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Frontiers in Endocrinology 2023Sex hormones and sex hormone-binding globulin (SHBG) may play a role in fatty liver development. We sought to examine the association of various endogenous sex hormones,... (Observational Study)
Observational Study
BACKGROUND
Sex hormones and sex hormone-binding globulin (SHBG) may play a role in fatty liver development. We sought to examine the association of various endogenous sex hormones, including testosterone (T), and SHBG with liver fat using complementary observational and Mendelian randomization (MR) analyses.
METHODS
The observational analysis included a total of 2,239 participants (mean age 60 years; 35% postmenopausal women) from the population-based KORA study (average follow-up time: 6.5 years). We conducted linear regression analysis to investigate the sex-specific associations of sex hormones and SHBG with liver fat, estimated by fatty liver index (FLI). For MR analyses, we selected genetic variants associated with sex hormones and SHBG and extracted their associations with magnetic resonance imaging measured liver fat from the largest up to date European genome-wide associations studies.
RESULTS
In the observational analysis, T, dihydrotestosterone (DHT), progesterone and 17α-hydroxyprogesterone (17-OHP) were inversely associated with FLI in men, with beta estimates ranging from -4.23 to -2.30 [p-value <0.001 to 0.003]. Whereas in women, a positive association of free T with FLI (β = 4.17, 95%CI: 1.35, 6.98) was observed. SHBG was inversely associated with FLI across sexes [men: -3.45 (-5.13, -1.78); women: -9.23 (-12.19, -6.28)]. No causal association was found between genetically determined sex hormones and liver fat, but higher genetically determined SHBG was associated with lower liver fat in women (β = -0.36, 95% CI: -0.61, -0.12).
CONCLUSION
Our results provide suggestive evidence for a causal association between SHBG and liver fat in women, implicating the protective role of SHBG against liver fat accumulation.
Topics: Male; Humans; Female; Middle Aged; Sex Hormone-Binding Globulin; Mendelian Randomization Analysis; Dihydrotestosterone; Fatty Liver
PubMed: 37900132
DOI: 10.3389/fendo.2023.1223162 -
The New Phytologist Oct 2023Progestogens and androgens have been found in many plants, but little is known about their biosynthesis and the evolution of steroidogenesis in these organisms. Here, we...
Progestogens and androgens have been found in many plants, but little is known about their biosynthesis and the evolution of steroidogenesis in these organisms. Here, we show that the occurrence and biosynthesis of progestogens and androgens are conserved across the viridiplantae lineage. An UHPLC-ESI-MS/MS method allowed high-throughput analysis of the occurrence and chemical conversion of progestogens and androgens in 41 species across the green plant lineage. Dehydroepiandrosterone, testosterone, and 5α-dihydrotestosterone are plants' most abundant mammalian-like steroids. Progestogens are converted into 17α-hydroxyprogesterone and 5α-pregnane-3,20-dione. Androgens are converted into testosterone and 5α-dihydrotestosterone. 17,20-Lyases, essential for converting progestogens to androgens, seem to be most effective in monocot species. Our data suggest that the occurrence of progestogens and androgens is highly conserved in plants, and their biosynthesis might favor a route using the Δ pathway.
Topics: Androgens; Dihydrotestosterone; Embryophyta; Progestins; Tandem Mass Spectrometry; Testosterone
PubMed: 37559351
DOI: 10.1111/nph.19163 -
Advanced Science (Weinheim,... Mar 2024Treatment of castration-resistant prostate cancer (CRPC) is a long-standing clinical challenge. Traditionally, CRPC drugs work by either reducing dihydrotestosterone...
Treatment of castration-resistant prostate cancer (CRPC) is a long-standing clinical challenge. Traditionally, CRPC drugs work by either reducing dihydrotestosterone biosynthesis or blocking androgen receptor (AR) signaling. Here it is demonstrated that AR inhibitor treatment gives rise to a drug-tolerant persister (DTP) state. The thioredoxin/peroxiredoxin pathway is up-regulated in DTP cells. Peroxiredoxin 5 (PRDX5) promotes AR inhibitor resistance and CRPC development. Inhibition of PRDX5 suppresses DTP cell proliferation in culture, dampens CRPC development in animal models, and stabilizes PSA progression and metastatic lesions in patients. Therefore, the study provides a novel mechanism and potential target for the management of castration-resistant prostate cancer.
Topics: Male; Animals; Humans; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Peroxiredoxins; Signal Transduction
PubMed: 38115765
DOI: 10.1002/advs.202304939 -
Cureus Nov 2023Prostate cancer is the second most frequently diagnosed cancer among men worldwide, and it represents a substantial worldwide health issue, primarily impacting men as... (Review)
Review
Prostate cancer is the second most frequently diagnosed cancer among men worldwide, and it represents a substantial worldwide health issue, primarily impacting men as they grow older. Understanding its epidemiology and etiology is crucial for crafting efficient preventive measures and enhancing treatment results. The epidemiology of this disease provides valuable insights into its prevalence and distribution. Age is a critical factor, with the risk of prostate cancer increasing with advancing years. Incidence rates are notably higher in developed countries, suggesting a role for lifestyle and environmental factors. Furthermore, there are significant racial and geographical disparities in prostate cancer incidence, with African-American men experiencing both a higher incidence and more aggressive forms of the disease. On the other hand, hormones, especially testosterone and its conversion to dihydrotestosterone (DHT), contribute to prostate cell growth and, potentially, cancer. Genetics also plays a pivotal role, with certain gene mutations, like Breast Cancer gene 1 & 2 (BRCA1 and BRCA2), elevating risk. Dietary habits and lifestyle choices influence susceptibility, with diets low in fruits and vegetables and high in saturated fats linked to higher risk. Chronic inflammation, often tied to prostatitis, may further increase susceptibility to prostate cancer. This review article explores the complex realm of prostate cancer, providing insights into its occurrence, factors that elevate risks, and the fundamental factors that play a role in its emergence and how we can prevent it.
PubMed: 38054148
DOI: 10.7759/cureus.48252 -
Factors Associated With Circulating Sex Hormones in Men : Individual Participant Data Meta-analyses.Annals of Internal Medicine Sep 2023Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements. (Review)
Review
BACKGROUND
Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements.
PURPOSE
To clarify factors associated with variations in sex hormone concentrations.
DATA SOURCES
Systematic literature searches (to July 2019).
STUDY SELECTION
Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry.
DATA EXTRACTION
Individual participant data (IPD) (9 studies; = 21 074) and aggregate data (2 studies; = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted.
DATA SYNTHESIS
Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone-binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years.
LIMITATION
Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data.
CONCLUSION
Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer.
PRIMARY FUNDING SOURCE
Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).
Topics: Humans; Male; Adolescent; Young Adult; Adult; Middle Aged; Aged; Sex Hormone-Binding Globulin; Cross-Sectional Studies; Prospective Studies; Gonadal Steroid Hormones; Testosterone; Luteinizing Hormone
PubMed: 37639720
DOI: 10.7326/M23-0342 -
Frontiers in Aging Neuroscience 2024Taurine, an amino acid abundantly found in the brain and other tissues, has potential neuroprotective properties. Alzheimer's disease (AD) is a commonly occurring type...
BACKGROUND
Taurine, an amino acid abundantly found in the brain and other tissues, has potential neuroprotective properties. Alzheimer's disease (AD) is a commonly occurring type of dementia, which becomes more prevalent as people age. This experiment aimed to assess the neuroprotective effects of taurine on SH-SY5Y cells by examining its impact on Dihydrotestosterone (DHT), Dihydroprogesterone (DHP), as well as the expression of miRNA-21 and miRNA-181.
METHODS
The effects of various taurine concentrations (0.25, and 0.75 mg/mL), and LPS (0.1, and 12 mg/mL) on the SH-SY5Y cell line were assessed using the MTT assay. The levels of DHT and DHP were quantified using an ELISA kit. Additionally, the expression levels of miRNA-181 and miRNA-21 genes were examined through Real-Time PCR analysis.
RESULTS
The results of the MTT assay showed that treatment with taurine at concentrations of 0.25, and 0.75 mg/mL reduces the toxicity of LPS in SH-SY5Y cells. ELISA results indicated that taurine at a concentration of 0.25, and 0.75 mg/mL significantly elevated DHT and DHP hormones in the SH-SY5Y cell line compared to the untreated group ( < 0.01). The expression levels of IL-1β and IL-6 were decreased under the influence of LPS in SH-SY5Y cells after taurine treatment (p < 0.01). Gene expression analysis revealed that increasing taurine concentration resulted in heightened expression of miRNA-181 and miRNA-21, with the most significant increase observed at a concentration of 0.75 mg/mL ( < 0.001).
CONCLUSION
Our study findings revealed that the expression of miRNA-181 and miRNA-21 can be enhanced by taurine. Consequently, exploring the targeting of taurine, miRNA-181, and miRNA-21 or considering hormone therapy may offer potential therapeutic approaches for treating AD or alleviating severe symptoms. Nonetheless, in order to fully comprehend the precise mechanisms involved, additional research is required.
PubMed: 38867846
DOI: 10.3389/fnagi.2024.1379431 -
Biology of Sex Differences Jan 2024Androgens are important sex hormones in both men and women and are supplemented when endogenous levels are low, for gender transitioning, or to increase libido....
BACKGROUND
Androgens are important sex hormones in both men and women and are supplemented when endogenous levels are low, for gender transitioning, or to increase libido. Androgens also circulate at higher levels in women with polycystic ovarian syndrome, a condition that increases the risk for cardiovascular diseases including hypertension and arterial stiffness. Since our previous work shows an important role for the G protein-coupled estrogen receptor (GPER) in arterial stiffness, we hypothesized that other hormones including androgens may impact arterial stiffness in female mice via downregulation of GPER.
METHODS
The impact of the non-aromatizable androgen dihydrotestosterone (DHT), the glucocorticoid dexamethasone, and the progestin medroxyprogesterone acetate (all 100 nM for 24 h) on GPER and ERα expression was assessed in cultured vascular smooth muscle cells using droplet digital PCR (ddPCR). To assess the in vivo impact of the DHT-induced downregulation of GPER, female ovary-intact C57Bl/6 mice at 15-16 weeks of age were treated with silastic capsules containing DHT for 4 weeks, one with a dosage expected to mimic human male DHT levels and another to double the expected human concentration (n = 8-9/group).
RESULTS
In cultured vascular smooth muscle cells, GPER mRNA was decreased by DHT (P = 0.001) but was not impacted by dexamethasone or medroxyprogesterone. In contrast, ERα expression in cultured cells was significantly suppressed by all three hormones (P < 0.0001). In control mice or mice treated with a single or double dose of DHT, a dose-dependent increase in body weight was observed (control 22 ± 2 g, single dose 24 ± 2 g, double dose 26 ± 2 g; P = 0.0002). Intracarotid stiffness measured via pulse wave velocity showed a more than two-fold increase in both DHT-treated groups (control 1.9 ± 0.3 m/s, single dose 4.3 ± 0.8 m/s, double dose 4.8 ± 1.0 m/s). This increase in arterial stiffness occurred independent of changes in blood pressure (P = 0.59). Histological analysis of aortic sections using Masson's trichrome showed a significant decrease in collagen between the control group (24 ± 5%) and the double dose group (17 ± 3%, P = 0.007), despite no changes in aortic wall thickness or smooth muscle content. Lastly, ddPCR showed that in vivo DHT treatment decreased aortic expression of both GPER (control 20 ± 5, single dose 10.5 ± 5.6, double dose 10 ± 4 copies/ng; P = 0.001) and ERα (control 54 ± 2, single dose 24 ± 13, and double dose 23 ± 12 copies/ng; P = 0.003).
CONCLUSIONS
These findings indicate that androgen promotes arterial stiffening and cardiovascular damage in female mice and is associated with decreased estrogen receptor expression. These data are important for transgender men, women using testosterone for fitness or reduced libido, as well as patients with polycystic ovarian syndrome.
Topics: Female; Humans; Male; Animals; Mice; Infant, Newborn; Dihydrotestosterone; Androgens; Estrogen Receptor alpha; Polycystic Ovary Syndrome; Pulse Wave Analysis; Estrogens; Receptors, Estrogen; Dexamethasone
PubMed: 38263051
DOI: 10.1186/s13293-024-00586-3 -
The Journal of Steroid Biochemistry and... Feb 2024Prostate cancer (PC) is dependent on androgen receptor (AR) activation by testosterone and 5α-dihydrotestosterone (DHT). Intratumoral androgen accumulation and...
Prostate cancer (PC) is dependent on androgen receptor (AR) activation by testosterone and 5α-dihydrotestosterone (DHT). Intratumoral androgen accumulation and activation despite systemic androgen deprivation therapy underlies the development of castration-resistant PC (CRPC), but the precise pathways involved remain controversial. Here we investigated the differential contributions of de novo androgen biosynthesis and androgen precursor conversion to androgen accumulation. Steroid flux analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed on (CR)PC cell lines and fresh patient PC tissue slices after incubation with classic and alternative biosynthesis intermediates, alongside quantitative PCR analysis for steroidogenic enzyme expression. Activity of CYP17A1 was undetectable in all PC cell lines and patient PC tissue slices. Instead, steroid flux analysis confirmed the generation of testosterone and DHT from adrenal precursors and reactivation of androgen metabolites. Precursor steroids upstream of DHEA were converted down the first steps of the alternative DHT biosynthesis pathway, but did not proceed through to active androgen generation. Comprehensive steroid flux analysis of (CR)PC cells provides strong evidence against intratumoral de novo androgen biosynthesis and demonstrates that androgen precursor steroids downstream of CYP17A1 activities constitute the major source of intracrine androgen generation.
Topics: Male; Humans; Prostatic Neoplasms; Androgens; Androgen Antagonists; Chromatography, Liquid; Tandem Mass Spectrometry; Testosterone; Dihydrotestosterone; Receptors, Androgen; Steroids; Cell Line, Tumor; Steroid 17-alpha-Hydroxylase
PubMed: 38104728
DOI: 10.1016/j.jsbmb.2023.106446 -
Phytomedicine : International Journal... Nov 2023Benign prostatic hyperplasia (BPH) is a common disease in older men worldwide. However, there is currently no effective treatment for BPH. Bushen Tongluo Formula...
BACKGROUND
Benign prostatic hyperplasia (BPH) is a common disease in older men worldwide. However, there is currently no effective treatment for BPH. Bushen Tongluo Formula (Kidney-supplementing and collaterals-unblocking formula [KCF]) is a traditional Chinese medicine formula commonly used to ameliorate the symptoms of BPH, although the specific molecular mechanisms remain unclear.
PURPOSE
We aimed to discover the effects and potential mechanisms of KCF against BPH.
METHODS
Sixty male SD rats were randomly assigned to one of six group (n = 10): control, low-dosage KCF, medium-dosage KCF, high-dosage KCF, BPH model, and finasteride. A rat model of BPH was established by surgical castration followed by subcutaneous injection of testosterone propionate (TP) for 4 weeks. After treatment, the prostate index, histopathological staining, serum levels of estradiol (E) and dihydrotestosterone (DHT), protein/mRNA levels of E-cadherin, TGF-β1, caspase-3, Ki67, and vimentin, abundances of serum metabolites, and the proliferation, cell cycle, and apoptosis of BPH-1 cells were documented.
RESULTS
KCF treatment for 4 weeks reduced the prostate volume and prostate index, alleviated histopathological changes to the prostate of rats with TP-induced BPH, decreased serum levels of E and DHT, reduced protein/mRNA levels of TGF-β1 and vimentin, and increased E-cadherin levels. Moreover, KCF-spiked serum inhibited proliferation of BPH-1 cells, blocked the cell cycle, and promoted apoptosis. KCF was also found to regulate the contents of three metabolites (D-maltose, citric acid, and fumaric acid).
CONCLUSION
The present study was the first to report that KCF exhibited therapeutic effects against BPH by regulating energy metabolism and inhibiting epithelial-mesenchymal transition in prostate tissues. Hence, KCF presents a viable treatment option for BPH.
Topics: Humans; Animals; Rats; Male; Aged; Rats, Sprague-Dawley; Prostatic Hyperplasia; Testosterone Propionate; Transforming Growth Factor beta1; Vimentin; Cadherins
PubMed: 37651753
DOI: 10.1016/j.phymed.2023.155048 -
Frontiers in Endocrinology 2023We performed a transcriptomic analysis of adrenal signaling pathways in various forms of endogenous Cushing's syndrome (CS) to define areas of dysregulated and druggable...
BACKGROUND
We performed a transcriptomic analysis of adrenal signaling pathways in various forms of endogenous Cushing's syndrome (CS) to define areas of dysregulated and druggable targets.
METHODOLOGY
Next-generation sequencing was performed on adrenal samples of patients with primary bilateral macronodular adrenal hyperplasia (PBMAH, n=10) and control adrenal samples (n=8). The validation groups included cortisol-producing adenoma (CPA, n=9) and samples from patients undergoing bilateral adrenalectomy for Cushing's disease (BADX-CD, n=8). findings were further characterized using three adrenocortical cell-lines (NCI-H295R, CU-ACC2, MUC1).
RESULTS
Pathway mapping based on significant expression patterns identified PPARG (peroxisome proliferator-activated receptor gamma) pathway as the top hit. Quantitative PCR (QPCR) confirmed that (l2fc<-1.5) and related genes - (l2fc<-5.5), (l2fc<-4.1) and (l2fc<-3.3) - were significantly downregulated (p<0.005) in PBMAH. Significant downregulation of was also found in BADX-CD (l2fc<-1.9, p<0.0001) and CPA (l2fc<-1.4, p<0.0001). studies demonstrated that the PPARG activator rosiglitazone resulted in decreased cell viability in MUC1 and NCI-H295R (p<0.0001). There was also a significant reduction in the production of aldosterone, cortisol, and cortisone in NCI-H295R and in Dihydrotestosterone (DHT) in MUC1 (p<0.05), respectively.
OUTCOME
This therapeutic effect was independent of the actions of ACTH, postulating a promising application of activation in endogenous hypercortisolism.
Topics: Humans; Adrenalectomy; Cushing Syndrome; Hydrocortisone; Hyperplasia; PPAR gamma
PubMed: 38098864
DOI: 10.3389/fendo.2023.1265794