Estrogen hormone therapy stabilizes lateral hairline in transfeminine patients: Implications for facial feminization surgery.

BACKGROUND: Although several studies report on the suppressing effects of estrogen therapy on facial and body hair in transgender and nonbinary (TGNB) individuals, few studies have elucidated its effects on hairline stability on the scalp. In this study, we assessed the influence of estrogen therapy on forehead length. METHODS: All TGNB patients, aged 30 years or older, assigned male at birth (AMAB) seeking facial feminization surgery were included in the study. Central and forehead lengths were collected at the initial consultation visits. Variables, including age, duration of hormone replacement therapy (HRT), presence of spironolactone, and presence of other hair treatments, such as finasteride, dutasteride, or minoxidil, that potentially influence hair growth were collected by chart review. Multivariable linear regressions were constructed with relevant predictor variables while also incorporating global health scores as a proxy for psychological effects on hair loss. RESULTS: Overall, 171 patients were included in this study, with a median age of 36.0 (interquartile range (IQR) 32.0-46.0) years and median HRT duration of 2.0 (IQR 1.0-6.0) years. Multivariable linear regressions revealed no significant predictors for central forehead length. However, lateral forehead length was positively predicted by age (B=0.06, 95% confidence interval (CI) [0.03-0.08], p < 0.001) and hair treatment (B=0.66, 95% CI [0.14-1.18], p = 0.01), but negatively predicted by HRT duration (B=-0.07, 95% CI [-0.10 to -0.04], p < 0.001). CONCLUSIONS: Although older age is a predictor of lateral hairline recession in TGNB AMAB individuals, lateral forehead length was also predicted to decrease by 0.07 cm with each year of feminizing hormone therapy in patients over 30 years of age.

Changing trends in anabolic-androgenic steroid use within Scottish prisons: Detection, prevalence, and quantitation.

Anabolic-androgenic steroids (AASs) are a subclassification of image performance enhancing drugs (IPEDs). While AAS use is most prevalent among people in athletics, there is also high lifetime prevalence of AAS use among prisoners. This study reports the qualitative detection of AASs in seized samples from the Scottish prisons from 2019-2023. Additionally, methods were developed for the quantitative analysis of AASs using gas chromatography-mass spectrometry (GC-MS) and applied to 61 samples of tablets or powders seized from Scottish prisons between July 2022 and July 2023. Since 2022, there has been an increase in AAS detections in the Scottish prisons. Oxymetholone was the most prevalent AAS, followed by metandienone (methandrostenolone, methandienone), methyltestosterone, oxandrolone, mestanolone (methylandrostanolone), stanozolol, and androstenedione. Multiple AASs were found in 21 samples and 10 samples contained other drugs, including amitriptyline, sertraline, zopiclone, mirtazapine, sildenafil, etizolam, Δ9-tetrahydrocannabinol, and the synthetic cannabinoid MDMB-INACA. Most AAS samples were tablets (77.0%), although they were also detected in powders, herbal material, e-cigarettes, and a fragmented soap bar-type sample. There was a large variation in the concentration of AASs in the tablets and powders seized from the Scottish prisons, demonstrating AASs are another highly variable component of the polydrug use situation in prisons, the effects of which need to be examined further.

Androgenetic Alopecia in Men: An Update On Genetics.

Androgenetic alopecia (AGA) is defined as the alopecia induced by androgens in genetically predisposed individuals. AGA results in progressive miniaturization of the hair follicles leading to vellus transformation of terminal hair. The high prevalence and wide range of expressed phenotypes in AGA is a result of a polygenic inheritance mode. The androgen receptor (AR) gene located on the X chromosome at Xq11-12 is the first gene to show genetic association with AGA. Newer genetic associations with AGA are under study. In early-onset AGA, obesity, diabetes, hypertension, dyslipidaemia, insulin resistance, benign prostatic hyperplasia (BPH), prostate cancers and coronary artery disease (CAD) are associated with AGA. Screening of early-onset AGA patients and intervention for metabolic syndrome and insulin resistance can prevent the development of cardiovascular disease (CVD) at an early stage. As effective treatments continue to be topical minoxidil, systemic finasteride and hair transplantations, newer modalities are under investigation. Understanding the genetic factors involved in AGA and continued research into newer therapies, such as cell-based therapies, will lead to effective treatment and improve the quality of life in patients with AGA.

What is the prevalence of anabolic-androgenic steroid use among women? A systematic review.

BACKGROUND AND AIM: Evidence suggests there has been an increase in anabolic-androgenic steroid (AAS) use among women, driven by the evolving landscape of women's participation in sport. However, the extent of use is unknown. This systematic review aimed to estimate the prevalence of women's AAS use. METHOD: We conducted a systematic review of peer-reviewed articles in English, focusing on AAS use among women aged 18 and above. We excluded grey literature and studies that measured doping through some form of analysis (e.g. urine or hair). Searched databases were MEDLINE, CINAHL, PsycINFO, SocINDEX, SPORTDiscus, Embase and Cochrane Library. Titles and abstracts for all articles were screened, followed by full-text assessment and data extraction of included articles by multiple authors for accuracy. The pooled prevalence of lifetime use was determined using a random effects model and the risk of bias was assessed using the Joanna Briggs Institute Prevalence Critical Appraisal Tool. RESULTS: Based on 18 studies, participant numbers averaged 669 per study (median = 189; range = 16 to 7051). The overall pooled AAS use prevalence was 4% (95% confidence interval [CI] = 2-9%) with high heterogeneity overall (I2 = 95%). In the subgroup analysis, AAS use prevalence was 16.8% (95% CI = 11.0-24.9%, I2 = 44%) in the bodybuilder subgroup, 4.4% (95% CI = 1.2-15.1%, I2 = 93%) in athletes/recreational gym user subgroup, and 1.4% (95% CI = 0.4-4.7%, I2 = 96%) in the general population/other subgroup. Meta-regression demonstrated significantly higher AAS use in bodybuilders compared with the other subgroup (P = 0.011). CONCLUSION: Anabolic-androgenic steroid use among women appears to be substantially higher among bodybuilders and athletes/recreational gym users than the general female population.

Causal effects of omega-6 and LDL-C on androgenetic alopecia: A Mendelian randomization study.

BACKGROUND: Increasing studies have reported a causal relationship between androgenetic alopecia (AGA) and lipid-related metabolites. However, the relationships between HDL-C, LDL-C, Omega-6, and Omega-3 with AGA remain unclear. Some research findings are even contradictory. Therefore, we designed this study to explore this issue. METHODS: In this study, we selected seven exposure factors, screened SNPs with significant associations, removed linkage disequilibrium and weak instrumental variables, and conducted bidirectional MR analysis. RESULTS: The study found that omega-6 and LDL-C, especially total cholesterol in medium LDL and total cholesterol in small LDL, are risk factors for the occurrence of androgenetic alopecia. CONCLUSION: In summary, we found that various lipid-related metabolites have a causal relationship with the occurrence of androgenetic alopecia, providing new insights into the pathogenesis of androgenetic alopecia and offering references for clinical treatment of androgenetic alopecia.

Impaired vascular function among young users of anabolic-androgenic steroids.

Supraphysiological doses of anabolic-androgenic steroids (AAS) is popular among recreational weightlifters and bodybuilders due to the performance-enhancing properties but is also associated with adverse cardiovascular effects. The knowledge about how AAS affect the vasculature is limited, although results from previous studies suggest alterations in vasoreactivity and morphology. In the present study we investigate the association between long-term use of AAS and vascular function. Hundred and twenty-three males were included in the study, 56 of them current AAS users and 67 weightlifting controls. Vascular function was evaluated by carotid artery reactivity and flow-mediated dilation. AAS users had significantly reduced carotid artery reactivity (p < 0.001) and flow-mediated dilation (p < 0.001) compared to weightlifting controls. Results from the present study indicate that long-term use of AAS affect the cardiovascular system negatively, measured as reduced carotid artery reactivity and flow-mediated dilation. These findings could partly explain sudden cardiovascular events among young long-term users of AAS.

The synergistic effect of phototherapy and active substances on hair growth.

Androgenic alopecia (AGA) typically manifests post-puberty, resulting in decreases in hair density, disruptions in the hair growth cycle, and alterations in hair follicle micro structure. Dihydrotestosterone (DHT) is a key hormone implicated in hair loss, especially on male. In this study, we found that each of arginine (Arg), arterial extract (AE) or biotin tripeptide-1 (BT-1), when combined with low level light therapy (LLLT, at 630 nm, 2 J/cm2), showed the efficacy in enhancing mitochondrial functions, cell proliferation and collagen synthesis in fibroblasts. Additionally, CARRIPOWER (the complexes of AE, BT-1, Arg, and Diaminopyrimidine derivatives), in conjunction with LLLT (630 nm, 2 J/cm2), showed promising results in dermal papilla cells (DPCs). The promising results contained not also inflammatory cytokines (IL-1ß and IL-6) and cell pro apoptotic factor (TGF-ß2) reduction, but also Wnt pathway inhibition by decreasing DKK1 level, and pro-hair growth factors (vascular endothelial growth factor (VEGF) and ß-catenin) increase. This innovative combination therapy offers a potential solution for the treatment of AGA, addressing both hormonal and cellular factors involved in hair loss.

Development and validation of dependence and craving measures specific to athletes who use anabolic-androgenic steroids.

Background: Anabolic-androgenic steroid (AAS) dependence affects approximately 30% of people who use AAS. Presently, measures to assess and diagnose AAS dependence are adapted from scales specific to other forms of drug misuse (e.g., alcohol), containing issues with internal consistency and breadth of construct capture. Additionally, there are no measures available to assess AAS craving, which represents a potentially important coeval factor to AAS dependence. Therefore, this study aimed to develop and provide evidence of validity for measures of AAS dependence and AAS craving. Methods: Data were collected from male and female strength athletes who use AAS across two samples (n sample 1 = 206; n sample 2 = 224). Sample 1 completed the new measures alongside instruments assessing theoretically related constructs (Doping Moral Disengagement, Doping Self-Regulatory Efficacy Scale, craving items from the Wisconsin Smoking Withdrawal Scale, AAS adapted Diagnostic and Statistical Manual for Mental Disorder 4th Edition), whereas Sample 2 completed the new instruments. Results: Exploratory and Confirmatory Factor Analyses (CFA) with Sample 1 data were used to finalize the item sets for both measures and determine the factorial structures of the AAS Dependence Scale (AASDS) and AAS Craving Scale (AASCS). The AASDS consists of 15-items across five first-order factors that are represented by one second-order factor. The AASCS consists of 16-items across four first-order factors that are represented by one second-order factor. Evidence supporting the concurrent, convergent and discriminant validity of scores obtained with both scales was provided through their associations with the theoretically related variables. CFA with the data from Sample 2 confirmed the factor structures for both scales. Conclusion: The AASDS and AASCS represent valid and reliable measures of AAS dependence and AAS craving for use in research with strength athletes who use AAS.

A user-friendly machine learning approach for cardiac structures assessment.

Background: Machine learning is increasingly being used to diagnose and treat various diseases, including cardiovascular diseases. Automatic image analysis can expedite tissue analysis and save time. However, using machine learning is limited among researchers due to the requirement of technical expertise. By offering extensible features through plugins and scripts, machine-learning platforms make these techniques more accessible to researchers with limited programming knowledge. The misuse of anabolic-androgenic steroids is prevalent, particularly among athletes and bodybuilders, and there is strong evidence of their detrimental effects on ventricular myocardial capillaries and muscle cells. However, most studies rely on qualitative data, which can lead to bias and limited reliability. We present a user-friendly approach using machine learning algorithms to measure the effects of exercise and anabolic-androgenic steroids on cardiac ventricular capillaries and myocytes in an experimental animal model. Method: Male Wistar rats were divided into four groups (n = 28): control, exercise-only, anabolic-androgenic steroid-alone, and exercise with anabolic-androgenic steroid. Histopathological analysis of heart tissue was conducted, with images processed and analyzed using the Trainable Weka Segmentation plugin in Fiji software. Machine learning classifiers were trained to segment capillary and myocyte nuclei structures, enabling quantitative morphological measurements. Results: Exercise significantly increased capillary density compared to other groups. However, in the exercise + anabolic-androgenic steroid group, steroid use counteracted this effect. Anabolic-androgenic steroid alone did not significantly impact capillary density compared to the control group. Additionally, the exercise group had a significantly shorter intercapillary distance than all other groups. Again, using steroids in the exercise + anabolic-androgenic steroid group diminished this positive effect. Conclusion: Despite limited programming skills, researchers can use artificial intelligence techniques to investigate the adverse effects of anabolic steroids on the heart's vascular network and muscle cells. By employing accessible tools like machine learning algorithms and image processing software, histopathological images of capillary and myocyte structures in heart tissues can be analyzed.

Does androgenic alopecia aggravate the risk of prostate cancer? Evidence from Mendelian randomization.

Background: Epidemiological reports indicate a potential association between androgenic alopecia (AGA) and increased prostate cancer (PC) prevalence, but conflicting reports also exist. This study aims to elucidate the causality of AGA on PC risk using Mendelian randomization (MR) analysis. Materials and methods: Two-sample MR analyses utilized public genome-wide association studies summary data for single-nucleotide polymorphisms associated with AGA. Four statistical methods were used: inverse variance weighted (IVW), MR-Egger, weighted median, and weighted mode, with IVW as the preliminary estimation method. Additionally, sensitivity analyses were conducted to address pleiotropic bias. Results: Genetically proxied AGA did not demonstrate a causal effect on PC risk (IVW P > 0.05). Consistently, complementary methods yielded results aligned with IVW. Conclusions: Our MR analysis indicates no causal relationship between genetically predicted AGA and PC risk, suggesting that observed associations in epidemiological studies may not be causal.

Crustacean endocrinology: Sexual differentiation and potential application for aquaculture.

Crustaceans, which represent a significant subset of arthropods, are classified into three major classes: Ostracoda, Malacostraca, and Branchiopoda. Among them, sex manipulation in decapod species from the Malacostraca class has been extensively researched for aquaculture purposes and to study reproductive physiology and sexual plasticity. Some decapods exhibit sexual dimorphism that influences their biological and economic value. Monosex culture, in which only one sex is cultivated, increases production yields while reducing the risk of invasiveness, as genetic leakage into natural waters is less likely to occur. Differences in yield are also observed when cultivating different sexes, with all-male cultures of Macrobrachium rosenbergii being more profitable than both mixed and all-female cultures. Research on decapod sexual differentiation has led to a better understanding of sex determination and sexual differentiation processes in arthropods. Similar to most mammals and other vertebrate classes, Malacostraca crustaceans, including decapods, exhibit a cell-non-autonomous mode of sexual development. Genetic factors (e.g., sex chromosomes) and endocrine factors (e.g., insulin-like androgenic gland factor and crustacean female sex hormone) play pivotal roles in the development of sexually dimorphic traits. This review synthesizes the existing understanding of sex determination mechanisms and the role of sex hormones in decapod species. Additionally, it provides an overview of the methyl farnesoate, which has been suggested to be involved in male sex differentiation in some crab species, as well as the phenomenon of male-to-female sex reversal in host decapods caused by parasitic crustaceans.

UHPLC-MS/MS profiling and in vivo aphrodisiac and androgenic effects of the aqueous extract of the roots of Schumanniophyton magnificum (K. Schum.) Harms.

ETHNOPHARMACOLOGICAL RELEVANCE: Schumanniophyton magnificum is a medicinal plant used to manage many ailments including malaria, skin diseases, parasitic infections, male sexual dysfunctions, female infertility and typhoid fever. However, no scientific investigation has been made for its folkloric use by the "Baka" Pygmies of Cameroon as an aphrodisiac. AIM OF THE STUDY: To investigate the aphrodisiac and androgenic activities of the aqueous extract of the roots of Schumanniophyton magnificum in male rats and analyze the phytoconstituents by UHPLC/MS. MATERIALS AND METHODS: Twenty-five male rats of 16-weeks old were divided into 5 groups and orally treated for 30 days with distilled water (10 ml/kg), or sildenafil citrate (5 mg/kg), or the aqueous extract of Schumanniophyton magnificum (43 mg/kg, 86 mg/kg and 172 mg/kg). The sexual behaviour parameters were monitored on day 1 and 30 by pairing male rats to receptive females. At the end of the experiment, rats were killed and the blood and reproductive organs were collected for histological sectioning, sperm analysis and biochemical analysis. The presence of phytoconstituents and their structures were revealed by UHPLC/MS. RESULTS: The plant extract significantly increased the mount, ejaculation and intromission frequencies in comparison to those in the normal control group; and significantly doubled the serum testosterone levels (2.15 ± 0.70 ng/ml) compared to the normal control group. UHPLC/MS of the aqueous extract of Schumanniophyton magnificum identified 7 major compounds such as Schumanniofioside A, Noreugenin and Rohitukine, with antioxidant and antibacterial activities. The plant extracts significantly increased the penile nitric oxide levels (P <0.05). These results were similar to those obtained after administration of sildenafil citrate. CONCLUSIONS: The aqueous extract of Schumanniophyton magnificum could be an alternative for erectile dysfunction management.

A Case Report of an Acute Severe Tachyarrhythmia Presentation With Underlying Cardiomyopathy in a Patient With Anabolic Androgenic Steroid and Thyroxine Misuse.

A description of an acute hospital presentation with severe tachyarrhythmia requiring multiple direct current cardioversions in a 45-year-old male bodybuilder with underlying cardiomyopathy possibly caused by long-term anabolic steroid abuse and more recent thyroxine misuse is described. A review of the literature regarding the above associations was also done. This case report further adds to the literature regarding the harmful effect of androgenic anabolic steroid misuse (with the added effect of thyroxine misuse in this case) on the heart.

Androgen abuse: Risks and adverse effects in men.

Androgens, formerly known as anabolic-androgenic steroids, mimic the effects of testosterone and are being increasingly abused for nonmedical purposes such as body and performance enhancement. Androgen abuse is associated with increased mortality, and multisystem adverse effects have been reported, including cardiovascular toxicity, infertility, hypogonadism, hepatotoxicity, and mental health disorders. Men may present with the negative health consequences of androgen abuse even despite cessation for a number of years. There is frequently a reluctance to disclose androgen abuse, and substances are often sourced from the black market, which is not regulated and where the products sold may be counterfeit. All men should be encouraged to stop androgen abuse. Managing associated adverse effects will be organ-specific and is complex due to physical and neuropsychiatric symptoms, substance dependence, and high rates of relapse. Given the broad reach and prolonged adverse effects of androgen abuse, clinicians across medical specialties should have an awareness of androgen abuse, its increasing prevalence, and the harms it poses to men and their families. This narrative review aims to summarize the adverse effects and risks associated with androgen abuse.

Optimized Depilation Method and Comparative Analysis of Hair Growth Cycle in Mouse Strains.

In mice, hair growth follows a mosaic or wavy patterning. Therefore, synchronization of the hair growth cycle is required to adequately evaluate any trichogenic interventions pre-clinically. Depilation is the established method for synchronizing the growth phase of mouse hair follicles. When attempting to reproduce procedures reported in the literature, C57BL/6J mice developed severe wounds. This led us not only to optimize the procedure, but also to test the procedure in other strains, namely Sv129 and the F1 generation from C57BL/6J crossed with Sv129 (B6129F1 mixed background), for which the hair growth cycle has not been ascertained yet. Here, we describe an optimized depilation procedure, using cold wax and an extra step to protect the animal skin that minimizes injury, improving experimental conditions and animal welfare in all strains. Moreover, our results show that, although hair cycle kinetics are similar in all the analyzed strains, Sv129 and B6129F1 skins are morphologically different from C57BL/6J skin, presenting an increased number and size of hair follicles in anagen, consistent to the higher hair density observed macroscopically. Altogether, the results disclose an optimized mouse depilation method that excludes the detrimental and confounding effects of skin injury in hair growth studies and reveals the hair cycle features of other mouse strains, supporting their use in hair growth pre-clinical studies.

The health effects of non-prescribed anabolic-androgenic steroid use: Findings from The Performance and image-enhancing drugs UseRS' Health (PUSH) audit.

INTRODUCTION: To ascertain the adverse health outcomes experienced by those using prescribed testosterone and non-prescribed anabolic-androgenic steroids presenting to general practitioner (GP) clinics. METHODS: Retrospective clinical audit from nine GP clinics in major metropolitan areas across three Australian states. Data included demographic and individual characteristics (age, sexuality, body mass index, smoking status and HIV status); performance and image-enhancing drug use (type, reasons for use, patient-reported adverse effects); and blood biochemistry measurements (lipid profiles, liver function tests and red blood cell tests). Adverse health outcomes included evidence of polycythaemia, hypertension, liver abnormalities and hypercholesterolemia. RESULTS: Three hundred men were identified as either using prescribed testosterone (66%; n = 197) or non-prescribed anabolic-androgenic steroids (AAS) (34%; n = 103). Individuals in the prescribed group were more likely to be older (p < 0.001), gay or bisexual (p < 0.001) and living with diagnosed HIV (p < 0.001) compared to individuals in the non-prescribed group. Abnormal liver function, polycythemia and gynecomastia were the top three adverse events experienced. When adjusting for age, sexuality, HIV status and smoking status, those who used non-prescribed AAS were more likely to experience any adverse event (aPR = 1.28; 95% CI 1.01-1.60; p = 0.038), hypertension (aPR = 1.86; 95% CI 1.19-2.91; p = 0.006) and liver abnormalities (aPR = 1.51; 95% CI 1.04-2.20; p = 0.030) compared to those using prescribed testosterone. DISCUSSION AND CONCLUSION: For GPs who have clients who may be using, or who they suspect of using, AAS, these findings highlight the importance of not only exploring a patient's history of the adverse effects they have experienced, but that measuring for these other conditions may provide a more accurate clinical picture.

Off-label use of clomiphene citrate to treat anabolic androgenic steroid induced hypogonadism upon cessation among men (CloTASH) - A pilot study protocol.

Background: Non-prescribed anabolic androgenic steroid (AAS) use is associated with AAS-induced hypogonadism (ASIH), and metabolic, cardiovascular, and mental health risks. Symptoms of ASIH (fatigue, depression, anxiety, sexual dysfunction) are hard to endure following cessation, but there is no consensus on whether endocrine treatment should be used to treat ASIH. This proof-of-concept study aims to explore safety of off-label clomiphene citrate therapy, whether the treatment will reduce the symptoms of androgen deficiency, and to study changes in health risks after cessation. Methods: In this open-labeled non-randomized off-label hormone intervention pilot study, we shall include males with AAS dependence intending to cease use. The 16-week intervention included clomiphene citrate, transdermal testosterone gel for the first four weeks and optional human chorionic gonadotropin (hCG) from week 4 if low treatment response. Measures of physical and mental health will be examined from ongoing AAS use, during the intervention, and at 6- and 12 months post cessation. Change in self-reported symptoms of hypogonadism and other withdrawal symptoms will be compared with data from a group of men who ended AAS use temporarily without the medical intervention. The study may provide valuable clinical insights and may be used to inform the design of future intervention studies.

Illegal Use of Testosterone and Other Anabolic-Androgenic Steroids in the Population of Amateur Athletes in Wroclaw, Poland-An Unfavorable Lifestyle Trend in the Population of Men of Reproductive Age.

Background: One factor that may negatively impact male reproductive health is the illegal use of testosterone and anabolic-androgenic steroids. This study aimed to evaluate the prevalence of testosterone use in recreational athletes, as well as factors associated with its use, and to determine the profile of a person using testosterone. Methods: A cross-sectional analysis of data from an anonymous, online questionnaire of men recruited from gyms, randomly selected in Wroclaw, Poland, has been performed. The minimal sample size was evaluated with the univariate logistic regression model. The association between testosterone use and other factors was also evaluated with the univariate logistic regression model. Results: A total of 35% of respondents used testosterone. The main purposes of testosterone use were the improvement of training effects and the improvement of body shape. The respondents most likely to use testosterone and other anabolic-androgenic steroids were men aged 26-35, whose earnings were at the level of the middle class or higher, who were married, had children, had training experience of at least 6 months, exercised at least once a week, took part in weightlifting competitions, were managers in a corporation or enterprise, or were self-employed. Most of the people using testosterone had self-treated side effects. Conclusions: The profile of the person most likely to use testosterone corresponds to the characteristics of men in optimal socio-demographic conditions for reproduction. These results indicate that this is a significant social problem that may impact male reproductive health.

The Impact of Vitamin D and L-Cysteine Co-Supplementation on Upregulating Glutathione and Vitamin D-Metabolizing Genes and in the Treatment of Circulating 25-Hydroxy Vitamin D Deficiency.

Vitamin D receptors are expressed in many organs and tissues, which suggests that vitamin D (VD) affects physiological functions beyond its role in maintaining bone health. Deficiency or inadequacy of 25(OH)VD is widespread globally. Population studies demonstrate that a positive association exists between a high incidence of VD deficiency and a high incidence of chronic diseases, including dementia, diabetes, and heart disease. However, many subjects have difficulty achieving the required circulating levels of 25(OH)VD even after high-dose VD supplementation, and randomized controlled clinical trials have reported limited therapeutic success post-VD supplementation. Thus, there is a discordance between the benefits of VD supplementation and the prevention of chronic diseases in those with VD deficiency. Why this dissociation exists is currently under debate and is of significant public interest. This review discusses the downregulation of VD-metabolizing genes needed to convert consumed VD into 25(OH)VD to enable its metabolic action exhibited by subjects with metabolic syndrome, obesity, and other chronic diseases. Research findings indicate a positive correlation between the levels of 25(OH)VD and glutathione (GSH) in both healthy and diabetic individuals. Cell culture and animal experiments reveal a novel mechanism through which the status of GSH can positively impact the expression of VD metabolism genes. This review highlights that for better success, VD deficiency needs to be corrected at multiple levels: (i) VD supplements and/or VD-rich foods need to be consumed to provide adequate VD, and (ii) the body needs to be able to upregulate VD-metabolizing genes to convert VD into 25(OH)VD and then to 1,25(OH)2VD to enhance its metabolic action. This review outlines the association between 25(OH)VD deficiency/inadequacy and decreased GSH levels, highlighting the positive impact of combined VD+LC supplementation on upregulating GSH, VD-metabolizing genes, and VDR. These effects have the potential to enhance 25(OH)VD levels and its therapeutic efficacy.