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PubMedDate not supplied

Androgen and estrogen-androgen hormone replacement therapy: a review of the safety literature, 1941 to 1996.

The endocrine physiology of the climacteric supports a rationale for the concomitant replacement of androgen and estrogen following menopause. Clinical and research experience with estrogen-androgen hormone replacement therapy, as well as androgen-only therapy, suggests that the health benefit offered by androgen replacement exceeds the potential risk when treatment is properly managed. In this review, we concentrate on the effects of oral alkylated androgens. The virilizing effects (e.g., hirsutism, acne, voice change, and alopecia) of oral androgens are typically dose and duration dependent; androgen replacement at doses < or = 10 mg once daily administered for prolonged periods (> 6 months) produces masculinization effects that generally abate with dose reduction or discontinuation of treatment. No clinical sequelae or irreversible pathophysiologic effects have been associated with any virilization that may occur. Changes in lipoprotein metabolism associated with oral estrogen-androgen use include reduced total cholesterol levels and reduced high-density lipoprotein cholesterol levels which may reduce the long-term risk of cardiovascular disease. No clinically identifiable risk with respect to other cardiovascular variables, such as blood pressure, has been associated with the longterm administration of low doses of oral androgen. With regard to liver toxicity, reports of jaundice, peliosis hepatis, and hepatocellular carcinoma are extremely rare at the dose levels of androgen used in hormone replacement therapy, although individual sensitivity to the potential hepatotoxic effects of oral alkylated and nonalkylated androgen may vary considerably. Daily dosing with oral alkylated androgen in combination with estrogen is well tolerated. Retrospective and prospective studies involving the use of androgens alone and in combination with estrogens demonstrate that concerns about the adverse effects of androgen use associated with supraphysiologic, self-escalated doses in men do not apply to the much lower doses combined with estrogens for hormone replacement in postmenopausal women.

Androgens↗
PubMed1996

Characteristics of androgen-independent growth of androgen-responsive Shionogi carcinoma 115 cells.

BACKGROUND: The effects of castration on the biological features of an androgen-responsive carcinoma were examined in order to clarify the mechanism responsible for the relapse of an androgen-responsive carcinoma after androgen ablation therapy. METHODS: A well-characterized androgen-responsive mammary carcinoma, Shionogi carcinoma 115 (SC115), was used for these experiments. Male mice were examined for the effects of castration on the growth rate of the tumor, the number of androgen receptor-positive cells, and the karyotype of the SC115 tumors. Castration was performed 1 week prior to tumor transplantation, or 2 or 3 weeks after tumor transplantation. RESULTS: SC115 tumors did not develop when transplanted into castrated male mice. When castration was performed 2 weeks after transplantation, the tumor showed androgen-independent growth with temporary regression of growth rate. However, when castration was performed more than 3 weeks after transplantation, the tumor showed androgen-independent growth not associated with any temporal regression of growth rate. There were no significant differences in histological features or the number of androgen receptor-positive cells between SC115 tumors in untreated or castrated mice. To test whether SC115 tumors growing under androgen-deprived conditions became fully androgen-independent, SC115 tumors were transplanted in both male and female mice. A transplanted tumor piece grew progressively only in male mice. This indicates that the SC115 tumor maintains its androgen response in the next generation, even though growth of the tumor resumed after temporary suppression due to castration. Chromosomal analyses revealed no apparent cytogenetic changes in the SC115 tumors that resumed growth under androgen-deprived conditions. CONCLUSION: These results suggest that no gross changes in the number of androgen receptor-positive cells or karyotype are necessary for androgen-independent growth in this system once the size of tumor increased.

Androgens↗
PubMed2006

Time-dependent rescue of gene expression by androgens in the mouse proximal caput epididymidis-1 cell line after androgen withdrawal.

Androgens are the primary regulators of epididymal structure and functions. Principal cells are the major cell type of the tissue and are particularly sensitive to androgen removal. To distinguish the direct effects of androgens on this cell type, DNA microarrays were used to identify androgen-regulated genes in the mouse proximal caput epididymidis (PC-1) cell line. PC-1 cells display tissue- and caput-specific gene expression. We examined changes in gene expression occurring 2, 4, and 6 d after androgen deprivation and 2 d after androgen supplementation after being deprived of androgen for 2 or 4 d. Changes in transcript levels were investigated for mediators of androgen action; selected genes were analyzed by real-time RT-PCR, and changes at the protein levels were examined. Four distinct patterns of gene expression were activated after androgen withdrawal; the vast majority of genes displayed an early or late transient increase in expression levels. A differential ability of rescue was seen among androgen-regulated genes, depending on time of androgen supplementation. Many of the genes that were rescued at 4 d were functionally linked by direct interactions and converged on IGF-I. The ability for rescue after 4 d of androgen deprivation was severely compromised in many genes belonging to specific functional gene families (cell adhesion, cell growth, apoptosis, and cell cycle) and may be mediated in part by changes in androgen receptor coregulator expression. These results provide novel insights into the mechanisms of androgen regulation in epididymal principal cells.

Androgens↗
PubMed2005

Induction of AP-1 activity by androgen activation of the androgen receptor in LNCaP human prostate carcinoma cells.

BACKGROUND: The androgen receptor and activator protein-1 (AP-1) transcription factors affect growth regulation in normal and cancerous prostate cells. Effects of androgen-activated androgen receptor on AP-1 activity were determined in the LNCaP human prostate carcinoma cell model. METHODS: Cells were exposed to 1 nM androgen +/- antiandrogen bicalutamide. Cellular growth and cell cycle effects were determined by DNA, viability, and bromodeoxyuridine (BrdU) fluorescence activated cell sorter (FACS) assays. AP-1 effects were determined by an AP-1-luciferase enzyme reporter vector for transcriptional activity, electrophoretic mobility shift assay (EMSA)/antibody supershift for DNA-binding, quantitative RT-PCR for mRNA, and immunoblot for protein. RESULTS: Androgen induced G(1) growth arrest. This growth arrest was abrogated by treatment with bicalutamide, demonstrating that growth arrest by androgen was due to androgen receptor activation. Concurrently, AP-1 DNA-binding and transcriptional activity was induced over 96 hr androgen exposure, which was also inhibited by bicalutamide. Interestingly, although no change in AP-1 transcriptional activity was observed 24 hr after androgen exposure, there was an increase in Fra-2 expression and AP-1 DNA-binding. Paradoxically, while Fra-2 mRNA and protein levels continued to increase, binding of Fra-2 to the AP-1 site decreased over 96 hr, with a concomitant increase in JunD AP-1-binding and a marked increase in expression of the 35 kDa form of JunD. Enhanced expression of this short form of JunD is a novel effect of androgen exposure that occurred during the 24-96 hr time period, as growth effects emerged. CONCLUSION: Activation of androgen receptor by androgen induces changes in AP-1 activity and AP-1 factor DNA-binding that may contribute significantly to androgen-induced changes in prostate cancer cell growth.

Androgen Antagonists↗
PubMed1988

Follicle-stimulating hormone and androgens increase the concentration of the androgen receptor in Sertoli cells.

The influence of FSH and androgens on androgen receptor levels in primary Sertoli cell cultures from immature rats is studied in a monolayer binding assay and by sucrose density gradient centrifugation using the synthetic radiolabeled androgen mibolerone (7 alpha, 17 alpha-dimethyl-19-nortestosterone) as a ligand. Preincubation of Sertoli cells for 4 days with FSH, testosterone, or 5 alpha-dihydrotestosterone results into a 2- to 3-fold increase in mibolerone binding, as measured 18 h after removal of the agonists. The combination of androgens and FSH has additive effects. The action of FSH can be mimicked by (Bu)2cAMP, and the activity of the androgens can be blocked by the antiandrogen cyproterone acetate. The mibolerone-binding protein has the ligand specificity, affinity, and sedimentation behavior characteristic for an androgen receptor. Using a DEAE-cellulose filter disc assay and 5 alpha-dihydrotestosterone as a ligand, androgen-binding protein (ABP) was measured in the media of the studied Sertoli cell cultures. Despite some similarity in the hormonal control of ABP and the androgen receptor, there are distinct differences in the ligand specificity of the two androgen binding proteins, which exclude that ABP might interfere with the receptor measurements. The effects of androgens and FSH on the androgen receptor are evident at concentrations equal to or lower than those required to provoke a measurable increase in ABP secretion. It is concluded that FSH and androgens control androgen receptor levels in Sertoli cells.

Androgen-Binding Protein↗
PubMed2002

Disruption of androgen receptor function inhibits proliferation of androgen-refractory prostate cancer cells.

Prostate cancer cells depend on androgens and the androgen receptor (AR) for survival. However, after androgen ablation therapy, tumors relapse to an androgen-refractory state. To determine whether the androgen receptor is critical for proliferation of androgen-refractory prostate cancer cells, we disrupted the activity of the androgen receptor with an antibody and an AR mRNA hammerhead ribozyme in the following cell lines: LNCaP (androgen-sensitive), LNCaP-Rf and LNCaP-C4 (androgen-refractory), and DU-145 (androgen-insensitive). Microinjection of either antibody or ribozyme inhibited proliferation of androgen-refractory cells. These findings demonstrate that the AR is critical for proliferation of androgen-refractory cells, even in the absence of androgens.

Androgen Antagonists↗
PubMed2003

Enhanced androgen receptor signaling correlates with the androgen-refractory growth in a newly established MDA PCa 2b-hr human prostate cancer cell subline.

Bone metastasis is commonly found in prostate cancer (PC) patients. Although the mechanisms for the recurrence of bone metastasis-derived PC during medical or surgical castration therapy are still unclear because of the lack of suitable experimental models, one hypothesis is that enhanced androgen receptor (AR) signaling causes androgen-refractory PC growth. To test this hypothesis, we first established a novel androgen-refractory MDA PCa 2b cell subline, MDA PCa 2b-hr, which was generated in vitro from bone metastasis-derived, androgen-dependent MDA PCa 2b human PC cells after approximately 35 weeks of growth suppression by androgen-depletion treatment to mimic the clinical PC recurrence during androgen-ablation therapy. The changes of the androgen responsiveness of growth and the AR expression levels during the transition from an androgen-dependent to androgen-refractory proliferative phase through a temporal growth-suppressed phase precisely paralleled that of the basal growth rate. Furthermore, the androgen-refractory growth of MDA PCa 2b-hr cells in androgen-depleted medium was suppressed by an antiandrogen, bicalutamide. Next, we established nude mouse xenograft models to clarify whether AR signaling in MDA PCa 2b-hr cells is also enhanced in vivo. Both the MDA PCa 2b and MDA PCa 2b-hr tumors grew in gonadally intact mice, but only the MDA PCa 2b-hr tumors grew in castrated mice. The growth rate of MDA PCa 2b-hr tumors was significantly higher in gonadally intact mice than in castrated mice. Treatment with dehydroepiandrosterone pellets, which produced clinical castration levels of serum testosterone, accelerated the MDA PCa 2b-hr but not MDA PCa 2b tumor growth in castrated mice and increased blood prostate-specific antigen levels in castrated mice bearing MDA PCa 2b-hr tumors but not in mice bearing MDA PCa 2b tumors. Our data suggest that the enhanced AR signaling should be closely correlated with the androgen-refractory growth of human bone metastasis-derived PC, which might come to use adrenal androgens remaining in the blood even after castration therapy and warrant the continuation of hormone therapy for the recurrent PC.

Androgen Antagonists↗
PubMed2006

Inhibition of interleukin-6 with CNTO328, an anti-interleukin-6 monoclonal antibody, inhibits conversion of androgen-dependent prostate cancer to an androgen-independent phenotype in orchiectomized mice.

Initially, prostate cancer is androgen dependent. However, most cases progress to an androgen-independent state through unknown mechanisms. Interleukin-6 (IL-6) has been associated with prostate cancer progression including activation of the androgen receptor (AR). To determine if IL-6 plays a role in the conversion of prostate cancer from androgen dependent to androgen independent, we established androgen-dependent LuCaP 35 human prostate cancer xenografts in nude mice, castrated the mice, and blocked IL-6 activity using a neutralizing antibody (CNT0328) for a period of 18 weeks. IL-6 inhibition increased survival of mice and inhibited tumor growth, as reflected by decreased tumor volume and prostate-specific antigen levels, compared with that in mice receiving isotype control antibody. To test the effect of IL-6 inhibition on the conversion from androgen dependent to androgen independent, tumor cells from the treated mice were assessed for their androgen dependence both in vitro and by implanting them into sham-operated or orchiectomized mice. Tumor cells derived from the isotype-treated animals converted to androgen-independent state, whereas tumor cells from the anti-IL-6 antibody-treated mice were still androgen dependent in vitro and in vivo. Although there was no difference in AR levels between the androgen-independent and androgen-dependent tumors, IL-6 inhibition promoted both apoptosis and inhibited cell proliferation in tumors and blocked the orchiectomy-induced expression of histone acetylases, p300 and CBP, which are AR cofactors. These data show that IL-6 contributes to the development of androgen independence in prostate cancer and suggest that it mediates this effect, in part, through modulation of p300 and CBP.

Animals↗
PubMed1994

An in vitro model for the effects of androgen on neurons employing androgen receptor-transfected PC12 cells.

Androgen alters neurite outgrowth, synaptic organization, and cell survival in various portions of the brain and spinal cord. However, examination of the specific effects of androgen on neurons in vivo has been difficult. Previously, an in vitro model for the effects of estrogen on neurons was developed and characterized, using an estrogen receptor (ER)-transfected PC12 rat pheochromocytoma cell line. This model demonstrated estrogenic regulation of neurite outgrowth, spine formation, and gap junction formation. Similarly, an in vitro model for the effects of androgen on neurons is now described. Wild-type cells (PC12-WT) were stably transfected with an expression vector coding for the full-length cDNA for the human androgen receptor (AR). Resultant clones were isolated, screened for incorporation of vector and expression of AR mRNA and protein, and analyzed for morphologic responses to androgen. PC12-WT, NE09 (ER-negative, AR-negative), SER8 (ER-positive, AR-negative), and AR8 (ER-negative, AR-positive) cells were exposed to 10 ng/ml nerve growth factor (NGF), along with 0-10(-7) M dihydrotestosterone (DHT) for 2 days. AR8 cells demonstrated an androgen dose-dependent increase in mean neurite length, branch order, and neurite field area, whereas neurite branch segment length and soma area were not affected by androgen. PC12-WT, NE09, and SER8 cells exhibited no alterations in cell morphology with DHT exposure. Because of the synergistic effects of DHT and NGF, the regulation of NGF receptor mRNA by DHT was evaluated; however, no significant induction of either trkA or p75 mRNA expression by androgen was documented. The results suggest that in AR-positive PC12 cells, androgen acts additively with NGF to increase neurite outgrowth; but androgen effects are mediated specifically through branching and arborization. These responses are similar to developmental studies of androgen effects in vivo. Thus, androgen appears to induce an inherent neural morphologic program in AR-containing cells, which increases the receptive field of these cells, increasing the likelihood for interneural communication, although not promoting communication itself. These cell lines will provide a unique in vitro system for studying mechanisms of androgen-neuron interactions.

Androgens↗
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↗
PubMed1997

Absence of androgen-mediated transcriptional effects in osteoblastic cells despite presence of androgen receptors.

Androgen excess and deficiency affect skeletal maturation and bone cell function. Understanding the molecular basis for these androgen effects could improve therapy/prevention of short stature and osteoporosis. Androgens act through binding to androgen receptors (ARs), which modulate gene transcription via interactions with DNA response elements on target genes. Because osteoblasts contain ARs at levels just below certain androgen-sensitive tissues, we sought to define the function of AR in a number of commonly used osteoblastic cell lines. Presence and quantification of AR protein and mRNA were evaluated by ligand binding assay, western blotting, and RNAse protection assay. AR-containing osteoblastic cell lines were exposed to nonaromatizable androgens and effects on gene expression were assessed. We found no evidence for direct effects of androgen on endogenous genes nor was androgen involved in modulation of parathyroid hormone effects on early gene activation. Androgen-sensitive reporter gene constructs were stimulated by androgen only when AR cDNA expression vectors were introduced into cells by cotransfection. We conclude that, in commonly used osteoblastic cell lines, the presence of AR at the levels described here does not guarantee androgen transcriptional activity. The effects of androgen on bone in vivo may involve direct stimulation of osteoblastic cells in a different setting or stage of differentiation. Alternatively, androgen may act on bone cells other than osteoblasts, or through metabolic conversion to estrogens.

Androgens↗
PubMed1988

A study of androgen-resistant subjects indicates that the 6.7 pI/56 kDa protein in genital skin fibroblasts is related to the androgen receptor.

Two-dimensional gel electrophoresis of cultured human skin fibroblast lysates reveals a silver-stained "spot" of molecular mass 56 kilodaltons (kDa) and isoelectric point (pI) 6.7, occasionally as part of a doublet with a minor pI 6.5 partner. Its presence in each of 23 genital skin fibroblast strains (6 labium majus, 17 prepuce) and its absence in 30 of 32 control non-genital skin fibroblast strains accords with the 3-fold greater concentration of androgen-receptor activity in the former. However, the size and intensity of the spot do not change when cells are preincubated for 48 hours with 3 nM methyltrienolone (MT, a non-metabolizable androgen), and it is pulse-labeled with [35S]methionine to an autoradiographically equal extent, with or without incubation in 3 nM MT for 2 or 16 hours. Furthermore, the protein identified by the spot is found in the labium majus skin fibroblast strains from 2 of 12 unrelated subjects with complete androgen resistance due to negligible androgen-receptor activity, but it is absent from those of 2 others who have the same phenotype despite a normal level of qualitatively abnormal androgen-receptor activity. Hence, it is very unlikely to be an androgen-induced protein, and it cannot be a functional version of the androgen receptor itself. Its absence in 12 of 14 labium majus strains of subjects with complete androgen resistance, regardless of 5 alpha-reductase activities, indicates that it is neither a constitutive cytotypic marker of genital skin fibroblast differentiation nor a reflection of that enzyme. When intact prepuce fibroblasts are covalently labeled by photolysis with 50 nM [3H]MT, the only specific labeling detectable after two-dimensional electrophoresis is in the 6.7 and 6.5 pI doublet of the 56 kDa protein. Considering the sensitivity of silver staining and the incomplete concordance between the androgen-receptor activity of a strain and the size/intensity of its 6.7 pI/56 kDa spot on the gels, we postulate the latter to be a comparatively abundant androgen-binding protein that is causally related to the androgen receptor. The precise nature of this relation remains to be elucidated by use of novel immunologic and/or nucleic acid probes for this protein and for the mature androgen receptor. In any event, the presence or absence of the 6.7 pI/56 kDa protein in genital skin fibroblast lysates is a new marker of genetic heterogeneity within the class of complete androgen resistance.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1997

Comparison of androgen-independent growth and androgen-dependent growth in BPH and cancer tissue from the same radical prostatectomies in sponge-gel matrix histoculture.

BACKGROUND: In order to determine androgen sensitivities of prostate cancer and benign prostatic hypertrophy (BPH) tissues from the same patient in vitro, we used a histoculture technique to measure androgen-independent and androgen-dependent growth and compared them in paired specimens of BPH and prostate cancer from 23 radical prostatectomies. Both androgen-independent growth and androgen-dependent growth are measures of important biological characteristics of benign and malignant prostate tissue. METHODS: The effect of hydroxyflutamide and antiandrogens on dihydrotestosterone (DHT)-stimulated incorporation of 3H-thymidine into both paired specimens of BPH and cancer was utilized to measure androgen-independent and androgen-dependent growth. The percentage decrease in 3H-thymidine incorporation/microgram protein in the flutamide-treated specimen compared to the DHT-treated specimen represented androgen-dependent growth. Residual 3H-thymidine incorporation/microgram protein during hydroxyflutamide administration represented androgen-independent growth. RESULTS: Androgen-independent growth was significantly greater (P = 0.015) in the BPH compared to the cancer paired tissue. Androgen-dependent growth was significantly higher in 23 paired specimens of cancer compared to BPH (P < 0.03). CONCLUSIONS: In paired specimens of BPH and prostate cancer from the same radical prostatectomy specimen, androgen-independent growth appeared greater in BPH compared to cancer specimens; androgen-dependent growth, however, was greater in prostate cancer than in BPH. There was no correlation of either growth parameter with Gleason tumor grade. Future clinical correlations will indicate whether either growth parameter represents an important prognostic factor for prostate cancer aggressiveness stimulated 3H-thymidine incorporation into DNA.

Androgens↗
PubMed2000

Differentially expressed mRNAs in androgen-independent but not androgen-dependent Shionogi carcinoma.

UNLABELLED: Recently, a new and highly effective method termed suppressive subtractive hybridization (SSH) has been introduced to clone differentially expressed mRNAs. Genes expressed in androgen-independent but not in androgen-dependent tumors, and vice versa, are obviously significant to delineate the mechanisms of androgen dependency/independency of these tumors. Mouse mammary cancer (Shionogi carcinoma-115) has been extensively used to analyze the mechanism of androgen-dependent cancer growth. METHODS: We cloned androgen-independent and androgen-dependent Shionogi carcinoma-115 specific mRNAs by the SSH method. Cloned sequences were compared with known sequences using NCBI BLAST across the Internet. Two clones were positive for cDNA insert when androgen-independent cDNA was used as tester cDNA, while no clones were positive using the androgen-dependent tester cDNA. One of the former was mouse protein kinase C beta-II while the other was a new DNA sequence. Mouse protein kinase C beta-II mRNA and the new mRNA were shown to be differentially expressed by RT-PCR analysis in androgen-independent but not androgen-dependent Shionogi carcinoma. Two mRNA species differentially expressed in androgen-independent but not androgen-dependent Shionogi carcinoma were cloned by the SSH method. The significance of these mRNAs for androgen-dependency/independency of Shionogi carcinoma should be explained in future studies.

Androgens↗
PubMed1995

Effect of androgens and their manipulation on cell growth and androgen receptor (AR) levels in AR-positive and -negative human hepatocellular carcinomas.

BACKGROUND/AIMS: Little is known about genuine roles of androgens and their receptor in hepatocellular carcinoma. METHODS: In the present study, two sublines derived from a human hepatocellular carcinoma cell line KYN-1 were used: KYN-1/SM10 with androgen receptor and KYN-1/SM2 without androgen receptor. RESULTS: The binding assay with 3H-R1881 identified the presence of both cytosolic and nucleosolic androgen receptors in KYN-1/SM10 but not in KYN-1/SM2. In serum-free medium, dihydrotestosterone was able to enhance the cell proliferation and 3H-thymidine incorporation in androgen receptor positive KYN-1/SM10 cells. Such effects of dihydrotestosterone were partially inhibited by an antiandrogen cyproterone acetate in a concentration-dependent manner. On the other hand, the growth of androgen receptor negative KYN-1/SM2 cells was not influenced by dihydrotestosterone and cyproterone acetate at all. When dihydrotestosterone was removed from the medium of KYN-1/SM10 cultures, the nucleosolic androgen receptor decreased to undetectable levels within 8 h and the cytosolic androgen receptor within 48 h. Addition of dihydrotestosterone (10 nM) to the cells that had been deprived of dihydrotestosterone for 24 h partially restored both cytosolic and nucleosolic androgen receptor within 12 h. CONCLUSION: The current results seem to indicate that the growth of androgen receptor positive human hepatocellular carcinoma may be enhanced with androgen through androgen receptors and that antiandrogen therapy with cyproterone acetate may be effective in the treatment of androgen receptor-positive hepatocellular carcinoma.

Carcinoma, Hepatocellular↗
PubMed2006

Androgen glucuronides, instead of testosterone, as the new markers of androgenic activity in women.

Despite the long series of cohort studies performed during the last 20 years, the correlation between serum testosterone and any clinical situation believed to be under androgen control in women has remained elusive. This is likely related to the recent finding that the androgens made locally in large amounts in peripheral tissues from the precursor dehydroepiandrosterone (DHEA) act in the same cells where synthesis takes place and are not released in significant amounts in the circulation, thus making unreliable the measurement of serum testosterone as marker of total androgenic activity. The objective is to determine if serum androgen glucuronides can be replaced by testosterone or another steroid as measure of androgenic activity. Since the glucuronide derivatives of androgens are the obligatory route of elimination of all androgens, these metabolites were measured by liquid chromatography tandem mass spectrometry under basal conditions in 377 healthy postmenopausal women aged 55-65 years as well as in 47 premenopausal women aged 30-35 years while testosterone was assayed by gas chromatography mass spectrometry. No correlation was found between the serum concentration of testosterone and that of androsterone glucuronide (ADT-G) or androstenediol glucuronide (3alpha-diol-G), the androgen metabolites which account for the total pool of androgens. The present data show that measurement of the total pool of androgens reflected by the serum levels of ADT-G and 3alpha-diol-G cannot be replaced by serum testosterone or any other steroid, including DHEA or DHEA sulphate. These findings may have implications for women with androgen deficiency involving osteoporosis, obesity, type 2 diabetes, sexual dysfunction, loss of muscular strength and a series of other clinical situations affecting women's health. Measuring ADT-G and 3alpha-diol-G might identify cases of true androgen deficiency and provide an opportunity to offer appropriate androgen therapy.

Adult↗
PubMed1990

Aberrant splicing of androgen receptor mRNA results in synthesis of a nonfunctional receptor protein in a patient with androgen insensitivity.

Androgen insensitivity is a disorder in which the correct androgen response in an androgen target cell is impaired. The clinical symptoms of this X chromosome-linked syndrome are presumed to be caused by mutations in the androgen receptor gene. We report a G----T mutation in the splice donor site of intron 4 of the androgen receptor gene of a 46,XY subject lacking detectable androgen binding to the receptor and with the complete form of androgen insensitivity. This point mutation completely abolishes normal RNA splicing at the exon 4/intron 4 boundary and results in the activation of a cryptic splice donor site in exon 4, which leads to the deletion of 123 nucleotides from the mRNA. Translation of the mutant mRNA results in an androgen receptor protein approximately 5 kDa smaller than the wild type. This mutated androgen receptor protein was unable to bind androgens and unable to activate transcription of an androgen-regulated reporter gene construct. This mutation in the human androgen receptor gene demonstrates the importance of an intact steroid-binding domain for proper androgen receptor functioning in vivo.

Animals↗
PubMed1992

Mechanism of androgen action in cultured dermal papilla cells derived from human hair follicles with varying responses to androgens in vivo.

Androgens are major regulators of human hair growth, but their effects vary: many follicles are stimulated by androgens, e.g., beard; some remain unaffected, e.g., eyelashes; whereas scalp follicles undergo regression and balding in genetically disposed individuals. Because the dermal papilla controls many aspects of the hair follicle, androgens may act via the dermal papilla, affecting the other follicular components indirectly. In this hypothesis androgens would alter dermal papilla cell production of regulatory substances, e.g., growth factors and/or extracellular matrix components. To test this theory the mechanism of androgen action has been compared in primary lines of dermal papilla cells cultured from androgen-dependent follicles and relatively androgen-independent non-balding scalp. Androgen receptor levels were assayed by saturation analysis (9-10 points; 0.05-10 nmol/l) using the synthetic androgen [3H]-mibolerone and specificity was confirmed by competition studies. Androgen metabolism was investigated both intracellularly and in the media after a 2-h incubation with 5 nM [3H]-testosterone. Carrier and [14C] steroids were added to the extracts before separation by thin-layer chromatography; steroid identity was confirmed by recrystallization. Dermal papilla cells from androgen-dependent follicles contained higher levels of specific, high-affinity, low-capacity androgen receptors than non-balding scalp cells. Testosterone metabolism also varied with beard, public and scalp cells containing testosterone and androstenedione intracellularly, but only beard cells producing 5 alpha-dihydrotestosterone, in line with the scanty beard growth found in 5 alpha-reductase deficiency. Elsewhere we have shown that cultured dermal papilla cells produce extracellular matrix components and mitogenic factors. These results all concur with our original hypothesis and suggest that further studies of such cells may elucidate the paradoxical effects of androgens on human hair follicles.

Androgens↗