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PubMed2002

An effective hormonal male contraceptive using testosterone undecanoate with oral or injectable norethisterone preparations.

Suppression of spermatogenesis to azoospermia is the goal of hormonal male contraception based on T combined with gestagens. The combination of the long-acting T, ester testosterone undecanoate (TU), with norethisterone (NET) enanthate (E) showed high efficacy. In the present study, we tested the validity of this approach by varying the NET dose and mode of application. The aim of the study was to achieve high rates of suppression of spermatogenesis as reflected by sperm counts, monitor gonadotropins as well as other hormones, and evaluate any possible side effects. In a phase II clinical trial, groups of normal volunteers received: 1000 mg TU im at wk 2, 6, 12, and 18 combined with 200 mg NETE im at wk 0, 6, 12, and 18 (group I); 1000 mg TU im and 400 mg NETE im at wk 0, 6, 12, and 18 (group II); and 1000 mg TU im at wk 0, 6, 12, and 18 with daily oral NET acetate (NETA) from wk 0 to 24 (group III). In all groups marked suppression of gonadotropins resulted in a significant decrease of spermatogenesis and azoospermia in 13/14, 11/12, and 12/14 men in groups I to III, respectively. The remaining men all had less than 1 million sperm/ml. Reversible side effects included increase in body weight, erythrocytes, hemoglobin, and hematocrit and decrease in high-density lipoprotein cholesterol and alkaline phosphatase in all groups and increase in liver enzymes in the oral NETA group. This study documents the high efficacy of TU in combination with NET and confirms that this dose and mode of application (1000 mg TU im every 6 wk plus 400 mg NETE im every 6 wk or plus 10 mg daily oral NETA) is as effective as the previously reported regimen containing 1000 mg TU + 200 mg NETE im every 6 wk. The contraceptive efficacy of this combination of TU and NETE should be evaluated in further clinical trials.

Administration, Oral↗
PubMed2002

Differential effects of oral estrogen versus oral estrogen-androgen replacement therapy on body composition in postmenopausal women.

Menopause is associated with decreased lean body mass and increased fat due to aging and declining hormone secretion. Estrogens or estrogen-progestins have been used to alleviate vasomotor symptoms. However, estrogen-androgen (E/A) therapy is also used for vasomotor symptom relief and has been shown to increase lean body mass while decreasing fat mass. The objective of this 16-wk, double-blind, randomized, parallel group clinical trial was to compare esterified estrogen plus methyltestosterone (1.25 mg estrogen + 2.5 mg methyltestosterone/d; E/A group) vs. esterified estrogen alone (1.25 mg/d; E group) on body composition. Forty postmenopausal women (mean age, 57 yr) participated. Compared with estrogen treatment alone, women in the E/A group increased their total lean body mass and reduced their percentage fat for all body parts (P < 0.05). After E/A treatment, there were statistically significant increases in lean body mass by 1.232 kg [0.181 +/- 0.004, 0.81 +/- 0.057, and 0.24 +/- 0.009 kg in the upper body (P = 0.021), trunk (P = 0.001), and lower body (P = 0.047), respectively]. In the E group, the increase was 0.31 +/- 0.004, 0.021 +/- 0.03, and 0.056 +/- 0.05 kg in the upper body, trunk, and lower body, respectively. In the E/A group, body fat was reduced by 0.90 kg (P = 0.18 for the trunk only), and percentage body fat declined by 7.4% (P < or = 0.05 for all body parts). Lower body strength increased by 23.1 kg (51 lb) in the E/A group vs. only 11 kg (24.25 lb) in the E group (P = 0.002 between groups). A statistically significant increase in weight (2.7 +/- 5.1 vs. 0.1 +/- 4.6 lb; P < 0.05) was observed in the E/A group compared with the E group. When subjects were given self-reporting questionnaires, more improvement was noted in sexual functioning and quality of life in the E/A group when compared with patients receiving E alone. There were no noteworthy side effects. In conclusion, E/A replacement therapy can improve body composition, lower-body muscle strength, quality of life, and sexual functioning in postmenopausal women.

Administration, Oral↗
PubMed2003

Selective modulation of genomic and nongenomic androgen responses by androgen receptor ligands.

Steroids can induce both transcription-dependent (genomic) and independent (nongenomic) signaling. Here, several classical androgen receptor ligands were tested for their ability to modulate genomic and nongenomic responses, focusing on the role of the oocyte-expressed Xenopus classical androgen receptor (XeAR) in mediating these processes. Cellular fractionation and immunohistochemistry revealed that the XeAR was located throughout oocytes, including within the plasma membrane. RNA interference and oocyte maturation studies suggested that androgen-induced maturation was mediated in part by the XeAR in a transcription-independent fashion, perhaps by altering G protein-mediated signaling. While inducing minimal transcription in oocytes, all AR ligands promoted significant XeAR-mediated transcription in CV1 cells. In contrast, only testosterone and androstenedione potently induced oocyte maturation, whereas dihydrotestosterone and R1881 actually inhibited testosterone and human chorionic gonadotropin-induced maturation and signaling. These results suggest that the nature of a steroid-induced signal (genomic vs. nongenomic) may depend on the type of target cell, the receptor location within cells, as well as the ligand itself. The identification of molecules capable of selectively altering genomic vs. nongenomic signaling may be useful in delineating the roles of these pathways in mediating androgen responses and might lead to the development of novel compounds that specifically modulate these signals in vivo.

Androgens↗
PubMed1990

Overexpression of a partial human androgen receptor in E. coli: characterization of steroid binding, DNA binding, and immunological properties.

The recent cloning of human androgen receptor (AR) cDNAs in this and other laboratories has provided valuable probes for investigating the structure and function of the AR at the molecular level. We now report the overexpression of a region of the human AR containing both the DNA- and hormone-binding domains in E. coli, which provides a means to produce large amounts of AR for analysis and use in functional studies. Under isopropyl-beta-D-thiogalactopyranoside induction, a tripartite protein, consisting of beta-galactosidase, a collagenase recognition site, and AR polypeptide, was produced in E. coli JM109 using pSS20 a as a vector. About 1 mg of the fused AR could be recovered per liter bacterial culture. The induced protein could readily be detected in a sodium dodecyl sulfate-polyacrylamide gel by Coomassie blue staining. Its identity was confirmed by Western blot analysis using antibodies to both beta-galactosidase and the AR. Scatchard analysis of the androgen-binding activity of the hybrid AR revealed high affinity binding to the synthetic androgen, Mibolerone (Kd, approximately 1.2 nM). Competition studies demonstrated the fusion protein's specificity for androgens. The hybrid receptor formed immune complexes with human anti-AR serum that sedimented at about 19S in 10-50% linear sucrose gradients containing 0.4 M KCl. Gel band shift assays revealed that the hybrid receptor protein forms specific complexes with a synthetic steroid response element derived from the mouse mammary tumor virus long terminal repeat region. These results demonstrate that the recombinant AR expressed in E. coli possesses many of the functional properties characteristic of DNA- and steroid-binding domains of the native AR.

Androgens↗
PubMed1997

An androgen response element in a far upstream enhancer region is essential for high, androgen-regulated activity of the prostate-specific antigen promoter.

Prostate-specific antigen (PSA) is expressed at a high level in the luminal epithelial cells of the prostate and is absent or expressed at very low levels in other tissues. PSA expression can be regulated by androgens. Previously, two functional androgen-response elements were identified in the proximal promoter of the PSA gene. To detect additional, more distal control elements, DNasel-hypersensitive sites (DHSs) upstream of the PSA gene were mapped in chromatin from the prostate-derived cell line LNCaP grown in the presence and absence of the synthetic androgen R1881. In a region 4.8 to 3.8 kb upstream of the transcription start site of the PSA gene, a cluster of three DHSs was detected. The middle DNAseI-hypersensitive site (DHSII, at approximately -4.2 kb) showed strong androgen responsiveness in LNCaP cells and was absent in chromatin from HeLa cells. Further analysis of the region encompassing DHSII provided evidence for the presence of a complex, androgen-responsive and cell-specific enhancer. In transient transfected LNCaP cells, PSA promoter constructs containing this upstream enhancer region showed approximately 3000-fold higher activity in the presence than in the absence of R1881. The core region of the enhancer could be mapped within a 440-bp fragment. The enhancer showed synergistic cooperation with the proximal PSA promoter and was found to be composed of at least three separate regulatory regions. In the center, a functionally active, high-affinity androgen receptor binding site (GGAACATATTGTATC) could be identified. Mutation of this element almost completely abolished PSA promoter activity. Transfection experiments in prostate and nonprostate cell lines showed largely LNCaP cell specificity of the upstream enhancer region, although some activity was found in the T47D mammary tumor cell line.

Androgens↗
PubMed1998

Progression of LNCaP prostate tumor cells during androgen deprivation: hormone-independent growth, repression of proliferation by androgen, and role for p27Kip1 in androgen-induced cell cycle arrest.

The molecular mechanism of androgen-independent growth of prostate cancer after androgen ablation was explored in LNCaP cells. An androgen-dependent clonal subline of the LNCaP human prostate carcinoma cell line, LNCaP 104-S, progressed to a slow growing stage (104-R1) and then to a faster growing stage (104-R2) during more than 2 yr of continuous culture in the absence of androgen. Androgen-induced proliferation of 104-S cells is inhibited by the antiandrogen Casodex, while proliferation of 104-R1 and 104-R2 cells is unaffected by Casodex. This indicates that proliferation of 104-R1 and 104-R2 cells is not supported by low levels of androgen in the culture medium. Compared with LNCaP 104-S cells, both 104-R1 and 104-R2 cells express higher basal levels of androgen receptor (AR), and proliferation of these two cell lines is paradoxically repressed by androgen. After continuous passage in androgen-containing medium, 104-R1 cells reverted back to an androgen-dependent phenotype. The mechanism of androgenic repression of 104-R1 and 104-R2 sublines was further evaluated by examining the role of critical regulatory factors involved in the control of cell cycle progression. At concentrations that repressed growth, androgen transiently induced the expression of the cyclin-dependent kinase (cdk) inhibitor p21waf1/cip1 in 104-R1 cells, while expression of the cdk inhibitor p27Kip1 was persistently induced by androgen in both 104-R1 and 104-R2 cells. Induced expression of murine p27Kip1 in 104-R2 cells resulted in G1 arrest. Specific immunoprecipitates of Cdk2 but not Cdk4 from androgen-treated 104-R1 cells contained both p21waf1/cip1 and p27Kip1. This observation was confirmed by in vitro assay of histone H1 and Rb (retinoblastoma protein) phosphorylation by the proteins associated with the immune complex. Furthermore, inhibition of Cdk2 activity correlated with the accumulation of p27Kip1 and not p21waf1/cip1. From these results we conclude that androgenic repression of LNCaP 104-R1 and 104-R2 cell proliferation is due to the induction of p27Kip1, which in turn inhibits Cdk2, a factor critical for cell cycle progression and proliferation.

Androgens↗
PubMed1999

Interaction of the putative androgen receptor-specific coactivator ARA70/ELE1alpha with multiple steroid receptors and identification of an internally deleted ELE1beta isoform.

Steroid-regulated gene transcription requires the coordinate physical and functional interaction of hormone receptors, basal transcription factors, and transcriptional coactivators. In this context ARA70, previously called RFG and ELE1, has been described as a putative coactivator that specifically enhances the activity of the androgen receptor (AR) but not that of the glucocorticoid receptor (GR), the progesterone receptor, or the estrogen receptor (ER). Here we describe the cloning of the cDNA for ELE1/ARA70 by RT-PCR from RNA derived from different cell lines (HeLa, DU-145, and LNCaP). In accordance with the previously described sequence, we obtained a 1845-bp PCR product for the HeLa and the LNCaP RNA. Starting from T-47D RNA, however, an 860-bp PCR product was obtained. This shorter variant results from an internal 985-bp deletion and is called ELE1beta; accordingly, the longer isoform is referred to as ELE1alpha. The deduced amino acid sequence of ELE1alpha, but not that of ELE1beta, differs at specific positions from the one previously published by others, suggesting that these two proteins are encoded by different nonallelic genes. ELE1alpha is expressed in the three prostate-derived cell lines examined (PC-3, DU-145, and LNCaP), and this expression is not altered by androgen treatment. Of all rat tissues examined, ELE1alpha expression is highest in the testis. This is also the only tissue in which we could demonstrate ELE1beta expression. Both ELE1alpha and ELE1beta interact in vitro with the AR, but also with the GR and the ER, in a ligand-independent way. Overexpression of either ELE1 isoform in DU-145, HeLa, or COS cells had only minor effects on the transcriptional activity of the human AR. ELE1alpha has no intrinsic transcription activation domain or histone acetyltransferase activity, but it does interact with another histone acetyltransferase, p/CAF, and the basal transcription factor TFIIB. The interaction with the AR occurs through the ligand-binding domain and involves the region corresponding to the predicted helix 3. Mutation in this domain of leucine 712 to arginine greatly reduces the affinity of the AR for ELE1alpha but has only moderate effects on its transcriptional activity. Taken together, we have identified two isoforms of the putative coactivator ARA70/ELE1 that may act as a bridging factor between steroid receptors and components of the transcription initiation complex but which lack some fundamental properties of a classic nuclear receptor coactivator. Further experiments will be required to highlight the in vivo role of ELE1 in nuclear receptor functioning.

Acetyltransferases↗
PubMed2000

Androgen induction of cyclin-dependent kinase inhibitor p21 gene: role of androgen receptor and transcription factor Sp1 complex.

Previous studies have shown that androgen up-regulates expression of the p21 (WAF1, CIP1, SDI1, CAP20) gene, which contains a canonical androgen response element (ARE) in its proximal promoter region. We undertook the current studies to determine whether elements in the p21 promoter other than the ARE mediate androgen action. We found that deletion of the ARE did not completely abolish the promoter responsiveness to androgen, suggesting that additional cis-regulatory elements within the p21 core promoter may also be involved in androgen responsiveness. The p21 core promoter is GC-rich and contains six binding sites for transcription factor Sp1. We determined whether one or more of these Sp1 sites mediate androgen responsiveness of the p21 promoter. To do so, we used a transient transfection assay with p21 promoter-luciferase reporter constructs. The reporter activity of a construct lacking the ARE but containing all six Sp1 sites was induced approximately 3-fold by androgen. Mutation of Sp1-3 nearly eliminated basal promoter activity as well as androgen responsiveness, whereas deletion of Sp1-1 and Sp1-2 sites and mutation of Sp1-4, Sp1-5, and Sp1-6 sites had relatively little effect. We also used the mammalian one-hybrid assay and coimmunoprecipitation assay to show that androgen receptor (AR) and transcription factor Sp1 interact with one another. The current studies suggest a model in which AR and transcription factor Sp1 not only bind to their respective consensus sites within the p21 promoter, but also complex with one another, thereby recruiting coactivators and general transcription factors and inducing p21 transcription.

Adenocarcinoma↗
PubMed1992

Transcriptional regulation of prostate kallikrein-like genes by androgen.

Using gene-specific synthetic oligonucleotides the expression and regulation of kallikrein-like genes in the human prostatic cancer cell line LNCaP were studied. Prostate-specific antigen (PSA) and human glandular kallikrein (hGK-1) together constitute a subfamily of serine proteases exclusively produced in the human prostate. RNA analysis revealed that both genes are expressed in LNCaP cells with PSA basal levels being 2-fold higher than hGK-1 levels. Both mRNAs are induced over a period of 24 h in the presence of 3.3 nM of the synthetic androgen mibolerone. Stimulation of PSA RNA is about 5-fold, whereas hGK-1 stimulation is less pronounced. Nuclear run-on analysis revealed that androgen induction of kallikrein-like genes in LNCaP cells is a rapid event (less than 3 h) occurring at the level of transcription initiation. Treatment of cells with cycloheximide demonstrates that, while PSA/hGK-1 basal transcription strictly depends on continuous protein synthesis, transcriptional induction by androgen does not. This suggests the direct involvement of the androgen receptor in the induction process independent of additional labile protein factors necessary for kallikrein basal transcription. A binding motif is present in the PSA and hGK-1 promoters, closely resembling the consensus sequence for steroid-responsive elements. The androgen antagonist cyproterone acetate was also able to stimulate transcription of kallikrein-like genes in LNCaP cells. In contrast, androgen-dependent transcriptional suppression of the protooncogene c-myc was strongly counteracted by cyproterone acetate. Thus, antiandrogens act differentially on androgen-regulated prostate-specific (PSA, hGK-1) and growth-related (c-myc) gene expression in LNCaP cells.

Androgen Antagonists↗
PubMed2004

Stereochemistry of NaBH4 reduction of a 19-carbonyl group of 3-deoxy androgens. Synthesis of [19S-3H]- and [19R-3H]-labeled aromatase inhibitors having a 19-hydroxy group.

To study the stereochemical aspects of the aromatase reaction of androst-4-en-17-one (1) and its 5-ene isomer 4, competitive inhibitors of aromatase, the [19S-(3)H]- and [19R-(3)H]-labeled 19-hydroxy derivatives 2 and 5, were synthesized through NaB(3)H(4) reduction of the corresponding 19-aldehydes 3 and 6 as a key reaction. The hitherto unknown stereochemistry of the NaB(3)H(4) reduction was established based on the deuterium-labeling experiments with NaB(2)H(4). A comparison of (1)H-NMR spectra of the NaB(2)H(4) reduction products of 19-als 3 and 6 with those of the respective authentic steroids revealed that the ratios of 19S-(2)H to 19R-(2)H were 90 : 10 for the 4-ene steroid 2 and 70 : 30 for the 5-ene isomer 5, respectively. Jones oxidation of the [19S-(2)H]19-ols, followed by the non-labeled NaBH(4) reduction, gave the corresponding [19R-(2)H]19-ols 2 and 5 (R-(2)H : S-(2)H=90 : 10 for steroid 2 and 70 : 30 for steroid 5). The stereoselectively (3)H-labeled compounds 2 and 5 were similarly obtained in these sequences.

Aromatase↗
PubMed2006

Anabolic androgenic steroids: a survey of 500 users.

PURPOSE: The use of anabolic androgenic steroids (AAS) to increase muscle size and strength is widespread. Information regarding self-administered AAS used nonmedically to enhance athletic performance or improve physical appearance is sparse and poorly documented. The purpose of this study is to identify current trends in the drug-taking habits of AAS users. METHODS: An anonymous self-administered questionnaire was posted on the message boards of Internet Web sites popular among AAS users. RESULTS: Of the 500 AAS users who participated in the survey, 78.4% (392/500) were noncompetitive bodybuilders and nonathletes; 59.6% (298/500) of the respondents reported using at least 1000 mg of testosterone or its equivalent per week. The majority (99.2%) of AAS users (496/500) self-administer injectable AAS formulations, and up to 13% (65/500) report unsafe injection practices such as reusing needles, sharing needles, and sharing multidose vials. In addition to using AAS, 25% of users admitted to the adjuvant use of growth hormone and insulin for anabolic effect, and 99.2% (496/500) of users reported subjective side effects from AAS use. CONCLUSIONS: This survey reveals several trends in the nonmedical use of AAS. Nearly four out of five AAS users are nonathletes who take these drugs for cosmetic reasons. AAS users in this sample are taking larger doses than previously recorded, with more than half of the respondents using a weekly AAS dose in excess of 1000 mg. The majority of steroid users self-administer AAS by intramuscular injection, and approximately 1 in 10 users report hazardous injection techniques. Polypharmacy is practiced by more than 95% of AAS users, with one in four users taking growth hormone and insulin. Nearly 100% of AAS users reported subjective side effects.

Adolescent↗
PubMed2006

Predictors of future anabolic androgenic steroid use.

PURPOSE: To prospectively study the stability of anabolic androgenic steroid (AAS) use and predictors of AAS use, and to investigate whether AAS use alters the risk of later emotional and behavioral problems. METHODS: Survey of a national sample of Norwegian high school students (age 15-19) in 1994 followed up in 1999 (N = 2924). Measures of frequent alcohol intoxication (50+ times per 12 months), cannabis use (12 months), hard drug use (12 months), being offered cannabis, eating problems, conduct problems, sexual debut before age 15, BMI, involvement in power sports, perceived physical appearance, and satisfaction with body parts were obtained. RESULTS: Life-time prevalence of AAS use were 1.9 and 0.8% in the follow-up period. Multivariate logistic regression revealed that future AAS use was predicted by young age, male gender, previous AAS use, involvement in power sports, and frequent alcohol intoxication. AAS use did not predict future emotional or behavioral problems other than reducing the risk of future frequent alcohol intoxication. CONCLUSION: Frequent alcohol intoxication and involvement in power sports appear to predict future AAS use. At the population level there was little stability in individual AAS use from adolescence to early adulthood. No detrimental effects of AAS use could be detected in this study, but low statistical power limits this conclusion.

Adolescent↗
PubMed2006

Anabolic-androgenic steroid abuse by physicians.

Physicians are not immune to the rising popularity of anabolic-androgenic steroid (AAS) abuse. We present three cases of physician-patients who recently required inpatient substance abuse treatment stemming from the abuse of AAS or related compounds. These individuals shared a number of clinical and psychological features that led to or resulted from their abuse of ergogenic substances. Each incurred severe professional, legal, domestic and/or health consequences as a result of their abuse. The common features identified in these patients suggest the presence of an overriding "risk behavior syndrome" that may predispose susceptible individuals to AAS abuse. The reinforcing properties of AAS and the potential for dependence remains an active area of research. Effective treatment of these individuals requires recognition of the causative factors as well as the high likelihood of other substance abuse that must also be addressed. With proper support and monitoring, these individuals can resume productive professional careers.

Adult↗
PubMed2006

Relationship of androgens to insulin resistance and chronic inflammation in morbidly obese premenopausal women: studies before and after vertical banded gastroplasty.

BACKGROUND: Morbid obesity is associated with insulin resistance (IR), type 2 diabetes, lipid abnormalities, and hypertension. The association of obesity with increased androgen production and low concentrations of sex hormone-binding globulin (SHBG) in women has been demonstrated as well as a strong association of androgens with markers of inflammation such as high-sensitive C-reactive protein (hsCRP). Because weight loss results in a significant decrease in cardiovascular risk factors, IR and inflammation, we questioned a possible interrelationship between androgens, IR and inflammation in a prospective study with 43 morbidly obese female patients undergoing bariatric surgery. METHODS: SHBG, dehydroepiandrosterone-sulfate (DHEA-S), and insulin were measured by ELISA, cortisol by fluorescence polarization immunoassay, androstendione by RIA, and testosterone by electrochemiluminescence immunoassay. The free androgen index (FAI) was calculated as the total testosterone/SHBG ratio. High sensitivity assays were used to obtain concentrations of fasting hsCRP, Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). RESULTS: Weight loss resulted in a significant increase in SHBG (17+/-12 vs 70+/-30 nmol/l, P<0.0001). Serum concentrations of androstendione, total testosterone, DHEA-S and the FAI decreased significantly (2.05+/-0.78 vs 1.40+/-0.54 ng/ml, P<0.0001; 1.88+/-0.84 vs 1.16+/-0.57 nmol/L, P<0.0001; 1.72+/-0.86 vs 1.49+/-0.78 microg/ml, P<0.01; 0.15+/-0.10 vs 0.02+/-0.01, P<0.0001; respectively). Preoperatively and postoperatively, no association between androgens and IR, chronic subclinical inflammation and lipid parameters could be observed. CONCLUSION: Massive weight loss induced by bariatric surgery is associated with a significant reduction of androgen concentrations but not related to the concomitant decline of chronic inflammation, IR, glucose and lipid abnormalities in premenopausal morbidly obese women.

Adult↗
PubMed1982

Hereditary angioneurotic edema: clinical management and case report.

Hereditary angioneurotic edema, although a rare clinical entity, can be fatal if diagnosis and appropriate therapy are not instituted before the performance of routine dental and oral surgical procedures. The pathophysiology, physical findings, and therapeutic treatment modalities have been reviewed, and a case involving both restorative and surgical dental intervention has been presented.

Adult↗