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At least 703 records · Page 39Linked to original sources
PubMed1994

Incomplete androgen insensitivity associated with a thermolabile androgen receptor.

One infant and a cousin with incomplete androgen insensitivity syndrome were reported. The familial pedigree showed that the disorder was inherited in three generations in X-linked recessive fashion. An androgen binding study of cultured genital skin fibroblast from patients showed normal maximum binding capacity and a normal apparent dissociation constant. Heat stability assay showed binding decreased to less than 30% at 41 degrees C compared with the amount at 30 degrees C, indicating that the androgen receptor was thermolabile.

Androgen-Insensitivity Syndrome↗
PubMed1998

Frame-shift mutation in hormone binding domain of human androgen receptor gene causes complete androgen insensitivity.

Mutation of the human androgen receptor gene impairs normal sexual differentiation and development in karyotypic males, resulting in a spectrum of external genital phenotypes ranging from complete female to nearly complete male. The androgen insensitivity syndrome (AIS) is an X-linked disorder in which genetic males fail to undergo normal fetal masculinization or pubertal virilization. PCR amplification of AR exons followed by SSCP analysis was performed with the genomic DNA of a patient having complete AIS. Mutation was observed at the exon E, where a single nucleotide deletion of T at the nucleotide 3286 was observed by cyclic sequencing. A single base deletion in Exon E in the hormone binding domain causes a frame-shift mutation, which leads to changes in the open reading frame, and causes the early termination of AR synthesis. The structural change of the hormone binding domain and AR might cause an insensitivity to the androgen thus leading to AIS.

Adult↗
PubMed1997

Effect of active immunization against luteinizing hormone-releasing hormone on the androgen-sensitive Dunning R3327-PAP and androgen-independent Dunning R3327-AT2.1 prostate cancer sublines.

BACKGROUND: The objective of this study was to determine the effect of active immunization against LHRH on the growth characteristics and histology of subcutaneously implanted tumors of the androgen-sensitive Dunning R3327-PAP and androgen-independent R3327-AT2.1 rat prostate adenocarcinoma sublines. RESULTS: We herein demonstrate that 1) active immunization with an LHRH-diphtheria toxoid-conjugate (LHRH-DT) leads to the downregulation of gonadotropins and testosterone and consequently the atrophy of testosterone-dependent organs such as the testes, prostate, and androgen-sensitive Dunning R3327-PAP tumors, 2) growth inhibition of Dunning R3327-PAP tumors is caused by suppression of cell division rather than by an increase in cell death and is associated with an increase of the tumor stroma content, and 3) volume increase of the androgen-independent Dunning R3327-AT2.1 tumor is slightly but significantly reduced, indicating a local stimulatory LHRH loop within this tumor cell line.

Analysis of Variance↗
PubMed1992

Maintenance by androgen and thyroid hormone of androgen-induced convoluted tubular cells in mouse submandibular glands.

Injection of 5 alpha-dihydrotestosterone (DHT) into castrated adult female mice stimulated the proliferation of a small proportion of the convoluted tubular cells in the submandibular glands. We investigated the effects of DHT and thyroxine (T4) on the maintenance of these proliferated convoluted tubular cells. For this, castrated adult female mice that had been treated daily with DHT for 3 days and then once with [3H]thymidine, received a first series of daily injections of DHT for various periods or T4 for 10 days, and then a second series of injections of treatment with DHT or T4, or no further treatment. The second series of treatments with DHT or T4 maintained the percentages of 3H-labeled convoluted tubular cells at similar or slightly lower levels than those at the end of the first series of treatments. In mice that did not receive the second series of treatments, the percentages of 3H-labeled convoluted tubular cells decreased markedly, becoming significantly lower than those at the end of the second series of treatment with DHT or T4. We also examined the effect of DHT on the proliferation of convoluted tubular cells of castrated adult female mice that had received 10 daily injections of DHT and then no treatment for 28 days. In these mice, the cells did not proliferate markedly on stimulation with DHT. These results suggest that androgen and thyroid hormone maintain convoluted tubular cells that have proliferated in response to androgen, and that the convoluted tubular cells may become unresponsive to androgen in terms of proliferation after their exposure to androgen.

Animals↗
PubMed1993

Clinical use of androgenic steroids at a major medical center: who prescribes androgens and how well do they do it?

To assess prescribing practices for androgens at Wilford Hall USAF Medical Center, the authors analyzed prescriptions for all patients receiving therapy during a 12-month period (n = 201) and reviewed the available outpatient records not maintained elsewhere (n = 105). The most commonly prescribed androgens were testosterone enanthate (144/201; 56.7%), and danazol (52/201; 25.9%). Review of the available outpatient medical records of 73 male patients using testosterone enanthate showed a mean age of 59.5 years, mean frequency of injection of 20 days, mean duration of therapy of 3.5 years, and mean dose of 226 mg. Therapy was initiated by a urologist (34/73; 46.6%), an endocrinologist (33/73; 45.2%), or an internist (6.73; 8.2%). Indications for therapy based on pretreatment laboratory and historical data included hypergonadotropic hypogonadism (24/73; 32.9%), hypogonadotropic hypogonadism (23/73; 31.5%), unspecified hypogonadism (7/73; 9.6%), and empiric treatment of elderly men with erectile dysfunction without evidence of hypogonadism (9/73; 26%). Pretreatment prostate examinations as well as measurement of serum testosterone (66/73; 90.4%) and serum gonadotropins (52/73; 71.2%) were often not performed. The authors conclude that records of patients treated with androgens show: 1) Doses are appropriate; 2) Empiric treatment of erectile dysfunction in elderly men is common despite the associated risks; 3) Laboratory and physical evaluation before treatment is often incomplete; 4) There was no evidence of androgenic substance abuse in patients studied.

Adolescent↗
PubMed1976

Early androgen action in kidney of normal and androgen-insensitive (tfm/y) mice. Changes in RNA polymerase and chromatin template activities.

Intranuclear accumulation of testosterone was compared with early changes in transcriptional events in kidneys from normal female and androgen-insensitive (tfm/y) mice. Following a subcutaneous injection of [3H] testosterone, total nuclear uptake of the steroid was maximal at 30 min and declined to about 40% of the peak value by 4 h after hormone administration. After a single subcutaneous dose of testosterone, RNA polymerase activity assayed in intact nuclei in the presence of Mg2+ and alpha-amanitin (nucleolar RNA polymerase I), as well as the enzyme activity sensitive to low concentration of the toxin (nucleoplasmic RNA polymerase II), increased within 15 min and attained peak values at 2 and 1 h, respectively. The activity of both polymerases declined almost to the control level by 4 h and then increased again with a second peak at 20 and 12 h for RNA polymerase I and II, respectively. Similarly, the template capacity of mouse kidney chromatin, as measured with mammalian RNA polymerase II, increased by 15 min, reached a peak at 1 h and returned to control level by 4 h following hormone treatment. A second dose of testosterone given at the nadir (4 h) was not capable of stimulating renal chromatin template activity significantly as compared to the effect observed after the initial hormone treatment. Contrary to the testosterone-stimulated changes in transcriptional events observed in normal female mice, androgens elicited no response in androgen-insensitive tfm/y mice, animals lacking cytosol androgen receptors. These results strongly support the contention that hormone-specific receptors are obligatory to steroid-mediated modifications in gene transcription.

Amanitins↗
PubMed2000

Therapeutic potential of curcumin in human prostate cancer-I. curcumin induces apoptosis in both androgen-dependent and androgen-independent prostate cancer cells.

In an effort to find an alternative nontoxic means of inducing the apoptosis potential in both androgen-dependent and hormone refractory prostate cancer cells, attention was focused on curcumin (turmeric), traditionally used in medicine and cuisine in India and other south-east Asian countries. The results indicate that curcumin is a novel and potent inducer of apoptosis in both androgen-dependent and androgen-independent prostate cancer cells. This was accomplished by down-regulating apoptosis suppressor proteins and other crucial proteins such as the androgen receptor. It is concluded that curcumin may provide an alternative, nontoxic modality by which the clinician may prevent the progression of prostate cancer to its hormone refractory state or to treat advanced prostate cancer by forcing them to undergo apoptosis. Prostate Cancer and Prostatic Diseases (2000) 3, 84-93

Journal Article↗
PubMed2004

Androgen signaling and post-transcriptional downregulation of Bcl-2 in androgen-unresponsive prostate cancer.

We previously characterized the LNCaP prostate cancer progression model and showed that despite loss of Bcl-2 protein in the androgen-unresponsive LNCaP-unresponsive (UR) cells, these cells maintained an increased resistance to the induction of apoptosis. Since the loss of Bcl-2 protein coincided with the progression to androgen-unresponsiveness, we sought to determine if Bcl-2 expression was regulated through androgen signaling pathways. LNCaP-responsive (R) and -UR cells grown in charcoal-stripped serum conditions for 3 months differentiated to a neuroendocrine (NE)-like morphology. Under these conditions, LNCaP-UR cells regained Bcl-2 protein expression, and LNCaP-R cells overexpressed Bcl-2. Chronic exposure to casodex resulted in differentiation of both LNCaP-R and -UR cells to the NE-type morphology accompanied by a marked downregulation of Bcl-2 protein, while Bax protein levels were unchanged. Downregulation of Bcl-2 was post-transcriptional since Bcl-2 message levels were unchanged in LNCaP cells treated with casodex. These data suggest that Bcl-2 is post-transcriptionally modulated by androgen signaling pathways in LNCaP cells.

Apoptosis↗
PubMed2002

Effects of androgen supplementation therapy on partial androgen deficiency in the aging male: a preliminary study.

OBJECTIVE: To assess the responses of a symptom complex related to partial androgen deficiency in the aging male (PADAM) to androgen supplementation. SUBJECTS AND METHODS: Eighty-six men from five hospitals in Beijing aged 50-70 years with symptoms related to PADAM received oral testosterone undecanoate for 2 months, and the effects of the therapy were evaluated. RESULTS: After treatment, the symptom scores were significantly improved (all p < 0.001). Serum levels of luteinizing hormone and follicle stimulating hormone were suppressed, and free testosterone and albumin-bound testosterone levels were elevated. However, they were not significantly different from the pretreatment values. Waist/hip ratio and blood pressure were markedly decreased, but no changes were found in serum levels of total cholesterol, triglyceride, albumin and prostate specific antigen. CONCLUSIONS: Two months of treatment with oral testosterone undecanoate clearly improved the symptoms related to PADAM. No statistical relationship was found between symptom improvement and androgen levels. Androgen therapy for 2 months was beneficial to the waist/hip ratio and blood pressure, and no harm was done to the prostate gland or lipid metabolism.

Aged↗
PubMed1995

Leu-676-Pro mutation of the androgen receptor causes complete androgen insensitivity syndrome in a large Hutterite kindred.

A large Manitoba Hutterite kindred with X-linked receptor negative complete androgen insensitivity syndrome (CAIS) was studied. In attempts to identify all carriers of the syndrome in this kindred, using the androgen receptor (AR) cDNA, we have found a novel diagnostic MspI polymorphic pattern, which cosegregates with the disease. This polymorphism was not detected in 79 unrelated X-chromosomes of which 22 were from Hutterite controls. We were able to localize the polymorphism to exon 4, which is known to encode part of the androgen receptor hormone binding domain. A single base substitution (T-->C) was detected, which creates a new MspI site. This novel transition mutation replaces Leu-676 with Pro at a site which is conserved in numerous members of the steroid receptor gene family. Sequencing all 8 exons of the AR revealed the Leu-676-->Pro mutation as the only change in the primary structure of the receptor. Transfection of COS-1 cells with an expression vector of the mutant AR demonstrates that this point mutation of nucleotide 2558 abolishes receptor binding activity. The mutation can easily be detected by MspI digestion of the polymerase chain reaction (PCR) amplified exon 4 product.

Amino Acid Sequence↗
PubMed2006

Five novel androgen receptor gene mutations associated with complete androgen insensitivity syndrome.

Mutations in the androgen receptor (AR) gene result in androgen insensitivity syndrome (AIS). We have identified five novel mutations that result in a complete loss in AR function and are associated with complete AIS. The mutations span all three AR major functional domains. In two cases, the loss of AR function could be explained on the basis of the current knowledge of AR molecular structure and function. N-terminal mutation c.256C>T (p.Gln86X) leads to an early stop codon and abolishes all DNA and ligand binding. The DNA-binding domain mutation c.1685G>A (p.Cys562Tyr) is located in the N-terminal part of the first zinc finger; a mutation in this position is likely to impair the association of the mutated AR with the androgen response element of target genes. The splice site mutation at intron 2/exon 3 junction (c.1766-1G>A) is shown to lead to c.1765_1766 ins69 (p.[Gly589_Lys590ins23;Gly589Glu]). The two novel ligand-binding domain mutations identified were recreated by site-directed mutagenesis. Both mutations c.2171G>T (p.Gly724Val) and c.2435T>C (p.Leu812Pro) abolished AR ligand binding and severely impaired AR mediated transactivation. Residue p.Gly724 is located in the ligand binding domain, between helices 3 and 4. This region is known to be involved not only in ligand binding but also in AR N/C-terminal interactions. The mutation p.Leu812Pro is located in the C-terminal end of helix 8. This domain is highly conserved and critical for ligand binding. This study extends current understanding of AR mutations associated with CAIS.

Adolescent↗
PubMedDate not supplied

Effect of MK-906, a specific 5 alpha-reductase inhibitor, on serum androgens and androgen conjugates in normal men.

To determine the hormonal effects of MK-906, an orally active 5 alpha-reductase inhibitor, on serum androgens and androgen conjugates, 12 healthy men were given 10, 20, 50, and 100 mg MK-906 2 weeks apart in randomized order in a 4-period crossover design. Serum testosterone (T), dihydrotestosterone (DHT), androstanediol glucuronide, and androsterone glucuronide were measured before and 24 hours after each dose. The effect of MK-906 on glucuronyl transferase activity, the enzyme responsible for androstanediol glucuronide and androsterone glucuronide formation, was assessed in vitro using rat prostate tissue. Serum T levels were unchanged after all doses. Serum DHT, androstanediol glucuronide, and androsterone glucuronide were suppressed by 70, 40, and 56%, respectively, after the 10-mg dose, and by 82, 52, and 66% after the 100-mg dose (P less than 0.02 for the comparison between the 10 and 100-mg doses for all three steroids), respectively. Baseline serum T and DHT levels were strongly correlated (R = 0.89, P = 0.0002), as were androstanediol glucuronide and androsterone glucuronide levels (R = 0.78, P = 0.003), but there was no correlation between DHT levels and the levels of either conjugated steroid. MK-906 had no effect on glucuronyl transferase activity in vitro. It was concluded that single doses of MK-906 suppress both conjugated and unconjugated 5 alpha-reduced androgens. While all three steroids appeared to be good markers of systemic 5 alpha-reductase inhibition, further research will be needed to determine which steroid best reflects tissue DHT levels in patients receiving these inhibitors.

5-alpha Reductase Inhibitors↗
PubMed1995

Distribution of androgen receptor immunoreactivity in the spinal cord of wild-type, androgen-insensitive and gonadectomized male rats.

The polyclonal antiserum PG21 was used to detect androgen receptor (AR) protein in three motoneuronal pools of the male rat lumbar spinal cord. In gonadally intact, wild-type males, the spinal nucleus of the bulbocavernosus (SNB), dorsolateral nucleus (DLN), and retrodorsolateral nucleus (RDLN) all displayed immunolabeling of cell nuclei. The percentage of motoneurons displaying such labeling was highest in the SNB and lowest in the RDLN. This pattern of AR immunocytochemical labeling agrees well with previous steroid autoradiographic studies of androgen accumulation in the rat spinal cord. In contrast, virtually no motoneurons in any of the three pools displayed nuclear AR immunostaining in long-term gonadectomized males or in gonadally intact males carrying the Tfm mutation, which renders the AR incompetent. In gonadectomized males, labeling was restored in the SNB and DLN, but not the RDLN, 30 min after an injection of replacement testosterone. Eight hours of testosterone exposure restored immunolabeling in all three motor nuclei. Apparent cytoplasmic staining was seen in SNB motoneurons of untreated castrates and Tfm rats, but not intact rats, suggesting that AR residing in the cytoplasm translocates to the nucleus on binding to androgen in these motoneurons.

Analysis of Variance↗
PubMed2007

Androgen-insensitive prostate cancer cells transiently respond to castration treatment when growing in an androgen-dependent prostate environment.

BACKGROUND: Castration-induced involution of the normal prostate is caused by primary effects in the prostate stroma and vasculature, but if this is the case also in tumors is unknown. METHODS: Androgen-independent AT-1 prostate tumor cells were therefore injected into the ventral prostate (VP) in Copenhagen rats. Seven days later when the growing tumor was surrounded by normal VP tissue the rats were castrated and the effect examined 3 and 7 days later. RESULTS: Castration reduced vascular density in the surrounding VP tissue and this was accompanied by tumor cell hypoxia, apoptosis, and temporarily retarded tumor growth. Castration-induced VP tissue regression occurred more rapidly in the contra-lateral than in the tumor-bearing lobe. CONCLUSIONS: Androgen-independent tumor cell respond to castration when growing in an androgen-dependent environment. The presence of a tumor influences the castration response in the surrounding normal tissue. The microenvironment determines how prostate epithelial cells respond to castration.

Androgens↗
PubMed1995

Androgen receptor binding studies on heterozygotes in a family with androgen insensitivity syndrome.

A large family with androgen insensitivity syndrome (AIS) has been investigated, in order to detect carrier individuals and to investigate their AR binding. We have previously reported that different affected members of this family have different AR gene deletions, and, testing normal female relatives of the affected individuals, we have identified three heterozygote females all of whom carry a deletion of exon E of the AR gene. Androgen binding capacity was measured in cultured genital skin fibroblasts from normal male and female controls, the affected, and the heterozygote individuals in this family. A significant difference was found between the binding ranges for normal male foreskin and suprapubic skin fibroblasts (P < 0.005), and the three individuals with AIS had very low androgen binding capacity in their genital skin fibroblasts (2.6, 5.0, and 3.4 fmol 3HR1881/mg protein) compared to the normal range. The heterozygote females all had binding within the normal female suprapubic skin fibroblast range (12.5, 6.1, and 6.4 fmol 3HR1881/mg protein, respectively, for the three heterozygotes). Thus, we conclude that the absence of one functional AR gene in heterozygote females has not effect on AR binding capacity in cultured genital skin fibroblasts. In addition, bone mineral density was measured in the affected aunt and found to be significantly lowered at the lumbar spine (Z = -2.81) and hip (Z = -1.54); however, the role of the AR in determination of bone mineral density remains to be elucidated.

Adult↗
PubMed1990

Androgen receptors, serum androgen levels and survival of breast cancer patients.

Steroid receptor levels and serum androgen levels were determined in 61 breast cancer patients and 34 patients with non-malignant breast lesions. Testosterone and dehydroepiandrosterone-sulfate did not and androstenedione did show a difference between the two groups. Androgen levels had no influence on survival rates. Androgen receptor (AR) levels correlated with progesterone receptor levels, but not with estrogen receptor levels or with tumor stage. Patients with positive AR findings had a better survival rate; this was independent of tumor stage. AR findings may therefore be a prognostic index in breast cancer patients.

Adult↗
PubMed2005

Molecular features and clinical phenotypes in androgen insensitivity syndrome in the absence and presence of androgen receptor gene mutations.

Androgen insensitivity syndrome (AIS) is characterized by deficient or absent virilization in 46,XY individuals despite normal or even elevated androgen levels. AIS is usually caused by mutations in the androgen receptor (AR) gene. We aimed at contrasting clinical, biochemical, and molecular genetic characteristics of three patients (P1-P3) with clinically evident partial (P1) and complete (P2, P3) AIS with and without AR gene mutations. AR expression was studied in cultured genital skin fibroblasts (GSF) by Western immunoblotting, ligand binding analyses, Northern blotting, semiquantitative reverse transcription-polymerase chain reaction (RT-PCR), and RT-PCR spanning exons 1-8. AR gene DNA sequence was analyzed by single-strand conformation analysis (SSCA), and DNA sequencing. GSF revealed reduced (P1) or absent (P2, P3) ligand binding. Northern blots showed either slightly reduced hybridization of the 10.5-kb AR transcript (P3) or no hybridization (P1, P2), as confirmed by semiquantitative RT-PCR. RT-PCR spanning exons 1-8 detected single AR mRNA bands in P1-P3 excluding splicing errors. Western analyses showed either low (P1) or no (P2, P3) AR protein. While SSCA initially did not reveal any molecular abnormality, sequencing showed a novel CAG (Gln) to TAG (stop) mutation at codon 59 (P3) and a previously described 2-bp deletion at codon 472, leading to a frameshift and premature stop in codon 499 (P2). Intriguingly, P1 showed an unaltered DNA sequence of the coding region of the AR gene including all intron-exon boundaries. In conclusion, patients with clinically evident complete AIS are likely to harbor an AR gene mutation, demanding that the two polymorphic regions must always be included in molecular analyses of the AR gene. Moreover, our data support the concept that in a subset of AIS patients, particularly those with partial AIS, molecular alterations outside the coding region of the AR gene must be presumed.

Androgen-Insensitivity Syndrome↗
PubMed1996

Androgen insensitivity syndrome due to new mutations in the DNA-binding domain of the androgen receptor.

Androgen insensitivity syndrome (AIS) is associated with a wide range of quantitative or qualitative defects in the androgen receptor (AR). In some patients with AIS, however, no defects are detectable in the ligand-binding properties of the AR. We have analyzed the ARs of two unrelated patients with this category (termed 'receptor-positive type') of AIS. Sequence analysis of these patients' AR gene revealed single amino acid substitutions (579Cys(TGC)-->Phe(TTC) and 582Phe(TTC)-->Tyr(TAC)) in exon B encoding the first zinc finger of the DNA-binding domain of the AR. These mutations have not been previously reported. Moreover, cotransfection assays and mobility shift assays revealed that these patients' mutant ARs had defective transcriptional activity of the target gene because of impaired DNA-binding ability to the androgen-responsive element. These findings strongly indicate that these mutations are responsible for the pathogenesis of AIS in these patients.

Adult↗