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Molecules (Basel, Switzerland) Feb 2022This study was conducted to examine the anti-hair loss mechanism of the supercritical fluid extraction-residues extract of by the regulation of cytokine production and...
This study was conducted to examine the anti-hair loss mechanism of the supercritical fluid extraction-residues extract of by the regulation of cytokine production and hormone function in human dermal follicle papilla cells (HDFPCs). To investigate the modulatory effects on HO-induced cytokines, we measured transforming growth factor-beta and insulin-like growth factor 1 secreted from HDFPCs. To investigate the regulatory effects of supercritical extraction-residues extract of on dihydrotestosterone hormone production, cells were co-incubated with high concentrations of testosterone. The supercritical extraction-residues extract of significantly inhibited the secretion of transforming growth factor-beta but rescued insulin-like growth factor 1 in a dose-dependent manner. The supercritical extraction-residues extract of markedly reduced dihydrotestosterone production. These results suggest that the supercritical fluid extract residues of and their functional molecules are candidates for preventing human hair loss.
Topics: Cytokines; Dihydrotestosterone; Hair Follicle; Humans; Plant Bark; Plant Extracts; Ulmus
PubMed: 35209207
DOI: 10.3390/molecules27041419 -
Current Medicinal Chemistry 2016This article summarizes the importance of different targets such as 5α-reductase, 17β-HSD, CYP17A, androgen receptor and protein kinase A for the treatment of prostate... (Review)
Review
This article summarizes the importance of different targets such as 5α-reductase, 17β-HSD, CYP17A, androgen receptor and protein kinase A for the treatment of prostate cancer and benign prostatic hyperplasia. It is a well known fact that dihydrotestosterone (DHT) is associated with the development of androgen-dependent afflictions. At the present time, several research groups are attempting to develop new steroidal and non-steroidal molecules with the purpose of inhibiting the synthesis and biological response of DHT. This review also discusses the most recent studies reported in the literature that describe the therapeutic potential of novel compounds, as well as the new drugs, principally inhibitors of 5α-reductase.
Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; 5-alpha Reductase Inhibitors; Androgens; Dihydrotestosterone; Drug Discovery; Humans; Male; Molecular Conformation; Prostatic Hyperplasia; Prostatic Neoplasms; Structure-Activity Relationship
PubMed: 26861003
DOI: 10.2174/0929867323666160210125642 -
Journal of Andrology 2008The 5 alpha-reductase inhibitors, which inhibit conversion of testosterone to dihydrotestosterone, are used for miscellaneous clinical applications, including the... (Review)
Review
The 5 alpha-reductase inhibitors, which inhibit conversion of testosterone to dihydrotestosterone, are used for miscellaneous clinical applications, including the treatment of benign prostatic hyperplasia and male pattern hair loss, and for possible reduction of the risk of prostate cancer. Erectile dysfunction has been associated with 5 alpha-reductase inhibitors. Overall, reports in the literature suggest rates of erectile dysfunction to be between 0.8%-33% in men using these medications. However, randomized controlled studies report the rates of erectile dysfunction to be between 0.8%-15.8%. The possible risk association is that these medications impact androgen function, which is understood to contribute to normal erectile physiology. The 5 alpha-reductase inhibitors result in a drop in median serum dihydrotestosterone levels by 60%-93% within 2 years, but there is no major change in testosterone levels. In this review, we surveyed studies on erectile dysfunction in patients treated with 5 alpha-reductase inhibitors and critically examined the evidence that associates 5 alpha-reductase inhibitors and erectile dysfunction. We conclude that 5 alpha-reductase inhibitors do not lead to erectile dysfunction to a significant degree, and we support the position that dihydrotestosterone is less relevant than testosterone in erectile function.
Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; 5-alpha Reductase Inhibitors; Androgens; Animals; Clinical Trials as Topic; Dihydrotestosterone; Erectile Dysfunction; Humans; Male; Models, Animal; Penile Erection; Testosterone
PubMed: 18421068
DOI: 10.2164/jandrol.108.005025 -
The Journal of Steroid Biochemistry and... Nov 2013To better understand how elevated androgen levels regulate food intake and obesity in females, we treated ovariectomized female mice with dihydrotestosterone (DHT)...
To better understand how elevated androgen levels regulate food intake and obesity in females, we treated ovariectomized female mice with dihydrotestosterone (DHT) (non-aromatazable androgen), measured food intake and body weight, and evaluated physiological changes in liver function, glucose tolerance, and leptin resistance. Ovariectomized mice were treated with DHT or placebo. Mice were then fed a high fat diet under free-feeding or pair-feeding conditions for 3 months. We found that when DHT-treated ovariectomized mice had free access to food (free-feeding), they had increased food intake and higher body weight compared with control animals. These mice also had a significantly greater accumulation of fat in the liver and exhibited increased fasting glucose, impaired glucose tolerance, and resistance to leptin. However, when these mice were placed on a restricted diet and fed the same caloric amounts as controls (pair-feeding), their body weight increased at the same rate as control animals. This suggests that androgen regulates food intake through altered leptin sensitivity, and this increase of food intake could significantly contribute to an obesity phenotype. In summary, we demonstrated a role for androgen in the regulation of food intake and weight gain in females using a mouse model. This model will be useful to further elucidate the role of elevated androgen in females.
Topics: Androgens; Animals; Body Weight; Dihydrotestosterone; Eating; Female; Mice; Mice, Inbred C57BL; Obesity; Ovariectomy; Real-Time Polymerase Chain Reaction
PubMed: 23665441
DOI: 10.1016/j.jsbmb.2013.04.001 -
Breast Cancer Research : BCR Nov 2014Breast cancer is currently the most frequent, fatal cancer of women in western countries. While estrogens have a widely understood involvement in breast cancer, a... (Review)
Review
Breast cancer is currently the most frequent, fatal cancer of women in western countries. While estrogens have a widely understood involvement in breast cancer, a significant but not yet fully understood role for androgens has also been suggested. The principal androgen, testosterone, is the obligate steroidal precursor of estradiol, but can equally be metabolized into dihydrotestosterone, a more potent, pure androgen. Both androgens exert their distinctive biological effects via the androgen receptor, which is coexpressed with estrogen receptor alpha in 80 to 90% of breast cancers. The hormonal control of breast development and pathology has been examined experimentally through the use of animal models, notably mice and rats. This review summarizes the data from experimental rodent models on the effects of androgens in experimental breast cancer, aiming to address the importance of androgens and the androgen receptor in the origins and pathogenesis of breast cancers, as well as to discuss potential biomarker and therapeutic opportunities arising from novel insights based on the experimental research.
Topics: Adenocarcinoma; Androgens; Animals; Carcinogenesis; Dihydrotestosterone; Female; Mammary Neoplasms, Experimental; Mice; Rats; Receptors, Androgen; Testosterone
PubMed: 25928046
DOI: 10.1186/s13058-014-0483-x -
Journal of the American Veterinary... Dec 2016
Topics: Adrenal Insufficiency; Adrenocortical Hyperfunction; Animals; Dihydrotestosterone; Dog Diseases; Dogs; Enzyme Inhibitors; Glucocorticoids
PubMed: 27901462
DOI: 10.2460/javma.249.12.1353 -
Endocrinology Mar 2017Androgen excess in women is associated with metabolic dysfunction (e.g., obesity, hyperinsulinemia, insulin resistance, and increased risk of type 2 diabetes) and...
Androgen excess in women is associated with metabolic dysfunction (e.g., obesity, hyperinsulinemia, insulin resistance, and increased risk of type 2 diabetes) and reproductive dysfunction (e.g., polycystic ovaries, amenorrhea, dysregulated gonadotropin release, and infertility). We sought to identify the effects of androgen excess on glucose metabolic dysfunction and the specific mechanisms of action by which androgens are inducing pathology. We developed a mouse model that displayed pathophysiological serum androgen levels with normal body mass/composition to ensure that the phenotypes were directly from androgens and not an indirect consequence of obesity. We performed reproductive tests, metabolic tests, and hormonal assays. Livers were isolated and examined via molecular, biochemical, and histological analysis. Additionally, a low-dose dihydrotestosterone (DHT) cell model using H2.35 mouse hepatocytes was developed to study androgen effects on hepatic insulin signaling. DHT mice demonstrated impaired estrous cyclicity; few corpora lutea in the ovaries; glucose, insulin, and pyruvate intolerance; and lowered hepatic insulin action. Mechanistically, DHT increased hepatic androgen-receptor binding to phosphoinositide-3-kinase (PI3K)-p85, resulting in dissociation of PI3K-p85 from PI3K-p110, leading to reduced PI3K activity and decreased p-AKT and, thus, lowered insulin action. DHT increased gluconeogenesis via direct transcriptional regulation of gluconeogenic enzymes and coactivators. The hepatocyte model recapitulated the in vivo findings. The DHT-induced hepatocyte insulin resistance was reversed by the androgen-receptor antagonist, flutamide. These findings present a phenotype (i.e., impaired glucose tolerance and disrupted glucose metabolism) in a lean hyperandrogenemia model (low-dose DHT) and data to support 2 molecular mechanisms that help drive androgen-induced impaired glucose metabolism.
Topics: Animals; Anovulation; Class Ia Phosphatidylinositol 3-Kinase; Cyclic AMP Response Element-Binding Protein; Dihydrotestosterone; Disease Models, Animal; Female; Forkhead Box Protein O1; Gluconeogenesis; Glucose Metabolism Disorders; Hepatocytes; Hyperandrogenism; Insulin Resistance; Liver; Mice, Inbred C57BL; Promoter Regions, Genetic; Receptors, Androgen
PubMed: 27967242
DOI: 10.1210/en.2016-1553 -
The Journal of Clinical Investigation Sep 1970Three types of studies have been performed in immature, mature, and hypertrophic prostate glands of the dog. First, the concentrations of testosterone and...
Dihydrotestosterone in prostatic hypertrophy. II. The formation and content of dihydrotestosterone in the hypertrophic canine prostate and the effect of dihydrotestosterone on prostate growth in the dog.
Three types of studies have been performed in immature, mature, and hypertrophic prostate glands of the dog. First, the concentrations of testosterone and dihydrotestosterone have been measured in the three types of gland. Dihydrotestosterone was the predominant hormone recovered in all prostates studied and was present in approximately five times higher concentration in the hypertrophic as compared to the other types of dog prostate. Second, pharmacological doses of dihydrotestosterone were administered to castrated dogs for 9 months and resulted in a distinct acceleration of prostatic growth as compared to testosterone treatment. Third, the rates of formation and degradation of dihydrotestosterone were measured in normal and hypertrophic tissue and were found to be essentially the same. These observations suggest that dihydrotestosterone accumulation may be causally linked to the development of canine prostatic hypertrophy. However, the mechanism by which dihydrotestosterone accumulates in the prostate remains to be determined.
Topics: Aging; Animals; Biological Transport; Castration; Culture Techniques; DNA; Dihydrotestosterone; Dogs; Male; NADP; Organ Size; Oxidoreductases; Prostate; Prostatic Hyperplasia; RNA; Testosterone; Tritium
PubMed: 4194769
DOI: 10.1172/JCI106392 -
PloS One 2016Androgen receptor (AR) signaling is crucial to the development and homeostasis of the prostate gland, and its dysregulation mediates common prostate pathologies. The...
Androgen receptor (AR) signaling is crucial to the development and homeostasis of the prostate gland, and its dysregulation mediates common prostate pathologies. The mechanisms whereby AR regulates growth suppression and differentiation of luminal epithelial cells in the prostate gland and proliferation of malignant versions of these cells have been investigated in human and rodent adult prostate. However, the cellular stress response of human prostate epithelial cells is not well understood, though it is central to prostate health and pathology. Here, we report that androgen sensitizes HPr-1AR and RWPE-AR human prostate epithelial cells to cell stress agents and apoptotic cell death. Although 5α-dihydrotestosterone (DHT) treatment alone did not induce cell death, co-treatment of HPr-1AR cells with DHT and an apoptosis inducer, such as staurosporine (STS), TNFt, or hydrogen peroxide, synergistically increased cell death in comparison to treatment with each apoptosis inducer by itself. We found that the synergy between DHT and apoptosis inducer led to activation of the intrinsic/mitochondrial apoptotic pathway, which is supported by robust cleavage activation of caspase-9 and caspase-3. Further, the dramatic depolarization of the mitochondrial membrane potential that we observed upon co-treatment with DHT and STS is consistent with increased mitochondrial outer membrane permeabilization (MOMP) in the pro-apoptotic mechanism. Interestingly, the synergy between DHT and apoptosis inducer was abolished by AR antagonists and inhibitors of transcription and protein synthesis, suggesting that AR mediates pro-apoptotic synergy through transcriptional regulation of MOMP genes. Expression analysis revealed that pro-apoptotic genes (BCL2L11/BIM and AIFM2) were DHT-induced, whereas pro-survival genes (BCL2L1/BCL-XL and MCL1) were DHT-repressed. Hence, we propose that the net effect of these AR-mediated expression changes shifts the balance of BCL2-family proteins, such that androgen signaling sensitizes mitochondria to apoptotic signaling, thus rendering HPr-1AR more vulnerable to cell death signals. Our study offers insight into AR-mediated regulation of prostate epithelial cell death signaling.
Topics: Androgens; Apoptosis; Cell Line; Dihydrotestosterone; Epithelial Cells; Humans; Immunoblotting; Male; Prostate; Receptors, Androgen; Signal Transduction; Staurosporine
PubMed: 27203692
DOI: 10.1371/journal.pone.0156145 -
The Journal of Physical Chemistry. B Sep 2019Androgen receptor (AR) is a steroid hormone nuclear receptor which upon binding its endogenous androgenic ligands (agonists), testosterone and dihydrotestosterone (DHT),...
Androgen receptor (AR) is a steroid hormone nuclear receptor which upon binding its endogenous androgenic ligands (agonists), testosterone and dihydrotestosterone (DHT), alters gene transcription, producing a diverse range of biological effects. Antiandrogens, such as the pharmaceuticals bicalutamide and hydroxyflutamide, act as agonists in the absence of androgens and as antagonists in their presence or in high concentration. The atomic level mechanism of action by agonists and antagonists of AR is less well characterized. Therefore, in this study, multiple 1 μs molecular dynamics (MD), docking simulations, and perturbation-response analyses were performed to more fully explore the nature of interaction between agonist or antagonist and AR and the conformational changes induced in the AR upon interaction with different ligands. We characterized the mechanism of the ligand entry/exit and found that helix-12 and nearby structural motifs respond dynamically in that process. Modeling showed that the agonist and antagonist/agonist form a hydrogen bond with Thr877/Asn705 and that this interaction is absent for antagonists. Agonist binding to AR increases the mobility of residues at allosteric sites and coactivator binding sites, while antagonist binding decreases mobility at these important sites. A new site was also identified as a potential surface for allosteric binding. These results shed light on the effect of agonists and antagonists on the structure and dynamics of AR.
Topics: Androgen Receptor Antagonists; Androgens; Anilides; Binding Sites; Dihydrotestosterone; Flutamide; Humans; Molecular Dynamics Simulation; Nitriles; Receptors, Androgen; Testosterone; Tosyl Compounds
PubMed: 31431014
DOI: 10.1021/acs.jpcb.9b05654