Steroid Pathways Research Articles

Clinical utility of serum 17-hydroxyprogesterone as a marker for medical therapy for male infertility: recommendations based on clinical scenarios.

Traditional serum hormone testing in the evaluation of male infertility consists of testosterone, follicle-stimulating hormone, luteinizing hormone, and estradiol. Based on these values, medical therapy is often initiated in an attempt to increase intratesticular testosterone levels and, in turn, promote spermatogenesis. While this hormone panel provides serum testosterone levels, it does not evaluate intratesticular testosterone, obviously an important factor that is critical for spermatogenesis. 17-hydroxyprogesterone (17-OHP) is an intermediate in the steroidal pathway of cholesterol to testosterone conversion that has recently demonstrated promise as an accurate serum biomarker for intratesticular testosterone. At present, 17-OHP has not been widely adopted as a clinical tool in the evaluation of male infertility, which likely stems, in part, from a lack of concrete indications for its use. In this review, we present five commonly encountered scenarios of male infertility where the utilization of 17-OHP has aided in the management and provided a more personalized approach to treatment.

Steroidal alkaloid biosynthesis is coordinately regulated and differs among tomatoes in the red-fruited clade.

The tomato (Solanum spp.) clade of Solanaceae features a unique assortment of cholesterol-derived steroidal alkaloids. However, little quantitative data exists reporting the profile and concentration of these alkaloids across diverse fruit germplasm. To address the lack of knowledge regarding the chemical diversity, concentration, and genetic architecture controlling tomato steroidal alkaloids, we quantitatively profiled and genotyped two tomato populations representing diversity in the red-fruited clade. We grew 107 genetically diverse fresh market, processing, landrace, and wild tomato in multiple environments. Nine steroidal alkaloid groups were quantified using ultra-high performance liquid chromatography tandem mass spectrometry. The diversity panel and a biparental population segregating for high alpha-tomatine were genotyped to identify and validate quantitative trait loci (QTL) associated with steroidal alkaloids. Landraces and wild material exhibited higher alkaloid concentrations and more chemical diversity. Average total content of steroidal alkaloids, often dominated by lycoperoside F/G/esculeoside A, ranged from 1.9 to 23.3 mg 100 g-1 fresh wt. across accessions. Landrace and wild cherry accessions distinctly clustered based on elevated concentrations of early or late-pathway steroidal alkaloids. Significant correlations were observed among alkaloids from the early and late parts of the biosynthetic pathway in a species-dependent manner. A QTL controlling multiple, early steroidal alkaloid pathway intermediates on chromosome 3 was identified by genome-wide association studies (GWAS) and validated in a backcross population. Overall, tomato steroidal alkaloids are diverse in the red-fruited clade and their biosynthesis is regulated in a coordinated manner.

Armillaria mellea Symbiosis Drives Metabolomic and Transcriptomic Changes in Polyporus umbellatus Sclerotia.

Sclerotia, the medicinal part of Polyporus umbellatus, play important roles in diuresis and renal protection, with steroids and polysaccharides as the main active ingredients. The sclerotia grow and develop only after symbiosis with Armillaria sp. In this study, a systematic metabolomics based on non-targeted UPLC-MS method was carried out between the infected part of the separated cavity wall of the sclerotia (QR) and the uninfected part (the control group, CK) to find and identify differential metabolites. The biosynthetic pathway of characteristic steroids in sclerotia of P. umbellatus was deduced and the content of ergosterol, polyporusterone A and B in the QR and CK groups were detected with the High Performance Liquid Chromatography (HPLC). Furthermore, the expression patterns of putative genes associated with steroid biosynthesis pathway were also performed with quantitative real-time PCR. The results showed that a total of 258 metabolites originated from fungi with the fragmentation score more than 45 and high resolution mass were identified, based on UPLC-MS metabolomic analysis, and there were 118 differentially expressed metabolites (DEMs) between both groups. The metabolic pathways indicated that steroids, fatty acid and carbohydrate were active and enriched during P. umbellatus sclerotia infected by A. mellea. The content of ergosterol, polyporusterone A and B in the QR group increased by 32.2, 75.0, and 20.0%, in comparison to that of the control group. The qRT-PCR analysis showed that series of enzymes including C-8 sterol isomerase (ERG2), sterol C-24 methyltransferase (ERG6) and sterol 22-desaturase (ERG5), which played important roles in the final steps of ergosterol biosynthesis, all presented up-regulated patterns in the QR group in P. umbellatus. The comprehensive metabolomic and transcriptomic information will contribute to further study concerning the mechanisms of P. umbellatus sclerotial formation infected by A. mellea in the future.

Effect of Ethylene and Abscisic Acid on Steroid and Triterpenoid Synthesis in Calendula officinalis Hairy Roots and Saponin Release to the Culture Medium.

Phytohormones (plant growth regulators) can be applied as efficient elicitors to enhance the productivity of plant in vitro cultures, due to their significance in regulating the plant metabolism and strong influence on plant defense responses. In the present study, the effects of exogenous ethylene (ETY, applied in the form of ethephon as an ethylene-generating agent) and abscisic acid (ABA) on the synthesis of triterpenoids and steroids in Calendula officinalis hairy roots were investigated. ABA appeared to be an efficient elicitor of the biosynthesis of triterpenoid oleanolic acid (almost two-fold) and the release of its glycosides (saponins) to the culture medium (up to 6.6-fold). ETY had only a slight effect on triterpenoid metabolism; instead, it strongly influenced steroid metabolism, leading to profound modifications of the quantitative profiles of these compounds, particularly the ratio of stigmasterol to sitosterol. Both the applied phytohormones influenced the interplay between steroid and triterpenoid biosynthetic pathways, revealing the symptoms of their competition.

Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids.

Androgen receptor (AR) ligand-binding domain (LBD) mutations occur in ~20% of all castration-resistant prostate cancer (CRPC) patients. These mutations confer ligand promiscuity, but the affinity for many steroid hormone pathway intermediates is unknown. In this study, we investigated the stimulation of clinically relevant AR-LBD mutants by endogenous and exogenous steroid hormones present in CRPC patients to unravel their potential contribution to AR pathway reactivation. A meta-analysis of studies reporting untargeted analysis of AR mutants was performed to identify clinically relevant AR-LBD mutations. Using luciferase reporter and quantitative fluorescent microscopy, these AR mutants were screened for sensitivity for various endogenous steroids and synthetic glucocorticoids used in the treatment of CRPC. The meta-analysis revealed that ARL702H (3.4%), ARH875Y (4.9%), and ART878A (4.4%) were the most prevalent AR-LBD mutations across 1614 CRPC patients from 21 unique studies. Testosterone (EC50: 0.22 nmol/L) and 11-ketotestosterone (11KT, EC50: 0.74 nmol/L) displayed subnanomolar affinity for ARWT. The p.H875Y mutation selectively increased sensitivity of the AR for 11KT (EC50: 0.15 nmol/L, p < 0.05 vs ARWT), whereas p.L702H decreased sensitivity for 11KT by almost 50-fold. While cortisol and prednisolone both stimulate ARL702H, dexamethasone importantly does not. Both testosterone and 11KT effectively contribute to ARWT activation, while selective sensitization positions 11KT as a more prominent activator of ARH875Y. Dexamethasone may be a suitable alternative to prednisolone and should be explored in patients bearing the ARL702H.

Parallel targeted and non-targeted quantitative analysis of steroids in human serum and peritoneal fluid by liquid chromatography high-resolution mass spectrometry

We developed and validated a liquid chromatography high-resolution mass spectrometry method for the absolute quantification of 51 steroids for clinical analysis of human serum and, for the first time, peritoneal fluid. Data acquisition was performed in both targeted and untargeted mode simultaneously, thus allowing the accurate and precise quantification of the main components of the classical steroid pathways (17 steroids) as well as the analysis of 34 additional non-classical steroids. For targeted analysis, validation was performed according to FDA guidelines, resulting, among other parameters, in accuracy < 13% RSD and precision < 10% relative error, for both inter- and intra-day validation runs. By establishing steroid-specific response factors, the calibration curves of the targeted analytes can be extended to untargeted analytes. This approach opens novel possibilities for the post hoc analysis of clinical samples as the data can be examined for virtually any steroid even after data acquisition, enabling facile absolute quantification once a standard becomes available. We demonstrate the applicability of the approach to evaluate the differences in steroid content between peripheral serum and peritoneal fluid across the menstrual cycle phases, as well as the effect of the synthetic gestagen dienogest on the steroid metabolome.Graphical abstract

Paternally expressed gene 3 (Pw1/Peg3) promotes sexual dimorphism in metabolism and behavior.

The paternally expressed gene 3 (Pw1/Peg3) is a mammalian-specific parentally imprinted gene expressed in stem/progenitor cells of the brain and endocrine tissues. Here, we compared phenotypic characteristics in Pw1/Peg3 deficient male and female mice. Our findings indicate that Pw1/Peg3 is a key player for the determination of sexual dimorphism in metabolism and behavior. Mice carrying a paternally inherited Pw1/Peg3 mutant allele manifested postnatal deficits in GH/IGF dependent growth before weaning, sex steroid dependent masculinization during puberty, and insulin dependent fat accumulation in adulthood. As a result, Pw1/Peg3 deficient mice develop a sex-dependent global shift of body metabolism towards accelerated adiposity, diabetic-like insulin resistance, and fatty liver. Furthermore, Pw1/Peg3 deficient males displayed reduced social dominance and competitiveness concomitant with alterations in the vasopressinergic architecture in the brain. This study demonstrates that Pw1/Peg3 provides an epigenetic context that promotes male-specific characteristics through sex steroid pathways during postnatal development.

Sex hormone-related polymorphisms in endometriosis and migraine: A narrative review

Some evidence indicates endometriosis and migraine have a common genetic predisposition in sex-hormone genes, which could have important implications for the treatment of these two heterogenous conditions. To date, the genes responsibility remains unknown. Based on the biological hypothesis that polymorphisms of genes involved in sex-hormone pathways may influence estrogen levels and phenotypes of both disorders, we did a literature search for candidate sex-hormone genes and genes involved in the metabolism of estradiol. The aim was to review the evidence for shared sex-hormone-related polymorphisms between endometriosis and migraine and provide an exhaustive overview of the current literature. We included case-control studies investigating associations between candidate sex-hormone-related genes and the disorders endometriosis and migraine, respectively. Results showed three overlapping sex-hormone-associated polymorphisms in estrogen receptor genes that are associated with both conditions. To confirm possible associations with other sex-hormone genes, larger studies are needed.

Metabolomic characteristics of spontaneously hypertensive rats under chronic stress and the treatment effect of Danzhi Xiaoyao Powder, a traditional Chinese medicine formula

ObjectiveNumerous studies have demonstrated the close relationship between chronic stress and blood pressure (BP). Hypertensive subjects exhibit exaggerated reactions to stress, especially higher BP. The mechanisms by which stress affects pre-existing hypertension still need to be explored. Danzhi Xiaoyao Powder (DP), a historical traditional Chinese medicine formula, is a promising treatment for BP control in hypertensive patients under stress. The present study investigated the metabolomic disruption caused by chronic stress and the treatment effect and mechanism of DP. MethodsSpontaneously hypertensive rats (SHRs) were subjected to chronic restraint stress (CRS) for 4 weeks. BP was measured via the tail-cuff method, and anxiety-like behavior was quantified using the elevated-plus-maze test. Meanwhile, DP was administered intragastrically, and its effects were observed. Global metabolomic analysis was performed using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry, followed by multivariate statistical analysis to detect differential metabolites and pathways. ResultsDP alleviated the CRS-induced increase in BP and anxiety-like behavior. Systematic metabolic differences were found among the three study groups. A total of 29 differential plasma metabolites were identified in both positive- and negative-ion modes. These metabolites were involved in triglyceride metabolism, amino acid (phenylalanine, tryptophan, and glycine) metabolism, and steroid hormone pathways. ConclusionThese findings expose the metabolomic disturbances induced by chronic stress in SHRs and suggest an innovative treatment for this disorder.

Urinary estrogen metabolites and gastric cancer risk among postmenopausal women.

BackgroundThe overall incidence of gastric cancer in women is half that in men for most global populations. Sex hormone pathways may be involved in carcinogenesis and estrogens have been postulated to protect women against gastric cancer.AimTo evaluate associations of gastric cancer with estrogen metabolites in postmenopausal women.Methods and resultsWe performed an analysis of 233 gastric cancer cases and 281 age‐matched controls from three prospective cohorts and two case‐control studies of early‐stage gastric cancer, mainly conducted in high‐risk Asian populations. Fifteen estrogen‐parent (estrone and estradiol) and ‐metabolite analytes (2‐hydroxyestrone, 2‐hydroxyestradiol, 2‐hydroxyestrone‐3‐methyl ether, 4‐hydroxyestrone; 4‐methoxyestrone, 4‐methoxyestradiol, 2‐methoxyestrone, 2‐methoxyestradiol, estriol, 16α‐hydroxyestrone, 16‐ketoestradiol, 16‐epiestriol, and 17‐epiestriol) were measured in spot urines using liquid chromatography–tandem mass spectrometry. Odds ratios for association with each marker were estimated by logistic regression. Heterogeneity was assessed by Cochran's Q test. Study‐specific odds ratios were pooled by fixed‐effects meta‐analysis. Urinary levels of estrogen‐related molecules were not associated with gastric cancer (adjusted odds ratios ranged from 0.87 to 1.27; p‐values >.05), with low between‐study heterogeneity (p‐values >.1) for all but two metabolites (2‐hydroxyestrone‐3‐methyl ether and 2‐methoxyestradiol).ConclusionTo date, this is the first comprehensive assessment of endogenous estrogens with gastric cancer risk in women. Estrogens do not appear to have an etiologic role in gastric cancer risk among postmenopausal women. Given the complex network of sex steroid hormones and their extreme variation over the lifespan, further evaluation of this hypothesis is warranted.

Alleviation of Androgenetic Alopecia with Aqueous Paeonia lactiflora and Poria cocos Extract Intake through Suppressing the Steroid Hormone and Inflammatory Pathway.

Paeonia lactiflora Pallas (PL) and Poria cocos Wolf (PC) have been traditionally used to treat inflammatory diseases reported in Dongui Bogam and Shen Nong Ben Cao Jing, traditional medical books in Korean and China, respectively. We determined the efficacies and the molecular mechanisms of PL, PC, and PL + PC aqueous extracts on androgenetic alopecia (AGA) induced by testosterone propionate in C57BL/6 mice. The molecular mechanisms of PL and PC in AGA treatment were examined using experimental assays and network pharmacology. The AGA model was generated by topically applying 0.5% testosterone propionate in 70% ethanol solution to the backs of mice daily for 28 days while the normal-control (Normal-Con; no AGA induction) mice applied 70% ethanol. The 0.1% PL (AGA-PL), 0.1% PC (AGA-PC), 0.05% PL + 0.05% PC (AGA-MIX), and 0.1% cellulose (AGA-Con; control) were supplemented in a high-fat diet for 28 days in AGA-induced mice. Positive-control (AGA-Positive) were administered 2% finasteride daily on the backs of the AGA mice. Hair growth rates decreased in the order of AGA-PL, AGA-MIX, AGA-PC, AGA-Positive, and AGA-Con after 21 days of treatment (ED21). On ED28, skins were completely covered with hair in the AGA-PL and AGA-MIX groups. Serum testosterone concentrations were lower in the AGA-PL group than in the AGA-Con group and similar to concentrations in the Normal-Con group, whereas serum 17β-estradiol concentrations showed the opposite pattern with increasing aromatase mRNA expression (p < 0.05). In the dorsal skin, DKK1 and NR3C2 mRNA expressions were significantly lower, but TGF-β2, β-Catenin, and PPARG expressions were higher in the AGA-PL and AGA-PC groups than in the AGA-Con group (p < 0.05), whereas TNF-α and IL-6 mRNA expressions were lower in the AGA-PL, AGA-MIX, and Normal-Con groups than in the AGA-Con group (p < 0.05). The phosphorylation of Akt and GSK-3β in the dorsal skin was lower in AGA-Con than normal-Con, and PL and MIX ingestion suppressed their decrease similar to the Normal-Con. In conclusion, PL or PL + PC intake had beneficial effects on hair growth similar to Normal-Con. The promotion was related to lower serum testosterone concentrations and pro-inflammatory cytokine levels, and inhibition of the steroid hormone pathway, consistent with network pharmacology analysis findings.

Steroid profiling and genetic variants in Chinese women with gestational diabetes mellitus

Previous studies have demonstrated that steroids were associated with gestational diabetes mellitus (GDM). However, results from different studies remained inconsistent, and only a limited range of steroids were investigated in these studies. Therefore, we aimed to analyze comprehensive steroid profiling in Chinese women with GDM during third-trimester pregnancy. In 97 Chinese pregnant women, we measured steroid profile using a LC–MS/MS method, and calculated product-to-precursor ratios in metabolic pathways of steroids. Then sixteen genetic variants of genes encoding steroidogenic enzymes were genotyped by MassARRAY system. There were significant differences (P < 0.05) and obvious changes (fold change <0.67 or>1.5) in steroids (testosterone, estriol, pregnenolone and dehydroepiandrosterone) and product-to-precursor ratios (E2/T and T/AD) between GDM and control groups. After adjusting for maternal age, the TT genotype and T allele of CYP19A1 rs10046 were associated with an increased risk of GDM. And the CC genotype and C allele of HSD17B3 rs2257157 were also associated with an increased risk of GDM. Besides, pregnant women carrying TT genotype of CYP19A1 rs10046 and CC genotype of HSD17B3 rs2257157 had a lower E2/T ratio and higher T/AD ratio respectively comparing with those carrying other genotypes. In conclusion, our study suggested that testosterone, estriol, pregnenolone and dehydroepiandrosterone might be differential metabolites for gestational diabetes mellitus. The genetic variants rs10046 of CYP19A1 and rs2257157 of HSD17B3 could predispose to GDM in Chinese women.

Exploring the Anti-Neuroinflammatory Potential of Steroid and Terpenoid-Derived Phytochemicals to Combat Alzheimer's Disease.

Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder that significantly affects cognitive functions in a way that causes loss of memory, thinking, and behavior. Multiple studies revealed that neuroinflammation associated with AD is linked with the amyloid-beta deposition in the brain. Elevated levels of expression of cytokines, microglial activation, nuclear factor kappa B, and reactive oxygen species play roles in AD-related inflammatory processes. Indeed, effective therapeutic approaches are urgently required to develop therapeutic agents to prevent and treat AD. So far, many anti-AD drug candidates have failed in the clinical stages and currently available drugs only provide symptomatic treatment. In recent times, pharmacologically active phytochemicals have been found to possess promising anti-neuroinflammatory effects; therefore, these natural products can be useful in AD treatment. In this review, we have comprehensively discussed the role of neuroinflammation and the molecular processes altered by multiple steroid and terpenoid-derived phytochemicals in various AD-related neuroinflammatory pathways. Indeed, steroid and terpenoid-derived phytochemicals show important therapeutic activities, which can be useful in ameliorating and treating AD-related neurodegeneration.

Identification of potential serum metabolic biomarkers for patient with keratoconus using untargeted metabolomics approach

This study aimed to investigate the metabolite differences between patients with keratoconus and control subjects and identify potential serum biomarkers for keratoconus using a non-targeted metabolomics approach. Venous blood samples were obtained from patients with keratoconus (n = 20) as well as from age-, gender- and race-matched control subjects (n = 20). Metabolites extracted from serum were separated and analyzed by liquid chromatography/quadrupole time-of-flight mass spectrometer. Processing of raw data and analysis of the data files was performed using Agilent Mass Hunter Qualitative software. The identified metabolites were subjected to a principal component and hierarchical cluster analysis. Appropriate statistical tests were used to analyze the metabolomic profiling data. Together, the analysis revealed that the dehydroepiandrosterone sulfate from the steroidal hormone synthesis pathway was significantly upregulated in patients with keratoconus (p < 0.05). Also, a combination of eicosanoids from the arachidonic acid pathway, mainly prostaglandin F2α, prostaglandin A2, 16,16-dimethyl prostaglandin E2, and 5-hydroxyeicosatetraenoic acid were collectively up-regulated as a group in keratoconus patients (p < 0.05). On the other hand, glycerophospholipid PS(17:2(9Z,12Z)/20:4(5Z,8Z,11Z,14Z)) was found to be significantly upregulated in the metabolomics profiles of control subjects (p < 0.05). The differently regulated metabolites provide insights into the pathophysiology of keratoconus and could potentially be used as biomarkers for keratoconus to aid in screening for individuals at risk hence, enabling early diagnosis and timely monitoring of disease.

Discussion on the Mechanism of Action of High-frequency Drugs for Treating Heart Failure Based on Network Pharmacology

Objective: To explore the target and mechanism of Astragalus membranaceus, poria, salvia miltiorrhiza and semen leiocarpa in the treatment of heart failure by network pharmacology. Methods: The active components of traditional Chinese medicine and the target of heart failure were screened by multi-platform, and the standard gene was transformed by Uniprot. CytoCasp 3.6.1 was used to draw the network diagram of traditional Chinese medicine - component - target. Go and KEGG analysis were performed by Metascape. Results: A total of 36 predictive target sites of Radix Astragalus, Fuling poria, Salvia miltiorrhiza and Draba nemorosa were screened for treatment of heart failure, mainly involving nerve and factor pathways: ADRB2, ADRA1B and AChE. Cancer pathway: TP53, TNF; Pathways of inflammation: IL1B, PTSG2, PTSG1; Sex hormone pathway: ESR1, AR, PGR; Others: SCN5A, HIF1A, etc. The results of GO and KEGG enrichment suggested that the treatment of heart failure with the top four drugs involved cancer pathway, calcium signaling pathway, HIF-1 signaling pathway, and involved in blood circulation, cell proliferation and other processes. Conclusion: This study combines the pharmacological studies of Chinese medicine and western medicine to reveal the mechanism of multi-target and multi-channel regulation of body balance in Chinese medicine treatment.

Oncostatin M Maintains Naïve Pluripotency of mESCs by Tetraploid Embryo Complementation (TEC) Assay.

It has been well established that leukemia inhibitory factor (LIF) is essential for maintaining naïve pluripotency of embryonic stem cells (ESCs). Oncostatin M (OSM) is a member of the IL-6 family of cytokines which share gp130 as a receptor subunit, and the OSM-gp130 complex can recruit either LIF receptor β or OSM receptor β. Here we show that OSM can completely replace LIF to maintain naïve pluripotency of ESCs. Mouse ESCs (mESCs) cultured in the presence of LIF or OSM not only express pluripotency genes at similar levels but also exhibit the same developmental pluripotency as evidenced by the generation of germline competent chimeras, supporting previous findings. Moreover, we demonstrate by tetraploid embryo complementation assay, the most stringent functional test of authentic pluripotency that mESCs cultured in OSM produce viable all-ESC pups. Furthermore, telomere length and telomerase activity, which are also crucial for unlimited self-renewal and genomic stability of mESCs, do not differ in mESCs cultured under OSM or LIF. The transcriptome of mESCs cultured in OSM overall is very similar to that of LIF, and OSM activates Stat3 signaling pathway, like LIF. Additionally, OSM upregulates pentose and glucuronate interconversion, ascorbate and aldarate metabolism, and steroid and retinol metabolic pathways. Although the significance of these pathways remains to be determined, our data shows that OSM can maintain naïve pluripotent stem cells in the absence of LIF.

Thermal evolution of steroids during anhydrous pyrolysis of cholesterol with and without elemental sulfur

Steroids are widely used in geochemical studies. They are common in living organisms, sediments and petroleum, and the diagenetic pathways of steroidal compounds in the subsurface are reasonably well understood. However, there are still some questions concerning their thermal evolution (i.e., isomerization, aromatization, and cracking), such as the rates of formation and alteration of various steroidal compounds and the effects of catalysis on these processes, specifically the possible influence of sulfur-containing species. To address these questions, cholesterol and a mixture of cholesterol and elemental sulfur were reacted to simulate the thermal evolution pathways of steroids in the laboratory. Anhydrous pyrolysis experiments were conducted in sealed gold tubes at temperatures ranging from 150 °C to 600 °C using heating rates of 2 °C/h and 20 °C/h, and the products were analyzed by gas chromatography and gas chromatography-mass spectrometry. For the pure cholesterol experiments, the formation of sterenes, steranes and monoaroamtic steroids, and finally triaromatic steroids occurred at EasyRo ~ 0.42%, 0.73%, and 1.36%, respectively. All species were converted into smaller moieties such as phenanthrenes, pyrenes, etc., at EasyRo > 1.69%. The presence of elemental sulfur in the pyrolysis experiments significantly increased the rate of the thermal evolution of steroids, with an earlier onset of the generation of smaller moieties such as methylphenanthrenes and dimethylphenanthrenes at EasyRo 0.86%. Diasterenes and diasteranes were not observed in either the pure cholesterol or the cholesterol with elemental sulfur experiments. The aromatization path starting from the C-ring of steroids was not observed in the experiments using pure cholesterol but occurred in the sulfur-containing series. The presence of sulfur significantly increased the rate of isomerization and aromatization of steranes, especially sterane ring isomerization, and increased the equilibrium values of isomerization parameters by 0.1–0.2 compared to that of the pure cholesterol series. These findings indicate that the presence of sulfur-containing species has important implications for the thermal evolution of steroids.

Clinical features and sex hormone profile in male patients with frontal fibrosing alopecia: A multicenter retrospective study with 33 patients

Clinical features and sex hormone profile in male patients with frontal fibrosing alopecia: A multicenter retrospective study with 33 patients

Circulating Levels of Testosterone, Sex Hormone Binding Globulin and Colorectal Cancer Risk: Observational and Mendelian Randomization Analyses.

Epidemiologic studies evaluating associations between sex steroid hormones and colorectal cancer risk have yielded inconsistent results. To elucidate the role of circulating levels of testosterone, and sex hormone-binding globulin (SHBG) in colorectal cancer risk, we conducted observational and Mendelian randomization (MR) analyses. The observational analyses included 333,530 participants enrolled in the UK Biobank with testosterone and SHBG measured. HRs and 95% confidence intervals (CI) were estimated using multivariable Cox proportional hazards models. For MR analyses, genetic variants robustly associated with hormone levels were identified and their association with colorectal cancer (42,866 cases/42,752 controls) was examined using two-sample MR. In the observational analysis, there was little evidence that circulating levels of total testosterone were associated with colorectal cancer risk; the MR analyses showed a greater risk for women (OR per 1-SD = 1.09; 95% CI, 1.01-1.17), although pleiotropy may have biased this result. Higher SHBG concentrations were associated with greater colorectal cancer risk for women (HR per 1-SD = 1.16; 95% CI, 1.05-1.29), but was unsupported by the MR analysis. There was little evidence of associations between free testosterone and colorectal cancer in observational and MR analyses. Circulating concentrations of sex hormones are unlikely to be causally associated with colorectal cancer. Additional experimental studies are required to better understand the possible role of androgens in colorectal cancer development. Our results from large-scale analyses provide little evidence for sex hormone pathways playing a causal role in colorectal cancer development.See related commentary by Hang and Shen, p. 1302.

Metabolite Profile of Treatment-Naive Metabolic Syndrome Subjects in Relation to Cardiovascular Disease Risk.

Metabolic syndrome (MetSyn) is an important risk factor for type 2 diabetes and cardiovascular diseases (CVD). This study aimed to find distinct plasma metabolite profiles between insulin-resistant and non-insulin resistant subjects with MetSyn and evaluate if MetSyn metabolite profiles are related to CVD risk and lipid fluxes. In a cross-sectional study, untargeted metabolomics of treatment-naive males with MetSyn (n = 132) were analyzed together with clinical parameters. In a subset of MetSyn participants, CVD risk was calculated using the Framingham score (n = 111), and lipolysis (n = 39) was measured by a two-step hyperinsulinemic euglycemic clamp using [1,1,2,3,3-2H5] glycerol to calculate lipolysis suppression rates. Peripheral insulin resistance was related to fatty acid metabolism and glycerolphosphorylcholine. Interestingly, although insulin resistance is considered to be a risk factor for CVD, we observed that there was little correspondence between metabolites associated with insulin resistance and metabolites associated with CVD risk. The latter mainly belonged to the androgenic steroid, fatty acid, phosphatidylethanolamine, and phophatidylcholine pathways. These data provide new insights into metabolic changes in mild MetSyn pathophysiology and MetSyn CVD risk related to lipid metabolism. Prospective studies may focus on the pathophysiological role of the here-identified biomarkers.