats was conducted after the administration of high levels of androgenic-anabolic steroids (AAS; 14 daily injections of sesame oil or a cocktail of 2 mg/kg testosterone cypionate, 2 mg/kg nandrolone decanoate, and 1 mg/kg boldenone undecylenate). In normal intact oil-treated males, nuclear androgen receptor immunoreactivity was present in many 'classical' and 'non-classical' androgen target sites in the brain. Administration of AAS increased the intensity of immunoreactivity in most classical androgen target sites and increased both the intensity of immunoreactivity and number of immunoreactive cells in most non-classical androgen target sites. These results may suggest that androgen receptors in the brain are up-regulated by AAS. The simultaneous androgen receptor up-regulation in these regions by AAS may account for the complex anabolic steroid abuse syndrome. Consistently, androgen receptor immunoreactivity in most brain regions was reduced or absent after castration, suggesting that endogenous androgen levels are necessary for normal androgen receptor immunoreactivity. These results identify the distribution of one central nervous system mechanism modified by AAS.

Anabolic Agents↗
PubMed1990

The 56 kDa androgen-binding protein in human genital skin fibroblasts: its relation to the human androgen receptor.

We have recently described in genital skin fibroblasts (GSF) a relatively abundant 56 kDa protein with androgen-binding activity. This protein is missing in GSF of most patients with complete androgen insensitivity syndrome (CAI). The protein has many characteristics compatible with the androgen receptor; it has in fact been tentatively considered as a precursor or degradation form of the prototypic (approximately 100 kDa) human androgen receptor. We have prepared an antiserum to this protein, which allowed us to detect it as a direct product by in vitro translation of mRNA from GSF. It is thus very unlikely to be a degradation product of a larger precursor. Furthermore, covalent photolytic labeling of this protein with the androgen analogue [3H]mibolerone revealed a much lower affinity for this protein than is known for the androgen receptor. Finally, the GSF of two exceptional patients with complete androgen insensitivity syndrome due to negligible androgen receptor-binding activity express this protein normally, as determined on two-dimensional gels by Western blot analysis with the antiserum and by photolytic covalent labeling with androgen analogues. These data indicate that the protein is not a precursor or a degradation product of the receptor; nor is it androgen-induced. They are more compatible with the idea that the protein is another member of the steroid/thyroid/retinoic acid receptor supergene family, perhaps as an unorthodox product of the human androgen receptor gene.

Androgen-Binding Protein↗
PubMed2004

Study on anti-androgenic effects of bisphenol a diglycidyl ether (BADGE), bisphenol F diglycidyl ether (BFDGE) and their derivatives using cells stably transfected with human androgen receptor, AR-EcoScreen.

We studied in vitro hormonal activity of bisphenol A diglycidyl ether (BADGE) and bisphenol F diglycidyl ether (BFDGE), which are used as a material of interior coating for food cans. We also examined related compounds such as 2,2-bis[4-(3-chloro-2-hydroxypropoxy)phenyl]propane (BADGE.2HCl), and bis[4-(3-chloro-2-hydroxypropoxy)phenyl]methane (BFDGE.2HCl) etc. For this purpose, we constructed two stably transfected CHO-K1 cell lines (AR-EcoScreen for androgenic activity and c-luc for cell toxicity evaluation). One stably expresses luciferase with induction of androgen. The other stably expresses luciferase without androgen induction. Also, we have determined the androgenic and anti-androgenic effects of the test chemicals by reporter gene assay with these cell lines. None of the chemicals tested by this assay exhibited androgen agonistic activity. However, BADGE.2HCl and BFDGE.2HCl had the conspicuous antagonistic activity for androgen. These compounds had a high binding affinity for androgen receptor. Furthermore, these two compounds did not show the estrogenic activity in vitro assays. On the contrary, bisphenol A and bisphenol F exhibited anti-androgenic activity in vitro in addition to the estrogenic activity. These results suggest that these chlorohydroxy compounds of BADGE and BFDGE act as androgen antagonist through the process of binding to androgen receptor.

Androgen Antagonists↗