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The Journal of Investigative... Jun 2003Androgens mediate a wide range of processes during embryogenesis and in the adult. In mammals, although a number of steroids can be shown to exert androgenic effects... (Review)
Review
Androgens mediate a wide range of processes during embryogenesis and in the adult. In mammals, although a number of steroids can be shown to exert androgenic effects using in vitro and in vivo assays, testosterone and its 5alpha reduced metabolite, 5alpha-dihydrotestosterone (DHT) are considered to represent the principal physiologic androgens. Furthermore, although the effects that androgens exert differ widely among different tissues and cell types, genetic and biochemical data suggest that these effects are mediated via the protein products of a single androgen receptor gene, which is encoded on the X-chromosome in mammals.
Topics: Androgens; Animals; Dihydrotestosterone; Humans; Molecular Structure; Receptors, Androgen; Testosterone
PubMed: 12894986
DOI: 10.1046/j.1523-1747.2003.12163.x -
Nucleic Acids Research Sep 2018The constitutive androstane receptor (CAR; NR1I3) is a nuclear receptor orchestrating complex roles in cell and systems biology. Species differences in CAR's effector...
The constitutive androstane receptor (CAR; NR1I3) is a nuclear receptor orchestrating complex roles in cell and systems biology. Species differences in CAR's effector pathways remain poorly understood, including its role in regulating liver tumor promotion. We developed transgenic mouse models to assess genome-wide binding of mouse and human CAR, following receptor activation in liver with direct ligands and with phenobarbital, an indirect CAR activator. Genomic interaction profiles were integrated with transcriptional and biological pathway analyses. Newly identified CAR target genes included Gdf15 and Foxo3, important regulators of the carcinogenic process. Approximately 1000 genes exhibited differential binding interactions between mouse and human CAR, including the proto-oncogenes, Myc and Ikbke, which demonstrated preferential binding by mouse CAR as well as mouse CAR-selective transcriptional enhancement. The ChIP-exo analyses also identified distinct binding motifs for the respective mouse and human receptors. Together, the results provide new insights into the important roles that CAR contributes as a key modulator of numerous signaling pathways in mammalian organisms, presenting a genomic context that specifies species variation in biological processes under CAR's control, including liver cell proliferation and tumor promotion.
Topics: Androstanes; Animals; Cell Proliferation; Constitutive Androstane Receptor; DNA-Binding Proteins; Forkhead Box Protein O3; Genes, myc; Genome; Growth Differentiation Factor 15; Hepatocytes; Humans; I-kappa B Kinase; Ligands; Liver; Liver Neoplasms; Mice; Mice, Transgenic; Protein Binding; Receptors, Cytoplasmic and Nuclear
PubMed: 30102401
DOI: 10.1093/nar/gky692 -
The Prostate Aug 2015The association between serum sex steroid hormones and PSA in a general population has not been described.
BACKGROUND
The association between serum sex steroid hormones and PSA in a general population has not been described.
METHODS
Included were 378 men aged 40-85 years who participated in the National Health and Nutrition Examination Survey in 2001-2004, who did not have a prostate cancer diagnosis, and had not had a recent biopsy, rectal examination, cystoscopy, or prostate infection or inflammation. Serum total PSA, total testosterone, androstanediol glucuronide (3α-diol-G), estradiol, and sex hormone binding globulin (SHBG) concentrations were previously measured. Free testosterone was estimated by mass action. We applied sampling weights and calculated geometric mean PSA concentration by hormone quintiles adjusting for age and race/ethnicity, and also for body mass index, waist circumference, smoking, diabetes, and mutually for hormones. We estimated the OR of PSA ≥2.5 ng/ml per hormone quintile using logistic regression.
RESULTS
Geometric mean PSA increased across testosterone quintiles after age and race/ethnicity (Q1: 0.80, Q5: 1.14 ng/ml; P-trend = 0.002) and multivariable (Q1: 0.79, Q5: 1.16 ng/ml; P-trend = 0.02) adjustment; patterns were similar for free testosterone and 3α-diol-G. SHBG was inversely associated with PSA only after multivariable adjustment (Q1: 1.32, Q5: 0.82 nmol/L; P-trend = 0.01). Estradiol and PSA were not associated. The OR of PSA ≥2.5 ng/ml was 1.54 (95% CI 1.18-2.01) per testosterone quintile after age and race/ethnicity adjustment, and 1.78 (95% CI 1.16-2.73) after multivariable adjustment.
CONCLUSIONS
In this nationally representative sample, men with higher testosterone had higher PSA even after taking into account other hormones and modifiable factors. Men with higher SHBG had lower PSA, but only after multivariable adjustment.
Topics: Adult; Aged; Aged, 80 and over; Androstane-3,17-diol; Body Mass Index; Effect Modifier, Epidemiologic; Estradiol; Ethnicity; Humans; Logistic Models; Male; Nutrition Surveys; Prostate-Specific Antigen; Sex Hormone-Binding Globulin; Statistics as Topic; Testosterone
PubMed: 25919471
DOI: 10.1002/pros.22998 -
BMC Public Health Mar 2018Most of the androgen replacement therapies were based on serum testosterone and without measurements of total androgen activities. Whether those with low testosterone...
BACKGROUND
Most of the androgen replacement therapies were based on serum testosterone and without measurements of total androgen activities. Whether those with low testosterone also have low levels of androgen activity is largely unknown. We hence examined the association between testosterone and androstanediol glucuronide (AG), a reliable measure of androgen activity, in a nationally representative sample of US men.
METHODS
Cross-sectional analysis was based on 1493 men from the Third National Health and Nutrition examination Survey (NHANES III) conducted from 1988 to 1991. Serum testosterone and AG were measured by immunoassay. Kernel density was used to estimate the average density of serum AG concentrations by quartiles of testosterone.
RESULTS
Testosterone was weakly and positively correlated with AG (correlation coefficient = 0.18). The kernel density estimates show that the distributions are quite similar between the quartiles of testosterone. After adjustment for age, the distributions of AG in quartiles of testosterone did not change. The correlation between testosterone and AG was stronger in men with younger age, lower body mass index, non-smoking and good self-rated health and health status.
CONCLUSIONS
Serum testosterone is weakly correlated with total androgen activities, and the correlation is even weaker for those with poor self-rated health. Our results suggest that measurement of total androgen activity in addition to testosterone is necessary in clinical practice, especially before administration of androgen replacement therapy.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Androstane-3,17-diol; Cross-Sectional Studies; Humans; Male; Middle Aged; Nutrition Surveys; Testosterone; United States; Young Adult
PubMed: 29523115
DOI: 10.1186/s12889-018-5255-6 -
Anesthesiology Oct 1971
Topics: Androstanes; Blood Pressure; Depression, Chemical; Ganglionic Blockers; Histamine Release; Humans; Pharmaceutic Aids; Piperidines; Stimulation, Chemical; Tubocurarine
PubMed: 4107153
DOI: 10.1097/00000542-197110000-00028 -
Cancer Research Communications Sep 2023Androgen receptor signaling inhibitors (ARSI) are used to treat castration-resistant prostate cancer (CRPC) to stop a resurgence of androgen receptor (AR) signaling....
UNLABELLED
Androgen receptor signaling inhibitors (ARSI) are used to treat castration-resistant prostate cancer (CRPC) to stop a resurgence of androgen receptor (AR) signaling. Despite early success, patients on ARSIs eventually relapse, develop drug resistance, and succumb to the disease. Resistance may occur through intratumoral steroidogenesis mediated by upregulation of aldo-keto reductase family 1C member 3 (AKR1C3). Patients treated with leuprolide (castrate) and those treated with leuprolide plus abiraterone (post-Abi) harbor a reservoir of DHEA-S which could fuel testosterone (T) biosynthesis via AKR1C3 to cause a resurgence of prostate cancer cell growth. We demonstrate that concentrations of DHEA-S found in castrate and post-Abi patients are (i) converted to T in an AKR1C3-dependent manner in prostate cancer cells, and (ii) in amounts sufficient to stimulate AKR1C3-dependent cell growth. We observed this in primary and metastatic prostate cancer cell lines, CWR22PC and DuCaP, respectively. Androgen measurements were made by stable isotope dilution LC-MS/MS. We demonstrate AKR1C3 dependence using stable short hairpin RNA knockdown and pharmacologic inhibitors. We also demonstrate that free DHEA is reduced to 5-androstene-3β,17β-diol (5-Adiol) by AKR1C3 and that this is a major metabolite, suggesting that in our cell lines 5-Adiol is a predominant precursor of T. We have identified a mechanism of ARSI resistance common to both primary and metastatic cell lines that is dependent on the conversion of DHEA to 5-Adiol on route to T catalyzed by AKR1C3.
SIGNIFICANCE
We show that reservoirs of DHEA-S that remain after ARSI treatment are converted into T in primary and metastatic prostate cancer cells in amounts sufficient to stimulate cell growth. Pharmacologic and genetic approaches demonstrate that AKR1C3 is required for these effects. Furthermore, the route to T proceeds through 5-Adiol. We propose that this is a mechanism of ARSI drug resistance.
Topics: Male; Humans; Testosterone; Prostatic Neoplasms; Testosterone Congeners; Androstenes; Dehydroepiandrosterone Sulfate; Aldo-Keto Reductase Family 1 Member C3
PubMed: 37772993
DOI: 10.1158/2767-9764.CRC-23-0235 -
Fertility and Sterility Mar 1992To explore the clinical usefulness of the antiandrogen flutamide in the treatment modality for hirsutism in women.
OBJECTIVE
To explore the clinical usefulness of the antiandrogen flutamide in the treatment modality for hirsutism in women.
DESIGN
Nine women with hirsutism were assessed before and then monthly for 3 months on a regimen of flutamide 250 mg three times a day as the sole therapeutic agent. Blood samples were taken at each assessment time for a battery of androgenic parameters.
SETTING
Patients were followed in the Out-Patient Department of the Hospital das Clinicas, Sao Paulo, Brazil. Hormonal assays were performed in the Hormone Laboratories of Hospital das Clinicas and the Endocrine Research Laboratory at Newark Beth Israel Medical Center, Newark, New Jersey.
PATIENTS
Nine women with moderate hirsutism were treated with flutamide. Six women were previously diagnosed as having idiopathic hirsutism, and three women were diagnosed as having polycystic ovary syndrome.
INTERVENTION
All women were treated with flutamide 250 mg three times a day for 3 months.
MAIN OUTCOME MEASURE
Improvement of hirsutism was assessed using the Ferriman-Gallwey hair density index. Side effects of drug therapy (deterioration of menses and dry skin) were explored. Androgen parameters included testosterone (T), sex hormone-binding globulin, bound, nonbound, and free T, androstanediol glucuronide, and others.
RESULTS
After 3 months of flutamide alone, Ferriman-Gallwey scores improved in seven of nine women with mean scores decreasing from 28.1 +/- 0.6 to 24.5 +/- 0.6. None of the androgenic parameters changed during this period of time. Follicle-stimulating hormone and luteinizing hormone response to gonadotropin-releasing hormone was unchanged after flutamide.
CONCLUSION
Flutamide favorably influenced hirsutism in women, with differences noted after only 3 months of therapy. More prolonged and detailed studies of this drug as the sole therapeutic agent for treatment of hirsutism seems warranted.
Topics: Adult; Analysis of Variance; Androstane-3,17-diol; Androstenedione; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Estradiol; Female; Flutamide; Hirsutism; Humans; Polycystic Ovary Syndrome; Sex Hormone-Binding Globulin; Testosterone; Treatment Outcome
PubMed: 1531466
DOI: 10.1016/s0015-0282(16)54897-3 -
Organic Letters Mar 2021The total synthesis of (+)-03219A, a rare Δ-pregnene isolated from the marine-derived sp. SCSIO 03219, is described that is based on a series of transformations that...
The total synthesis of (+)-03219A, a rare Δ-pregnene isolated from the marine-derived sp. SCSIO 03219, is described that is based on a series of transformations that enable progression from epichlorohydrin to an -estrane, then conversion to a -androstane, and finally establishment of the natural product target. Key to the success of these studies was implementation of two rearrangement processes to formally invert the quaternary center at C13 and establish the C10 quaternary center.
Topics: Androstanes; Estranes; Molecular Structure; Pregnenes; Streptomyces
PubMed: 33635666
DOI: 10.1021/acs.orglett.1c00382 -
Journal of Cancer Research and... 2005The profiles of lipids in normal and cancerous tissues may differ revealing information about cancer development and progression. Lipids being surface active, changes in...
BACKGROUND
The profiles of lipids in normal and cancerous tissues may differ revealing information about cancer development and progression. Lipids being surface active, changes in lipid profiles can manifest as altered surface activity profiles. Langmuir monolayers offer a convenient model for evaluating surface activity of biological membranes.
AIMS
The aims of this study were to quantify phospholipids and their effects on surface activity of normal and cancerous human cervical tissues as well as to evaluate the role of phosphatidylcholine (PC) and sphingomyelin (SM) in cervical cancer using Langmuir monolayers.
METHODS AND MATERIALS
Lipid quantification was done using thin layer chromatography and phosphorus assay. Surface activity was evaluated using Langmuir monolayers. Monolayers were formed on the surface of deionized water by spreading tissue organic phase corresponding to 1 mg of tissue and studying their surface pressure-area isotherms at body temperature. The PC and SM contents of cancerous human cervical tissues were higher than those of the normal human cervical tissues. Role of PC and SM were evaluated by adding varying amounts of these lipids to normal cervical pooled organic phase.
STATISTICAL ANALYSIS
Student's t-test (p < 0.05) and one-way analysis of variance (ANOVA) was used.
RESULTS
Our results reveals that the phosphatidylglycerol level in cancerous cervical tissue was nearly five folds higher than that in normal cervical tissue. Also PC and sphingomyelin SM were found to be the major phospholipid components in cancerous and normal cervical tissues respectively. The addition of either 1.5 microg DPPC or 0.5 microg SM /mg of tissue to the normal organic phase changed its surface activity profile to that of the cancerous tissues. Statistically significant surface activity parameters showed that PC and SM have remarkable roles in shifting the normal cervical lipophilic surface activity towards that of cancerous lipophilic component.
CONCLUSION
The Langmuir monolayer technique was sensitive to detect changes in tensiometric profiles of cervical cancers and these could be modulated by alterations in phosphatidylcholine and sphingomyelin levels. Therapeutic strategies may be designed to modulate these tensiometric profiles and lipid constituents of cancerous tissues.
Topics: Androstanes; Cervix Uteri; Chromatography, Thin Layer; Female; Humans; Phosphatidylcholines; Phospholipids; Sphingomyelins; Surface Properties; Uterine Cervical Neoplasms
PubMed: 17998650
DOI: 10.4103/0973-1482.19600 -
Fertility and Sterility Oct 1992Assessment of an in vivo test for 5 alpha-reductase activity using serum markers, 5 alpha-androstane-3 alpha,17 beta-diol glucuronide and androsterone glucuronide, after...
OBJECTIVE
Assessment of an in vivo test for 5 alpha-reductase activity using serum markers, 5 alpha-androstane-3 alpha,17 beta-diol glucuronide and androsterone glucuronide, after the cutaneous application of androstenedione (A).
DESIGN
An A gel was applied for 6 days to the skin of normal women, male volunteers, and hirsute and nonhirsute patients with polycystic ovarian syndrome (PCOS). Blood samples were obtained at baseline and on day 6 of the A gel application. Blood samples were assayed for A, 5 alpha-androstane-3 alpha,17 beta-diol glucuronide, and androsterone glucuronide. In three hirsute women, the protocol was followed before and after receiving an oral contraceptive (OC) and spironolactone 200 mg/d for 3 months.
SETTING
The study was performed in the outpatient clinic of the Division of Reproductive Endocrinology and Infertility, Women's Hospital of the Los Angeles County and University of Southern California Medical Center in Los Angeles, California.
PATIENTS, PARTICIPANTS
A total of eight nonhirsute patients with PCOS, seven hirsute patients with PCOS, and six male volunteers were enrolled in the study. Five normal women served as a control group.
MAIN OUTCOME MEASURE
Serum A increased after 6 days by a similar magnitude in all groups. Serum androsterone glucuronide showed a significant increase from baseline only in the hirsute group (P < 0.03), whereas the increase in 5 alpha-androstane-3 alpha,17 beta-diol glucuronide was not statistically significant.
RESULTS
The ratio of the increases in serum androsterone glucuronide over serum A was significantly higher in the hirsute group (P < 0.02). In the three hirsute patients who were placed on an OC and spironolactone, serum 5 alpha-androstane-3 alpha,17 beta-diol glucuronide and androsterone glucuronide decreased after 3 months and did not increase with application of the gel for another 6 days.
CONCLUSION
The cutaneous application of A provides a useful assessment of in vivo 5 alpha-reductase activity. However, because we found that A absorption varied considerably (30% to 62%), we suggest that this in vivo test may not provide more information than baseline determinations of 5 alpha-androstane-3 alpha,17 beta-diol glucuronide and androsterone glucuronide. It may, however, be useful as a parameter for assessing the effectiveness of various treatment regimens for hirsutism.
Topics: Administration, Cutaneous; Adult; Androstane-3,17-diol; Androstenedione; Androsterone; Cholestenone 5 alpha-Reductase; Female; Gels; Hirsutism; Humans; Male; Oxidoreductases; Polycystic Ovary Syndrome
PubMed: 1426314
DOI: 10.1016/s0015-0282(16)55316-3