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Scientific Reports Sep 2022Many conjunctival inflammatory diseases differ between the sexes and altered conjunctival goblet cells (CGCs) response is often involved. Inflammation is initiated by...
Many conjunctival inflammatory diseases differ between the sexes and altered conjunctival goblet cells (CGCs) response is often involved. Inflammation is initiated by the release of pro-inflammatory mediators and terminated by the biosynthesis of specialized pro-resolution mediators (SPMs). Herein, we determined the sex-based difference in the responses of CGCs to inflammatory stimuli or pro-resolving lipid SPMs and their interaction with sex hormones. GCs were cultured from pieces of human conjunctiva in RPMI media. CGCs were transferred 24 h before the start of experiments to phenol red-free and FBS-free media to minimize exogenous hormones. RT-PCR, immunofluorescence microscopy (IF), and Western Blot (WB) were performed to determine the presence of sex hormone receptors. Cellular response to pro-inflammatory stimuli or SPMs was studied by measuring the increase in intracellular [Ca] ([Ca]) using fura 2/AM microscopy. Use of RT-PCR demonstrated estrogen receptor (ER) α in 4/5 males and 3/3 females; ERβ in 2/4 males and 2/3 females; and androgen receptors (AR) in 3/3 male and 3/3 female CGCs. Positive immunoreactivity by IF and protein expression by WB was detected using antibodies for the ERα and ERβ in 3/3 males and 3/3 females, while AR were only present in males. Significantly different Ca responses between sexes were found with carbachol only at 10 M, but not with histamine or leukotriene (LT) B at any concentration used. Incubation with dihydrotestosterone (DHT), estrone (E1), or estradiol (E2) at 10 M for 30 min significantly inhibited the LTB-stimulated [Ca] increase in male and female CGCs. Incubation with DHT, E1, and E2 overnight significantly inhibited the LTB response in females, while DHT and E2 significantly inhibited the LTB response in males. The SPM lipoxin A (LXA) (10-10 M), but not the resolvins D1 or D2, induced an [Ca] increase that was significantly higher in males compared to females. We conclude that male and female CGCs showed differences in the expression of sex hormone receptors. Treatment with sex hormones altered pro-inflammatory mediator LTB-induced response. Males compared to females have a higher response to the ω-6-fatty acid derived SPM LXA, indicating males may terminate inflammation in conjunctival goblet cells faster than females.
Topics: Carbachol; Conjunctiva; Conjunctival Diseases; Dihydrotestosterone; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrone; Female; Fura-2; Goblet Cells; Histamine; Humans; Leukotrienes; Lipoxins; Male; Receptors, Androgen; Receptors, Estrogen
PubMed: 36175572
DOI: 10.1038/s41598-022-20177-9 -
Frontiers in Endocrinology 2022The role of endogenous androgens in kidney function and disease has not been extensively explored in men and women.
INTRODUCTION
The role of endogenous androgens in kidney function and disease has not been extensively explored in men and women.
RESEARCH DESIGN AND METHODS
We analyzed data from the observational KORA F4 study and its follow-up examination KORA FF4 (median follow-up time 6.5 years) including 1293 men and 650 peri- and postmenopausal women, not using exogenous sex hormones. We examined the associations between endogenous androgens (testosterone [T], dihydrotestosterone [DHT], free T [fT], free DHT [fDHT], and T/DHT), with estimated glomerular filtration rate (eGFR) at baseline and follow-up, prevalent, and incident chronic kidney disease (CKD) adjusting for common CKD risk factors.
RESULTS
At baseline, 73 men (5.7%) and 54 women (8.4%) had prevalent CKD. Cross-sectionally, no significant associations between androgens and kidney function were observed among men. In women, elevated T (β=-1.305, [95% CI -2.290; -0.320]) and fT (β=-1.423, [95% CI -2.449; -0.397]) were associated with lower eGFR. Prospectively, 81 men (8.8%) and 60 women (15.2%) developed incident CKD. In women, a reverse J-shaped associations was observed between DHT and incident CKD (P=0.029), while higher fDHT was associated with lower incident CKD risk (odds ratio per 1 standard deviation=0.613, [95% CI 0.369; 0.971]. Among men, T/DHT (β=-0.819, [95% CI -1.413; -0.226]) and SHBG (P=0.011) were associated with eGFR at follow-up but not with incident CKD. Some associations appeared to be modified by type 2 diabetes (T2D).
CONCLUSION
Suggestive associations are observed of androgens and SHBG with kidney impairment among men and women. However, larger well-phenotyped prospective studies are required to further elucidate the potential of androgens, SHBG, and T2D as modifiable risk factors for kidney function and CKD.
Topics: Male; Humans; Female; Androgens; Diabetes Mellitus, Type 2; Sex Hormone-Binding Globulin; Dihydrotestosterone; Renal Insufficiency, Chronic; Kidney
PubMed: 36601008
DOI: 10.3389/fendo.2022.1000650 -
Skin Pharmacology and Physiology 2022Reconstructing sebaceous glands is one goal of functionally healing patients who have suffered severe burns, instead of the simple pursuit of wound closure. Effective...
INTRODUCTION
Reconstructing sebaceous glands is one goal of functionally healing patients who have suffered severe burns, instead of the simple pursuit of wound closure. Effective regeneration of skin appendages remains a challenge in skin wound management and research.
OBJECTIVE
The aim of this study was to evaluate the differentiation of adipose-derived stem cells (ADSCs) into sebaceous glands and clarified the involvement of hepatocyte growth factor (HGF) and 5α-dihydrotestosterone (5α-DHT) in this process.
METHODS
This study used HGF- and 5α-DHT-gelatin microspheres to treat human ADSCs and investigated the reconstruction of sebaceous glands. HGF- and 5α-DHT-gelatin microspheres were constructed using microcapsule slow-release technology. A mice full-thickness skin-wound model was established to evaluate wound healing, and hematoxylin-eosin staining was utilized to determine the skin structure.
RESULTS
In vitro analyses found that HGF- and 5α-DHT-gelatin microspheres promoted migration of and tube formation by ADSCs. Furthermore, AKT/ERK signaling, which is related to sebocyte and sweat gland epithelial-cell growth, was activated after HGF and 5α-DHT treatment. An in vivo wound healing model demonstrated that ADSCs primed with amnion-loaded HGF- and 5α-DHT-gelatin microspheres promoted wound healing and increased sebaceous gland formation compared to the control group.
CONCLUSIONS
This study confirms the efficacy of ADSCs treated with amnion and HGF- and 5α-DHT-gelatin microspheres in accelerating wound healing and effectively restoring sebaceous glands. This engineered tissue provides insight into and a novel therapeutic material for burns and full-thickness skin wounds.
Topics: Animals; Burns; Dihydrotestosterone; Gelatin; Hepatocyte Growth Factor; Mice; Microspheres; Stem Cells; Wound Healing
PubMed: 35439758
DOI: 10.1159/000524188 -
Aquatic Toxicology (Amsterdam,... Jun 2021Despite of physiological and toxicological relevance, the potential of androgens to influence fish lipid metabolism remains poorly explored. Here, brown trout primary...
Despite of physiological and toxicological relevance, the potential of androgens to influence fish lipid metabolism remains poorly explored. Here, brown trout primary hepatocytes were exposed to six concentrations (1 nM to 100 μM) of dihydrotestosterone (DHT) and testosterone (T), to assess changes in the mRNA levels of genes covering diverse lipid metabolic pathways. Acsl1, essential for fatty acid activation, was up-regulated by T and DHT, whereas the lipogenic enzymes FAS and ACC were up-regulated by the highest (100 μM) concentration of T and DHT, respectively. ApoA1, the major component of high-density lipoprotein (HDL), was down-regulated by both androgens. PPARγ, linked to adipogenesis and peroxisomal β-oxidation, was down-regulated by T and DHT, while Acox1-3I, rate-limiting in peroxisomal β-oxidation, was down-regulated by T. Fabp1, StAR and LPL were not altered. Our findings suggest that androgens may impact on lipid transport, adipogenesis and fatty acid β-oxidation and promote lipogenesis in fish liver.
Topics: Androgens; Animals; Dihydrotestosterone; Fatty Acid-Binding Proteins; Fatty Acids; Hepatocytes; Lipid Metabolism; Lipogenesis; Liver; PPAR gamma; Testosterone; Trout; Water Pollutants, Chemical
PubMed: 33873058
DOI: 10.1016/j.aquatox.2021.105819 -
The Journal of Urology Dec 2022Dihydrotestosterone and testosterone are thought to be major contributors of prostate cancer progression and resistance. We studied the modulation of 15 circulating...
PURPOSE
Dihydrotestosterone and testosterone are thought to be major contributors of prostate cancer progression and resistance. We studied the modulation of 15 circulating steroids by castration and their association with dihydrotestosterone and testosterone levels.
MATERIALS METHODS
A total of 116 serum samples were collected from 99 prostate cancer patients and categorized as eugonadal, castration-sensitive prostate cancer, castration-resistant prostate cancer, or castration-resistant prostate cancer under abiraterone acetate. Serum levels of 15 steroids were measured using mass spectrometry and compared between groups using analysis of variance. Intrapatient association of steroid levels and the androgens testosterone and dihydrotestosterone were assessed using Pearson correlation and linear regression.
RESULTS
Testosterone, dihydrotestosterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androsterone, androstenediol, estrone, estrone-sulfate, estradiol, and androsterone/3α-diol-3/3α-diol-17-glucuronide levels were significantly decreased in castration-sensitive prostate cancer (castrated) compared to eugonadal patients. Testosterone levels were strongly associated with multiple steroids under eugonadal conditions, whereas they were weakly affected by precursor steroids in castrated patients. By contrast, dihydrotestosterone levels under androgen deprivation therapy were associated with testosterone and the backdoor pathway metabolite androsterone. In castration-resistant prostate cancer patients, levels of androstenedione were significantly associated with testosterone level, while testosterone was the only steroid associated with dihydrotestosterone levels.
CONCLUSIONS
Androgen deprivation therapy significantly reduces the levels of 13 circulating steroids. Upon androgen deprivation therapy initiation, the backdoor pathway metabolite androsterone are strongly associated with dihydrotestosterone levels. Under castration-resistant prostate cancer conditions, androstenedione was significantly associated with testosterone levels, suggesting the presence of tumor-related circulating androgens in these patients. These results provide further rationale to intensify treatments with androgen receptor axis signaling pathway inhibitors in patients with prostate cancer.
Topics: Male; Humans; Androgens; Androstenedione; Prostatic Neoplasms; Dihydrotestosterone; Androgen Antagonists; Androsterone; Prostatic Neoplasms, Castration-Resistant; Estrone; Testosterone; Orchiectomy; Dehydroepiandrosterone; Sulfates
PubMed: 36102111
DOI: 10.1097/JU.0000000000002923 -
Chemistry (Weinheim An Der Bergstrasse,... May 2020The hydroxylation of nonreactive C-H bonds can be easily catalyzed by a variety of metalloenzymes, especially cytochrome P450s (P450s). The mechanism of P450 mediated...
The hydroxylation of nonreactive C-H bonds can be easily catalyzed by a variety of metalloenzymes, especially cytochrome P450s (P450s). The mechanism of P450 mediated hydroxylation has been intensively studied, both experimentally and theoretically. However, understanding the regio- and stereoselectivities of substrates hydroxylated by P450s remains a great challenge. Herein, we use a multi-scale modeling approach to investigate the selectivity of testosterone (TES) and dihydrotestosterone (DHT) hydroxylation catalyzed by two important P450s, CYP3A4 and CYP19A1. For CYP3A4, two distinct binding modes for TES/DHT were predicted by dockings and molecular dynamics simulations, in which the experimentally identified sites of metabolism of TES/DHT can access to the catalytic center. The regio- and stereoselectivities of TES/DHT hydroxylation were further evaluated by quantum mechanical and ONIOM calculations. For CYP19A1, we found that sites 1β, 2β and 19 can access the catalytic center, with the intrinsic reactivity 2β>1β>19. However, our ONIOM calculations indicate that the hydroxylation is favored at site 19 for both TES and DHT, which is consistent with the experiments and reflects the importance of the catalytic environment in determining the selectivity. Our study unravels the mechanism underlying the selectivity of TES/DHT hydroxylation mediated by CYP3A4 and CYP19A1 and is helpful for understanding the selectivity of other substrates that are hydroxylated by P450s.
Topics: Aromatase; Catalysis; Cytochrome P-450 CYP3A; Dihydrotestosterone; Humans; Hydroxylation; Kinetics; Oxidation-Reduction; Testosterone
PubMed: 32049373
DOI: 10.1002/chem.201905272 -
Dermatologic Therapy Jul 2022Hirsutism is defined as an excessive terminal hair growth in female over male pattern distribution areas. Traditional methods of hair removal have been replaced by...
Comparison of efficacy of diode laser in patients of facial hirsutism with normal dehydroepiandrosterone sulfate and dihydrotestosterone versus deranged dehydroepiandrosterone sulfate and dihydrotestosterone level-A longitudinal study.
Hirsutism is defined as an excessive terminal hair growth in female over male pattern distribution areas. Traditional methods of hair removal have been replaced by lasers. The aim of the study was to observe the effect of diode laser in hirsutism patient with normal and deranged dehydroepiandrosterone sulfate (DHEAS) and dihydrotestosterone (DHT) level. Fifty patients of facial hirsutism with skin type IV and V were enrolled. Eighteen patients with deranged DHEAS and DHT level were allocated in group A whereas 16 patients with normal level were allocated in group B. Three sittings of diode laser was done in all subjects with varying session within a period of 6 months. At first follow-up visit, the percentage of hair reduction was fair in 62.5% of patients in group B and 16.7% of patients in group A, whereas at second follow-up visit, it was good in 56.3% of patients in group B and 11.1% of patients in group A. Increase in vellus hair and reduction in percentage of terminal hair were more significant in group B. Hair free interval and satisfaction level was significantly higher in group B. Diode laser is effective mode of treatment in hirsutism patient irrespective of hormone level. But, the effect is observed to be more efficacious in patients with normal DHEAS and DHT level.
Topics: Dehydroepiandrosterone Sulfate; Dihydrotestosterone; Female; Hair Removal; Hirsutism; Humans; Hypertrichosis; Lasers, Semiconductor; Longitudinal Studies; Male
PubMed: 35419916
DOI: 10.1111/dth.15509 -
Annales D'endocrinologie Jun 2021Male hypogonadism, arising from a range of etiologies including androgen-deprivation therapies (ADTs), has been reported as a risk factor for acquired long-QT syndrome...
BACKGROUND
Male hypogonadism, arising from a range of etiologies including androgen-deprivation therapies (ADTs), has been reported as a risk factor for acquired long-QT syndrome (aLQTS) and torsades de pointes (TdP). A full description of the clinical features of aLQTS associated with ADT and of underlying mechanisms is lacking.
METHODS
We searched the international pharmacovigilance database VigiBase for men (n=6 560 565 individual case safety reports) presenting with aLQTS, TdP, or sudden death associated with ADT. In cardiomyocytes derived from induced pluripotent stem cells from men, we studied electrophysiological effects of ADT and dihydrotestosterone.
RESULTS
Among subjects receiving ADT in VigiBase, we identified 184 cases of aLQTS (n=168) and/or TdP (n=68; 11% fatal), and 99 with sudden death. Of the 10 ADT drugs examined, 7 had a disproportional association (reporting odds ratio=1.4-4.7; P<0.05) with aLQTS, TdP, or sudden death. The minimum and median times to sudden death were 0.25 and 92 days, respectively. The androgen receptor antagonist enzalutamide was associated with more deaths (5430/31 896 [17%]; P<0.0001) than other ADT used for prostate cancer (4208/52 089 [8.1%]). In induced pluripotent stem cells, acute and chronic enzalutamide (25μM) significantly prolonged action potential durations (action potential duration at 90% when paced at 0.5Hz; 429.7±27.1 (control) versus 982.4±33.2 (acute, P<0.001) and 1062.3±28.9ms (chronic; P<0.001), and generated afterdepolarizations and/or triggered activity in drug-treated cells (11/20 acutely and 8/15 chronically). Enzalutamide acutely and chronically inhibited delayed rectifier potassium current, and chronically enhanced late sodium current. Dihydrotestosterone (30nM) reversed enzalutamide electrophysiological effects on induced pluripotent stem cells.
CONCLUSION
QT prolongation and TdP are a risk in men receiving enzalutamide and other ADTs.
CLINICAL TRIAL REGISTRATION
URL: https://www.clinicaltrials.gov. Unique identifier: NCT03193138.
Topics: Androgens; Cell Differentiation; Cells, Cultured; Databases, Factual; Death, Sudden, Cardiac; Dihydrotestosterone; Electrophysiological Phenomena; Eunuchism; Heart Ventricles; Humans; Induced Pluripotent Stem Cells; Internationality; Long QT Syndrome; Male; Membrane Potentials; Myocytes, Cardiac; Pharmacovigilance; Torsades de Pointes; Translational Research, Biomedical; Ventricular Function
PubMed: 32171470
DOI: 10.1016/j.ando.2020.02.008 -
The Journal of Endocrinology Oct 2016The 5α-reductase enzymes play an important role during male sexual differentiation, and in pregnant females, especially equine species where maintenance relies on...
The 5α-reductase enzymes play an important role during male sexual differentiation, and in pregnant females, especially equine species where maintenance relies on 5α-reduced progesterone, 5α-dihydroprogesterone (DHP). Epididymis expresses 5α-reductases but was not studied elaborately in horses. Epididymis from younger and older postpubertal stallions was divided into caput, corpus and cauda and examined for 5α-reductase activity and expression of type 1 and 2 isoforms by quantitative real-time polymerase chain reaction (qPCR). Metabolism of progesterone and testosterone to DHP and dihydrotestosterone (DHT), respectively, by epididymal microsomal protein was examined by thin-layer chromatography and verified by liquid chromatography tandem mass spectrometry (LC-MS/MS). Relative inhibitory potencies of finasteride and dutasteride toward equine 5α-reductase activity were investigated. Pregnenolone was investigated as an additional potential substrate for 5α-reductase, suggested previously from in vivo studies in mares but never directly examined. No regional gradient of 5α-reductase expression was observed by either enzyme activity or transcript analysis. Results of PCR experiments suggested that type 1 isoform predominates in equine epididymis. Primers for the type 2 isoform were unable to amplify product from any samples examined. Progesterone and testosterone were readily reduced to DHP and DHT, and activity was effectively inhibited by both inhibitors. Using epididymis as an enzyme source, no experimental evidence was obtained supporting the notion that pregnenolone could be directly metabolized by equine 5α-reductases as has been suggested by previous investigators speculating on alternative metabolic pathways leading to DHP synthesis in placenta during equine pregnancies.
Topics: 17-Ketosteroids; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; 5-alpha Reductase Inhibitors; Androstanols; Animals; Dihydrotestosterone; Dutasteride; Epididymis; Female; Finasteride; Horses; Male; Pregnancy; Pregnenolone
PubMed: 27466384
DOI: 10.1530/JOE-16-0175 -
British Journal of Cancer Sep 2014Despite our most vigorous efforts, prostate cancer remains the second leading cause of cancer death in men. Understanding the intricacies of androgen metabolism is vital... (Review)
Review
Despite our most vigorous efforts, prostate cancer remains the second leading cause of cancer death in men. Understanding the intricacies of androgen metabolism is vital to finding therapeutic targets, particularly with progression of advanced prostate cancer after initial hormone therapy, where adrenal precursors are involved. Such is the case with castration-resistant prostate cancer, where adrenal androgens, for example, dehydroepiandrosterone, are a source for intratumoural synthesis of dihydrotestosterone. As prostate cancer progresses, androgen metabolism changes due to altered expression of steroidogenic enzymes and mutations in the components of the steroidogenic machinery. These alterations sustain disease and allow progression; mechanistically, they may also enable development of hormone therapy resistance. With the development of the newer agents, abiraterone acetate and enzalutamide, efforts have been made to better define the basis for response and resistance. This work can be carried out in cell lines, animal models, as well as with ex vivo analysis of tissues obtained from patients. Efforts to further elucidate the finer details of the steroidogenic pathway are necessary to move toward a curative paradigm for patients with localised disease at high risk for recurrence.
Topics: Androgens; Animals; Dihydrotestosterone; Drug Resistance, Neoplasm; Humans; Hydroxysteroid Dehydrogenases; Male; Molecular Targeted Therapy; Prostatic Neoplasms, Castration-Resistant; Testosterone
PubMed: 24867689
DOI: 10.1038/bjc.2014.268