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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.Circulating levels of DHT in response to testosterone replacement therapy (TRT) do not correlate with those found in androgen sensitive tissue due to homeostatic control of intracellular DHT.

Males are generally more susceptible to impaired glucose metabolism and type 2 diabetes (T2D) than females. However, the underlying mechanisms remain to be determined. Here, we revealed that gut microbiome depletion abolished sexual dimorphism in glucose metabolism. The transfer of male donor microbiota into antibiotics-treated female mice led the recipients to be more insulin resistant. Depleting androgen via castration changed the gut microbiome of male mice to be more similar to that of females and improved glucose metabolism, while reintroducing dihydrotestosterone (DHT) reversed these alterations. More importantly, the effects of androgen on glucose metabolism were largely abolished when the gut microbiome was depleted. Next, we demonstrated that androgen modulated circulating glutamine and glutamine/glutamate (Gln/Glu) ratio partially depending on the gut microbiome, and glutamine supplementation increases insulin sensitivity in vitro. Our study identifies the effects of androgen in deteriorating glucose homeostasis partially by modulating the gut microbiome and circulating glutamine and Gln/Glu ratio, thereby contributing to the difference in glucose metabolism between the two sexes. Male sex is a risk factor for impaired glucose metabolism and type 2 diabetes. Here the authors identify that androgen modulates the gut microbiome, which drives insulin resistance and contributes to sexual dimorphism in glucose metabolism in mice.

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.

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.

Abstract Background Arteries from boys with hypospadias demonstrate hypercontractility and impaired vasorelaxation. The role of sex hormones in these responses in unclear. Aims We compared effects of sex steroids on vascular reactivity in healthy boys and boys with hypospadias. Methods Excess foreskin tissue was obtained from 11 boys undergoing hypospadias repair (cases) and 12 undergoing routine circumcision (controls) (median age [range], 1.5 [1.2-2.7] years) and small resistance arteries were isolated. Vessels were mounted on wire myographs and vascular reactivity was assessed in the absence/presence of 17β-estradiol, dihydrotestosterone (DHT), and testosterone. Results In controls, testosterone and 17β-estradiol increased contraction (percent of maximum contraction [Emax]: 83.74 basal vs 125.4 after testosterone, P < .0002; and 83.74 vs 110.2 after estradiol, P = .02). 17β-estradiol reduced vasorelaxation in arteries from controls (Emax: 10.6 vs 15.6 to acetylcholine, P < .0001; and Emax: 14.6 vs 20.5 to sodium nitroprusside, P < .0001). In hypospadias, testosterone (Emax: 137.9 vs 107.2, P = .01) and 17β-estradiol (Emax: 156.9 vs 23.6, P < .0001) reduced contraction. Androgens, but not 17β-estradiol, increased endothelium-dependent and endothelium-independent vasorelaxation in cases (Emax: 77.3 vs 51.7 with testosterone, P = .02; and vs 48.2 with DHT to acetylcholine, P = .0001; Emax: 43.0 vs 39.5 with testosterone, P = .02; and 39.6 vs 37.5 with DHT to sodium nitroprusside, P = .04). Conclusion In healthy boys, testosterone and 17β-estradiol promote a vasoconstrictor phenotype, whereas in boys with hypospadias, these sex hormones reduce vasoconstriction, with androgens promoting vasorelaxation. Differences in baseline artery function may therefore be sex hormone-independent and the impact of early-life variations in androgen exposure on vascular function needs further study.

Context: Anti-Mullerian hormone (AMH) and AMH type II receptor (AMHR2) are overexpressed in granulosa cells (GCs) from women with polycystic ovary syndrome (PCOS), the most common cause of female infertility. Objective: The aim of the study was to compare the regulation of the AMH/AMHR2 system by 5adihydrotestosterone (5a-DHT) and estradiol (E2) in GCs from control subjects and women with PCOS. Design, Setting, Patients: Experiments were performed on follicular fluids (FF) and GCs from women undergoing in vitro fertilization. Main Outcome Measures: FF steroid levels were measured by mass spectrometry, and messenger RNA (mRNA) accumulation was quantified by reverse transcription real-time polymerase chain reaction. Results: Total testosterone (T), free T, and 5 alpha-DHT FF levels were significantly higher (P < 0.001) in women with PCOS than in controls. However, E2 and sex hormone-binding globulin concentrations were comparable between the two groups. In GCs from control women, the AMH and AMHR2 expression were not affected by 5a-DHT treatment, whereas AMH mRNA levels were upregulated by 5a-DHT in GCs from patients with PCOS (2.3-fold, P < 0.01) overexpressing the androgen receptor (1.4-fold, P < 0.05). E2 downregulated the AMH and AMHR2 expression in GCs from control women (1.4-fold, P < 0.001 and 1.8-fold, P < 0.01, respectively) but had no effect on these genes in GCs from women with PCOS. This differential effect of E2 was associated with a higher estrogen receptor 1 expression in GCs from women with PCOS (1.9-fold, P < 0.05). Conclusions: In GCs from women with PCOS, the regulation of AMH and AMHR2 expression is altered in a way that promotes the overexpression of the AMH/AMHR2 system, and could contribute to the follicular arrest observed in these patients.

The role of androgen and androgen receptor (AR) in breast carcinogenesis has long been a disputed issue. This report provides a mechanistic insight into how androgen and AR contributes to invasion and metastasis of breast cancer. We find that dihydrotestosterone (DHT) is able to induce the epithelial-to-mesenchymal transition in breast cancer cells in an AR-dependent/estrogen receptor-independent manner. This process is dependent on the demethylation activity of lysine-specific demethylase 1A (LSD1) by epigenetically regulating the target genes E-cadherin and vimentin. In vivo , DHT promotes metastasis in a nude mouse model, and AR and LSD1 are indispensable in this process. We establish that higher expression of nucleus AR to cytoplasm AR associated with worse prognostic outcomes in breast cancer patient samples. This study maps an ‘androgen-AR/LSD1-target genes’ pathway in breast carcinogenesis, implicating the importance of hormonal balance in women, and the potential clinical significance of serum androgen and AR in prediction of breast cancer and selection of breast cancer therapy.

Many patients undergoing gender-affirming surgery (GAS) opt for reconstructive procedures rather than total mastectomy to achieve a more masculine chest contour. The impact of dihydrotestosterone (DHT) treatment on breast tissue remains unclear. This study evaluates the morphological changes and protein expression levels in breast tissue associated with hormonal and molecular pathways in patients receiving short-term or long-term DHT treatment before GAS. A total of 230 breast tissue samples were categorized into three groups: nontreatment, short-term treatment (STT, < 12 months), and long-term treatment (LTT, ≥ 12 months). Paired samples (n = 33) were stained for estrogen receptor (ER) and androgen receptor (AR). NanoString Digital Spatial Profiling (DSP) analysis was conducted on a subset (n = 17), including two incidental breast cancer (BC) cases. Among morphological parameters assessed, atrophy and secretory changes differed significantly among groups. In the LTT group, ER-alpha expression was elevated in lactiferous ducts, while AR H-scores were higher in both STT and LTT groups. ER and AR expression levels were strongly correlated in the STT and LTT groups (r = 0.93–0.99). DSP analysis revealed increased ER expression in the treated groups and higher AR expression in peripheral lobules of the LTT group (log2FC = 1.3, p = 0.03). Ki-67, CDK6, and CD45 levels decreased in the LTT group, while INPP4B and BCL6 increased. DHT treatment leads to significant morphological and molecular changes in both benign and cancerous breast tissue. Altered expression of biomarkers such as INPP4B and CD45 in the LTT group and breast cancer samples suggests a potential role in BC development, warranting further investigation.

Prostaglandin E2 (PGE2) is known to be effective in regenerating tissues, and bimatoprost, an analog of PGF2α, has been approved by the FDA as an eyelash growth promoter and has been proven effective in human hair follicles. Thus, to enhance PGE2 levels while improving hair loss, we found dihydroisoquinolinone piperidinylcarboxy pyrazolopyridine (DPP), an inhibitor of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), using DeepZema®, an AI-based drug development program. Here, we investigated whether DPP improved hair loss in human follicle dermal papilla cells (HFDPCs) damaged by dihydrotestosterone (DHT), which causes hair loss. We found that DPP enhanced wound healing and the expression level of alkaline phosphatase in DHT-damaged HFDPCs. We observed that DPP significantly down-regulated the generation of reactive oxygen species caused by DHT. DPP recovered the mitochondrial membrane potential in DHT-damaged HFDPCs. We demonstrated that DPP significantly increased the phosphorylation levels of the AKT/ERK and activated Wnt signaling pathways in DHT-damaged HFDPCs. We also revealed that DPP significantly enhanced the size of the three-dimensional spheroid in DHT-damaged HFDPCs and increased hair growth in ex vivo human hair follicle organ culture. These data suggest that DPP exhibits beneficial effects on DHT-damaged HFDPCs and can be utilized as a promising agent for improving hair loss.

To investigate the effects and mechanisms of dihydrotestosterone (DHT) and 17β-estradiol on temporomandibular joint osteoarthritis (TMJ-OA) to understand sex differences and apply findings to TMJ-OA prevention and treatment. Ten-week-old male C57BL/6J mice were divided into six groups to study the effects of mechanical stress (MS), aromatase inhibitors (Ai), orchiectomy (ORX), and 17β-estradiol supplementation on TMJ-OA. Interventions included mechanical stress induction and hormone manipulations. Analyses included serum hormone levels, micro-CT, histomorphometry, immunohistochemistry, RT-qPCR for gene expression, and statistical evaluations. ORX and Ai-induced reductions in DHT and 17β-estradiol caused bone loss, including decreased BV/TV and trabecular thickness, and increased trabecular spacing. MS further reduced cartilage thickness, Safranin O-positive areas, and increased osteoclast counts. Matrix metalloproteinase-13(MMP13) and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) levels were highest in MS + Ai and MS + Ai + ORX groups. In contrast, 17β-estradiol supplementation restored cartilage thickness, reduced osteoclast activity, suppressed inflammatory markers ( NFκB , Gremlin 1 , RelA ), and increased BMP7 expression. The lower incidence of TMJ-OA in males may result from testosterone and DHT being converted to 17β-estradiol by adrenal aromatase, mitigating mechanical stress effects and protecting the temporomandibular joint via the Gremlin-1-NF-κB pathway.