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Neurobiology of Disease Jul 2020Microglia-induced neuroinflammation plays a vital role in the etiology and progression of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease...
Microglia-induced neuroinflammation plays a vital role in the etiology and progression of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and multiple sclerosis. The neuroprotective role of androgens, including testosterone and its metabolite dihydrotestosterone (DHT), has been increasingly demonstrated in these diseases, but few studies investigated the effects of androgen on neuroinflammation. This study investigated the role of DHT in lipopolysaccharide (LPS)-induced neuroinflammation, neuronal damage and behavioral dysfunction, as well as underlying mechanisms. We showed that DHT inhibited LPS-induced release of proinflammatory factors, including TNF-α, IL-1β, IL-6; iNOS, COX-2, NO, and PGE2 in BV2 cells and primary microglia by suppressing the TLR4-mediated NF-κB and MAPK p38 signaling pathways, thus protecting SH-SY5Y neurons from inflammatory damage induced by activated microglia. In an LPS-induced neuroinflammation mouse model, endogenous DHT depletion by castration exacerbated inflammatory responses by upregulating the levels of TNF-α, IL-1β, IL-6, iNOS, and COX-2 in the serum and brain by increasing the LR4-mediated NF-κB and MAPK pathway activation, but these effects were restored by exogenous DHT supplementation. Moreover, DHT also regulated the mRNA levels of the anti-inflammatory cytokines IL-10 and IL-13 in the brain. In addition, DHT modulated the expression of Aβ, the apoptotic proteins caspase-3, Bcl-2, and Bax, and synaptophysin, as well as neuronal damage in LPS-treated mouse brains. Further behavioral tests revealed that DHT ameliorated LPS-induced spatial and learning impairment and motor incoordination, and partly improved the locomotor activity in LPS-injected mice. Therefore, this study suggests that DHT exerts anti-neuroinflammatory and neuroprotective effects; thus, androgen replacement therapy is a potential therapeutic strategy for improving cognitive and behavioral function in neuroinflammation-related diseases.
Topics: Androgens; Animals; Anti-Inflammatory Agents; Brain; Cyclooxygenase 2; Cytokines; Dihydrotestosterone; Inflammation; Lipopolysaccharides; MAP Kinase Signaling System; Mice; Microglia; NF-kappa B; Neurons; Neuroprotection; Neuroprotective Agents; Nitric Oxide Synthase Type II; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha
PubMed: 32087283
DOI: 10.1016/j.nbd.2020.104814 -
The Canadian Veterinary Journal = La... Apr 2018Many articles published in the past few years have contributed to a better understanding of the use of trilostane in dogs. Trilostane is a competitive inhibitor of... (Review)
Review
Many articles published in the past few years have contributed to a better understanding of the use of trilostane in dogs. Trilostane is a competitive inhibitor of 3β-hydroxysteroid dehydrogenase, the enzyme essential for synthesis of cortisol and all other steroids. Trilostane is reported to be safe and effective in the treatment of pituitary-dependent hyperadrenocorticism (HAC), adrenal-dependent HAC, and alopecia X. While trilostane controls most of the clinical signs associated with HAC, abnormalities such as hypertension, hypercoagulability, and proteinuria may persist despite therapy. Because the duration of cortisol suppression after a dose of trilostane is often less than 12 hours, many dogs with HAC could benefit from low dose trilostane treatment every 12 hours. Many controversies regarding trilostane still exist. This review provides a comprehensive commentary on trilostane's indications, mode of action, dose, monitoring, efficacy, and adverse effects.
Topics: Adrenocortical Hyperfunction; Alopecia; Animals; Dihydrotestosterone; Dog Diseases; Dogs; Enzyme Inhibitors; Pituitary ACTH Hypersecretion
PubMed: 29606727
DOI: No ID Found -
Endocrine Reviews Jun 2017Benefits associated with lowered serum DHT levels after 5α-reductase inhibitor (5AR-I) therapy in men have contributed to a misconception that circulating DHT levels... (Review)
Review
Benefits associated with lowered serum DHT levels after 5α-reductase inhibitor (5AR-I) therapy in men have contributed to a misconception that circulating DHT levels are an important stimulus for androgenic action in target tissues (e.g., prostate). Yet evidence from clinical studies indicates that intracellular concentrations of androgens (particularly in androgen-sensitive tissues) are essentially independent of circulating levels. To assess the clinical significance of modest elevations in serum DHT and the DHT/testosterone (T) ratio observed in response to common T replacement therapy, a comprehensive review of the published literature was performed to identify relevant data. Although the primary focus of this review is about DHT in men, we also provide a brief overview of DHT in women. The available published data are limited by the lack of large, well-controlled studies of long duration that are sufficiently powered to expose subtle safety signals. Nonetheless, the preponderance of available clinical data indicates that modest elevations in circulating levels of DHT in response to androgen therapy should not be of concern in clinical practice. Elevated DHT has not been associated with increased risk of prostate disease (e.g., cancer or benign hyperplasia) nor does it appear to have any systemic effects on cardiovascular disease safety parameters (including increased risk of polycythemia) beyond those commonly observed with available T preparations. Well-controlled, long-term studies of transdermal DHT preparations have failed to identify safety signals unique to markedly elevated circulating DHT concentrations or signals materially different from T.
Topics: 5-alpha Reductase Inhibitors; Animals; Dihydrotestosterone; Female; Humans; Male; Prostate; Prostatic Neoplasms; Sex Characteristics; Testosterone
PubMed: 28472278
DOI: 10.1210/er.2016-1067 -
Journal of Biomedical Science Mar 2022Androgenetic alopecia (AGA) is a genetic disorder caused by dihydrotestosterone (DHT), accompanied by the senescence of androgen-sensitive dermal papilla cells (DPCs)...
BACKGROUND
Androgenetic alopecia (AGA) is a genetic disorder caused by dihydrotestosterone (DHT), accompanied by the senescence of androgen-sensitive dermal papilla cells (DPCs) located in the base of hair follicles. DHT causes DPC senescence in AGA through mitochondrial dysfunction. However, the mechanism of this pathogenesis remains unknown. In this study, we investigated the protective role of cyanidins on DHT-induced mitochondrial dysfunction and DPC senescence and the regulatory mechanism involved.
METHODS
DPCs were used to investigate the effect of DHT on mitochondrial dysfunction with MitoSOX and Rhod-2 staining. Senescence-associated β-galactosidase activity assay was performed to examine the involvement of membrane AR-mediated signaling in DHT-induced DPC senescence. AGA mice model was used to study the cyanidins on DHT-induced hair growth deceleration.
RESULTS
Cyanidin 3-O-arabinoside (C3A) effectively decreased DHT-induced mtROS accumulation in DPCs, and C3A reversed the DHT-induced DPC senescence. Excessive mitochondrial calcium accumulation was blocked by C3A. C3A inhibited p38-mediated voltage-dependent anion channel 1 (VDAC1) expression that contributes to mitochondria-associated ER membrane (MAM) formation and transfer of calcium via VDAC1-IP3R1 interactions. DHT-induced MAM formation resulted in increase of DPC senescence. In AGA mice models, C3A restored DHT-induced hair growth deceleration, which activated hair follicle stem cell proliferation.
CONCLUSIONS
C3A is a promising natural compound for AGA treatments against DHT-induced DPC senescence through reduction of MAM formation and mitochondrial dysfunction.
Topics: Animals; Anthocyanins; Cellular Senescence; Dihydrotestosterone; Hair Follicle; Mice; Mitochondria
PubMed: 35255899
DOI: 10.1186/s12929-022-00800-7 -
Fertility and Sterility Dec 2022To characterize the circulating androgen levels across the menstrual cycle in healthy women using highly sensitive and accurate methods and report sex differences in the...
OBJECTIVE
To characterize the circulating androgen levels across the menstrual cycle in healthy women using highly sensitive and accurate methods and report sex differences in the relative levels of dihydrotestosterone (DHT) to testosterone (T) levels.
DESIGN
Prospective cohort study.
SETTING
Research clinic, academic teaching hospital.
PATIENT(S)
Twenty-one healthy premenopausal women, aged 19-40 years, with regular menstrual cycles.
INTERVENTION(S)
Not applicable.
MAIN OUTCOME MEASURE(S)
Serum total T and DHT levels measured using liquid chromatography-tandem mass spectrometry, free T levels measured using a standardized equilibrium dialysis method coupled with measurement of the T levels in the dialysate using liquid chromatography-tandem mass spectrometry, and comparison of the DHT-to-T ratio between healthy women and age-matched healthy men.
RESULT(S)
The serum total and free T levels increased across the follicular phase and peaked at midcycle (total T, 43.6 ± 16.2 ng/dL; free T, 15.6 ± 11.9 pg/mL) and gradually declined in the luteal phase. The DHT level did not significantly change across the menstrual cycle. The DHT-to-T ratios were 1:4 and 1:13 in women and men, respectively.
CONCLUSION(S)
In healthy premenopausal women, the total and free T levels varied significantly across the menstrual cycle, whereas the DHT levels did not change; the peak total and free T levels in the midcycle period were higher than previously reported, underscoring the importance of establishing menstrual phase-specific reference ranges to avoid misdiagnosis of hyperandrogenism. Women have significantly higher DHT levels relative to total T than men; the significance of this sex difference in the DHT-to-T ratio needs further investigation.
Topics: Female; Humans; Male; Testosterone; Prospective Studies; Dihydrotestosterone; Chromatography, Liquid; Menstrual Cycle
PubMed: 36371319
DOI: 10.1016/j.fertnstert.2022.09.011 -
Journal of Veterinary Internal Medicine Nov 2021The use of adrenocorticotropic hormone stimulation test as method to monitor efficacy of trilostane treatment of hypercortisolism (HC) in dogs has been questioned.
BACKGROUND
The use of adrenocorticotropic hormone stimulation test as method to monitor efficacy of trilostane treatment of hypercortisolism (HC) in dogs has been questioned.
OBJECTIVES
To evaluate and compare 12 methods with which to monitor efficacy of trilostane treatment in dogs with HC.
ANIMALS
Forty-five client-owned dogs with HC treated with trilostane q12h.
METHODS
Prospective cross-sectional observational study. The dogs were categorized as well-controlled, undercontrolled, and unwell through a clinical score obtained from an owner questionnaire. The ability to correctly identify trilostane-treatment control of dogs with HC with the following variables was evaluated: before trilostane serum cortisol (prepill), before-ACTH serum cortisol, post-ACTH serum cortisol, plasma endogenous ACTH concentrations, prepill/eACTH ratio, serum haptoglobin (Hp) concentration, serum alanine aminotransferase (ALT), gamma-glutamyl transferase (γGT) and alkaline phosphatase activity, urine specific gravity, and urinary cortisol : creatinine ratio.
RESULTS
Ninety-four re-evaluations of 44 dogs were included; 5 re-evaluations of 5 unwell dogs were excluded. Haptoglobin was significantly associated with the clinical score (P < .001) and in the receiver operating characteristic analysis, Hp cutoff of 151 mg/dL correctly identified 90.0% of well-controlled dogs (specificity) and 65.6% of undercontrolled dogs (sensitivity). Alanine aminotransferase (P = .01) and γGT (P = .009) were significantly higher in undercontrolled dogs. Cutoff of ALT and γGT greater than or equal to 86 U/L and 5.8 U/L, respectively, were significantly associated with poor control of HC by trilostane.
CONCLUSIONS AND CLINICAL IMPORTANCE
Of all the 12 variables, Hp, and to a lesser degree ALT and γGT, could be considered additional tools to the clinical picture to identify well-controlled and undercontrolled trilostane-treated dogs.
Topics: Adrenocortical Hyperfunction; Animals; Cross-Sectional Studies; Cushing Syndrome; Dihydrotestosterone; Dog Diseases; Dogs; Enzyme Inhibitors; Hydrocortisone; Prospective Studies
PubMed: 34672018
DOI: 10.1111/jvim.16269 -
The Veterinary Record Dec 2016It is recommended that trilostane therapy of canine hyperadrenocorticism is monitored using an ACTH stimulation test, however this has never been validated. Three...
It is recommended that trilostane therapy of canine hyperadrenocorticism is monitored using an ACTH stimulation test, however this has never been validated. Three cortisol concentrations (pre-trilostane, 3-hour posttrilostane and 1-hour post-ACTH stimulation) were compared to a clinical score obtained from an owner questionnaire. There were 110 sets of 3 cortisol measurements and questionnaires obtained from 67 trilostane treated dogs. Questionnaire results were used to classify each dog as well or unwell. Well dogs were then categorised as having excellent, moderate or poor hyperadrenocorticism control, using thresholds produced by 14 independent veterinarians. Correlation co-efficients were used to compare the three cortisol concentrations to the owner score and the Kruskal Wallis and Mann-Whitney U tests were used to compare the three cortisol concentrations between categories of control. Cortisol cut-off values between significantly different categories were determined using ROC curves. Pre-trilostane and 3-hour post-trilostane cortisol were better correlated to the owner score and had cut-offs to differentiate between categories of control that had superior sensitivity and specificity results, than the post-ACTH cortisol. Iatrogenic hypoadrenocorticism was not detected in any unwell dog. This study shows that the pre-trilostane and 3-hour post-trilostane cortisol are potentially better monitoring methods than the ACTH stimulation test.
Topics: Adrenocortical Hyperfunction; Adrenocorticotropic Hormone; Animals; Diagnostic Techniques, Endocrine; Dihydrotestosterone; Dog Diseases; Dogs; Female; Hydrocortisone; Male; Prospective Studies; Reproducibility of Results; Surveys and Questionnaires
PubMed: 27803375
DOI: 10.1136/vr.103744 -
International Journal of Molecular... Mar 2023Androgenic alopecia (AGA) is the most common type of hair loss, where local high concentrations of dihydrotestosterone (DHT) in the scalp cause progressive shrinkage of...
Adipose Mesenchymal Stromal Cell-Derived Exosomes Carrying MiR-122-5p Antagonize the Inhibitory Effect of Dihydrotestosterone on Hair Follicles by Targeting the TGF-β1/SMAD3 Signaling Pathway.
Androgenic alopecia (AGA) is the most common type of hair loss, where local high concentrations of dihydrotestosterone (DHT) in the scalp cause progressive shrinkage of the hair follicles, eventually contributing to hair loss. Due to the limitations of existing methods to treat AGA, the use of multi-origin mesenchymal stromal cell-derived exosomes has been proposed. However, the functions and mechanisms of action of exosomes secreted by adipose mesenchymal stromal cells (ADSCs-Exos) in AGA are still unclear. Using Cell Counting Kit-8 (CCK8) analysis, immunofluorescence staining, scratch assays, and Western blotting, it was found that ADSC-Exos contributed to the proliferation, migration, and differentiation of dermal papilla cells (DPCs) and up-regulated the expression of cyclin, β-catenin, versican, and BMP2. ADSC-Exos also mitigated the inhibitory effects of DHT on DPCs and down-regulated transforming growth factor-beta1 (TGF-β1) and its downstream genes. Moreover, high-throughput miRNA sequencing and bioinformatics analysis identified 225 genes that were co-expressed in ADSC-Exos; of these, miR-122-5p was highly enriched and was found by luciferase assays to target SMAD3. ADSC-Exos carrying miR-122-5p antagonized DHT inhibition of hair follicles, up-regulated the expression of β-catenin and versican in vivo and in vitro, restored hair bulb size and dermal thickness, and promoted the normal growth of hair follicles. So, ADSC-Exos enhanced the regeneration of hair follicles in AGA through the action of miR-122-5p and the inhibition of the TGF-β/SMAD3 axis. These results suggest a novel treatment option for the treatment of AGA.
Topics: Humans; Hair Follicle; Transforming Growth Factor beta1; Dihydrotestosterone; beta Catenin; Exosomes; Versicans; Mesenchymal Stem Cells; Signal Transduction; MicroRNAs; Alopecia; Smad3 Protein
PubMed: 36982775
DOI: 10.3390/ijms24065703 -
Aging May 2018The cardiovascular effects of testosterone and dihydrotestosterone are generally attributed to their modulatory action on lipid and glucose metabolism. However, no...
The cardiovascular effects of testosterone and dihydrotestosterone are generally attributed to their modulatory action on lipid and glucose metabolism. However, no studies suggest that circulating androgen levels influence the activation and reactivity of blood platelets - one of the main components of the haemostasis system directly involved in atherosclerosis. The levels of testosterone, dihydrotestosterone and oestradiol in plasma from men and women aged from 60 to 65 years were measured by LC-MS; the aim was to identify any potential relationships between sex steroid levels and the markers of platelet activation (surface membrane expression of GPII/IIIa complex and P-selectin) and platelet reactivity in response to arachidonate, collagen or ADP, monitored with whole blood aggregometry and flow cytometry. The results of the part of the study indicate that the concentrations of testosterone and its reduced form, dihydrotestosterone are significantly negatively associated with platelet activation and reactivity. These observations were confirmed in an model: testosterone and dihydrotestosterone significantly inhibited platelet aggregation triggered by arachidonate or collagen. Our findings indicate that testosterone and dihydrotestosterone are significant haemostatic steroids with inhibitory action on blood platelets in older people.
Topics: Aged; Blood Platelets; Dihydrotestosterone; Estradiol; Female; Humans; Male; Middle Aged; Platelet Activation; Platelet Aggregation; Testosterone
PubMed: 29723157
DOI: 10.18632/aging.101438 -
FEBS Open Bio Feb 2022Sex hormone-binding globulin (SHBG) regulates the bioavailability of sex steroid hormones in the blood. Levels of SHBG increase markedly in brown bears (Ursus arctos)...
Sex hormone-binding globulin (SHBG) regulates the bioavailability of sex steroid hormones in the blood. Levels of SHBG increase markedly in brown bears (Ursus arctos) during hibernation, suggesting that a key regulatory role of this protein is to quench sex steroid bioavailability in hibernation physiology. To enable characterization of ursine SHBG and a cross species comparison, we established an insect cell-based expression system for recombinant full-length ursine and human SHBG. Compared with human SHBG, we observed markedly lower secretion levels of ursine SHBG, resulting in a 10-fold difference in purified protein yield. Both human and ursine recombinant SHBG appeared as dimeric proteins in solution, with a single unfolding temperature of ~ 58 °C. The thermal stability of ursine and human SHBG increased 5.4 and 9.5 °C, respectively, in the presence of dihydrotestosterone (DHT), suggesting a difference in affinity. The dissociation constants for [ H]DHT were determined to 0.21 ± 0.04 nm for human and 1.32 ± 0.10 nm for ursine SHBG, confirming a lower affinity of ursine SHBG. A similarly reduced affinity, determined from competitive steroid binding, was observed for most steroids. Overall, we found that ursine SHBG had similar characteristics to human SHBG, specifically, being a homodimeric glycoprotein capable of binding steroids with high affinity. Therefore, ursine SHBG likely has similar biological functions to those known for human SHBG. The determined properties of ursine SHBG will contribute to elucidating its potential regulatory role in hibernation physiology.
Topics: Animals; Dihydrotestosterone; Humans; Recombinant Proteins; Sex Hormone-Binding Globulin; Steroids; Ursidae
PubMed: 34855305
DOI: 10.1002/2211-5463.13341