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The Journal of Clinical Endocrinology... Jul 2019The lifetime prevalence of anabolic androgenic steroid (AAS) use is estimated at 1% to 5% worldwide. AAS use occurs primarily male elite athletes and men who want a... (Review)
Review
CONTEXT
The lifetime prevalence of anabolic androgenic steroid (AAS) use is estimated at 1% to 5% worldwide. AAS use occurs primarily male elite athletes and men who want a muscular appearance. The evidence for effective, safe management of AAS cessation and withdrawal is weak.
DESIGN
Key studies were extracted from PubMed (1990-2018) and Google Scholar with reference searches from relevant retrieved articles.
RESULTS
The proven adverse effects of AASs include suppression of the gonadal axis and infertility, hirsutism and defeminization in women, and erythrocytosis. Alkylated AASs that are taken orally may cause hepatopathy. There is an association between high-dosage AAS use and increased risk of cardiovascular disease. Clues for AAS use include very low serum high-density cholesterol and sex hormone-binding globulin concentrations and unexplained erythrocytosis. For elite athletes, the biological passport (monitoring of blood or urinary androgen and androgen precursor concentrations after determining the athlete's baseline) is useful for detecting AAS use. For nonelite athletes, the best method to confirm AAS use is to inquire in a nonjudgmental manner. Cessation of chronic AAS use is associated with a withdrawal syndrome of anxiety and depression.
CONCLUSIONS
Men who use AASs <1 year typically recover normal hypothalamic-pituitary-testicular axis function within 1 year after cessation. Men who have infertility due to high-dosage AAS use ≥1 year might benefit from short-term treatment with clomiphene or human chorionic gonadotropin.
Topics: Anabolic Agents; Androgens; Athletes; Doping in Sports; Dose-Response Relationship, Drug; Female; Humans; Male; Performance-Enhancing Substances; Prevalence; Sex Factors; Substance Abuse Detection; Substance-Related Disorders
PubMed: 30753550
DOI: 10.1210/jc.2018-01882 -
Neurobiology of Disease Jul 2020Microglia-induced neuroinflammation plays a vital role in the etiology and progression of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease...
Microglia-induced neuroinflammation plays a vital role in the etiology and progression of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and multiple sclerosis. The neuroprotective role of androgens, including testosterone and its metabolite dihydrotestosterone (DHT), has been increasingly demonstrated in these diseases, but few studies investigated the effects of androgen on neuroinflammation. This study investigated the role of DHT in lipopolysaccharide (LPS)-induced neuroinflammation, neuronal damage and behavioral dysfunction, as well as underlying mechanisms. We showed that DHT inhibited LPS-induced release of proinflammatory factors, including TNF-α, IL-1β, IL-6; iNOS, COX-2, NO, and PGE2 in BV2 cells and primary microglia by suppressing the TLR4-mediated NF-κB and MAPK p38 signaling pathways, thus protecting SH-SY5Y neurons from inflammatory damage induced by activated microglia. In an LPS-induced neuroinflammation mouse model, endogenous DHT depletion by castration exacerbated inflammatory responses by upregulating the levels of TNF-α, IL-1β, IL-6, iNOS, and COX-2 in the serum and brain by increasing the LR4-mediated NF-κB and MAPK pathway activation, but these effects were restored by exogenous DHT supplementation. Moreover, DHT also regulated the mRNA levels of the anti-inflammatory cytokines IL-10 and IL-13 in the brain. In addition, DHT modulated the expression of Aβ, the apoptotic proteins caspase-3, Bcl-2, and Bax, and synaptophysin, as well as neuronal damage in LPS-treated mouse brains. Further behavioral tests revealed that DHT ameliorated LPS-induced spatial and learning impairment and motor incoordination, and partly improved the locomotor activity in LPS-injected mice. Therefore, this study suggests that DHT exerts anti-neuroinflammatory and neuroprotective effects; thus, androgen replacement therapy is a potential therapeutic strategy for improving cognitive and behavioral function in neuroinflammation-related diseases.
Topics: Androgens; Animals; Anti-Inflammatory Agents; Brain; Cyclooxygenase 2; Cytokines; Dihydrotestosterone; Inflammation; Lipopolysaccharides; MAP Kinase Signaling System; Mice; Microglia; NF-kappa B; Neurons; Neuroprotection; Neuroprotective Agents; Nitric Oxide Synthase Type II; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha
PubMed: 32087283
DOI: 10.1016/j.nbd.2020.104814 -
Endocrinology and Metabolism Clinics of... Mar 2022All approved testosterone replacement methods, when used according to recommendations, can restore normal serum testosterone concentrations, and relieve symptoms in most... (Review)
Review
All approved testosterone replacement methods, when used according to recommendations, can restore normal serum testosterone concentrations, and relieve symptoms in most hypogonadal men. Selection of the method depends on the patient's preference with advice from the physician. Dose adjustment is possible with most delivery methods but may not be necessary in all hypogonadal men. The use of hepatotoxic androgens must be avoided. Testosterone treatment induces reversible suppression of spermatogenesis; if fertility is desired in the near future, human chronic gonadotropin, selective estrogen receptor modulator, estrogen antagonist, or an aromatase inhibitor that stimulates endogenous testosterone production may be used.
Topics: Androgens; Hormone Replacement Therapy; Humans; Hypogonadism; Male; Spermatogenesis; Testosterone
PubMed: 35216722
DOI: 10.1016/j.ecl.2021.11.005 -
Nature Genetics May 2022HOXB13, a homeodomain transcription factor, critically regulates androgen receptor (AR) activities and androgen-dependent prostate cancer (PCa) growth. However, its...
HOXB13, a homeodomain transcription factor, critically regulates androgen receptor (AR) activities and androgen-dependent prostate cancer (PCa) growth. However, its functions in AR-independent contexts remain elusive. Here we report HOXB13 interaction with histone deacetylase HDAC3, which is disrupted by the HOXB13 G84E mutation that has been associated with early-onset PCa. Independently of AR, HOXB13 recruits HDAC3 to lipogenic enhancers to catalyze histone deacetylation and suppress lipogenic regulators such as fatty acid synthase. Analysis of human tissues reveals that the HOXB13 gene is hypermethylated and downregulated in approximately 30% of metastatic castration-resistant PCa. HOXB13 loss or G84E mutation leads to lipid accumulation in PCa cells, thereby promoting cell motility and xenograft tumor metastasis, which is mitigated by pharmaceutical inhibition of fatty acid synthase. In summary, we present evidence that HOXB13 recruits HDAC3 to suppress de novo lipogenesis and inhibit tumor metastasis and that lipogenic pathway inhibitors may be useful to treat HOXB13-low PCa.
Topics: Androgens; Cell Line, Tumor; Epigenesis, Genetic; Histone Deacetylases; Homeodomain Proteins; Humans; Lipogenesis; Male; Prostatic Neoplasms; Receptors, Androgen; Transcription Factors
PubMed: 35468964
DOI: 10.1038/s41588-022-01045-8 -
Journal of Cosmetic Dermatology Aug 2022The humans have been disproportionately affected by the coronavirus disease (COVID-19) pandemic. The novel coronavirus or the severe acute respiratory syndrome... (Review)
Review
BACKGROUND
The humans have been disproportionately affected by the coronavirus disease (COVID-19) pandemic. The novel coronavirus or the severe acute respiratory syndrome coronavirus 2 (SARS-COV2) causing coronavirus disease (COVID-19) has spread across the globe. Androgens have been suggested to have a role in COVID-19 pathogenesis.
OBJECTIVE
The objective of this review article is to study the link between androgens and COVID-19.
METHODOLOGY
PubMed and Google Scholar search was performed to retrieve literature related to the topic. Review articles, clinical trials, retrospective studies, observational studies, and case-control studies were considered for the review.
RESULTS
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected men are more inclined to be hospitalized for intensive care unit (ICU) as compared with women. This difference in the ICU admissions provides some clue for possible influence of androgens in the severity of COVID-19. The contribution of androgen and androgen receptor in COVID-19 disease and its severity, as well as the numerous medications targeting androgen and its receptor for lowering COVID-19 disease severity, are discussed in this review. Available literature suggests the role of androgen in the pathogenesis and severity of COVID-19. Sensitivity for androgen may be an important factor in regulating the severity of COVID-19 disease.
CONCLUSION
There is a scope for the development of COVID-19 treatments based on androgen suppression. Clinical trials may furnish pivotal data and add more evidence-based options for the management of COVID-19.
Topics: Androgens; COVID-19; Female; Humans; Male; RNA, Viral; Retrospective Studies; SARS-CoV-2
PubMed: 35576054
DOI: 10.1111/jocd.15090 -
Advanced Science (Weinheim,... Jun 2023Great attention is paid to the role of androgen receptor (AR) as a central transcriptional factor in driving the growth of prostate cancer (PCa) epithelial cells....
Great attention is paid to the role of androgen receptor (AR) as a central transcriptional factor in driving the growth of prostate cancer (PCa) epithelial cells. However, the understanding of the role of androgen in PCa-infiltrated immune cells and the impact of androgen deprivation therapy (ADT), the first-line treatment for advanced PCa, on the PCa immune microenvironment remains limited. On the other hand, immune checkpoint blockade has revolutionized the treatment of certain cancer types, but fails to achieve any benefit in advanced PCa, due to an immune suppressive environment. In this study, it is reported that AR signaling pathway is evidently activated in tumor-associated macrophages (TAMs) of PCa both in mice and humans. AR acts as a transcriptional repressor for IL1B in TAMs. ADT releases the restraint of AR on IL1B and therefore leads to an excessive expression and secretion of IL-1β in TAMs. IL-1β induces myeloid-derived suppressor cells (MDSCs) accumulation that inhibits the activation of cytotoxic T cells, leading to the immune suppressive microenvironment. Critically, anti-IL-1β antibody coupled with ADT and the immune checkpoint inhibitor anti-PD-1 antibody exerts a stronger anticancer effect on PCa following castration. Together, IL-1β is an important androgen-responsive immunotherapeutic target for advanced PCa.
Topics: Animals; Humans; Male; Mice; Androgen Antagonists; Androgens; Immunotherapy; Macrophages; Prostatic Neoplasms; Tumor Microenvironment
PubMed: 37092583
DOI: 10.1002/advs.202206889 -
Cancer Discovery Sep 2022In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various disease stages. However, therapy resistance inevitably occurs, and little is...
UNLABELLED
In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various disease stages. However, therapy resistance inevitably occurs, and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multiomics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from patients with high-risk prostate cancer enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors toward a neuroendocrine-like disease state. Additionally, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 from inactive chromatin sites toward active cis-regulatory elements that dictate prosurvival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian clock component ARNTL. Posttreatment ARNTL levels were associated with patients' clinical outcomes, and ARNTL knockout strongly decreased prostate cancer cell growth. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy and revealed an acquired dependency on the circadian regulator ARNTL, a novel candidate therapeutic target.
SIGNIFICANCE
Understanding how prostate cancers adapt to AR-targeted interventions is critical for identifying novel drug targets to improve the clinical management of treatment-resistant disease. Our study revealed an enzalutamide-induced epigenomic plasticity toward prosurvival signaling and uncovered the circadian regulator ARNTL as an acquired vulnerability after AR inhibition, presenting a novel lead for therapeutic development. See related commentary by Zhang et al., p. 2017. This article is highlighted in the In This Issue feature, p. 2007.
Topics: ARNTL Transcription Factors; Androgens; Cell Line, Tumor; Circadian Rhythm; Drug Resistance, Neoplasm; Epigenomics; Humans; Male; Nitriles; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen
PubMed: 35754340
DOI: 10.1158/2159-8290.CD-21-0576 -
The Journal of Clinical Investigation Apr 2023After androgen deprivation, prostate cancer frequently becomes castration resistant (CRPC), with intratumoral androgen production from extragonadal precursors that...
After androgen deprivation, prostate cancer frequently becomes castration resistant (CRPC), with intratumoral androgen production from extragonadal precursors that activate the androgen receptor pathway. 3β-Hydroxysteroid dehydrogenase-1 (3βHSD1) is the rate-limiting enzyme for extragonadal androgen synthesis, which together lead to CRPC. Here, we show that cancer-associated fibroblasts (CAFs) increased epithelial 3βHSD1 expression, induced androgen synthesis, activated the androgen receptor, and induced CRPC. Unbiased metabolomics revealed that CAF-secreted glucosamine specifically induced 3βHSD1. CAFs induced higher GlcNAcylation in cancer cells and elevated expression of the transcription factor Elk1, which induced higher 3βHSD1 expression and activity. Elk1 genetic ablation in cancer epithelial cells suppressed CAF-induced androgen biosynthesis in vivo. In patient samples, multiplex fluorescent imaging showed that tumor cells expressed more 3βHSD1 and Elk1 in CAF-enriched areas compared with CAF-deficient areas. Our findings suggest that CAF-secreted glucosamine increases GlcNAcylation in prostate cancer cells, promoting Elk1-induced HSD3B1 transcription, which upregulates de novo intratumoral androgen synthesis to overcome castration.
Topics: Male; Humans; Prostatic Neoplasms; Androgens; Receptors, Androgen; Prostatic Neoplasms, Castration-Resistant; Androgen Antagonists; Up-Regulation; Glucosamine; Cancer-Associated Fibroblasts; Multienzyme Complexes; Cell Line, Tumor
PubMed: 37009898
DOI: 10.1172/JCI161913 -
Reviews in Endocrine & Metabolic... Dec 2022In men > ~35 years, aging is associated with perturbations in the hypothalamus-pituitary-testicular axis and declining serum testosterone concentrations. The... (Review)
Review
In men > ~35 years, aging is associated with perturbations in the hypothalamus-pituitary-testicular axis and declining serum testosterone concentrations. The major changes are decreased gonadotropin-releasing hormone (GnRH) outflow and decreased Leydig cell responsivity to stimulation by luteinizing hormone (LH). These physiologic changes increase the prevalence of biochemical secondary hypogonadism-a low serum testosterone concentration without an elevated serum LH concentration. Obesity, medications such as opioids or corticosteroids, and systemic disease further reduce GnRH and LH secretion and might result in biochemical or clinical secondary hypogonadism. Biochemical secondary hypogonadism related to aging often remits with weight reduction and avoidance or treatment of other factors that suppress GnRH and LH secretion. Starting at age ~65-70, progressive Leydig cell dysfunction increases the prevalence of biochemical primary hypogonadism-a low serum testosterone concentration with an elevated serum LH concentration. Unlike biochemical secondary hypogonadism in older men, biochemical primary hypogonadism is generally irreversible. The evaluation of low serum testosterone concentrations in older men requires a careful assessment for symptoms, signs and causes of male hypogonadism. In older men with a body mass index (BMI) ≥ 30, biochemical secondary hypogonadism and without an identifiable cause of hypothalamus or pituitary pathology, weight reduction and improvement of overall health might reverse biochemical hypogonadism. For older men with biochemical primary hypogonadism, testosterone replacement therapy might be beneficial. Because aging is associated with decreased metabolism of testosterone and increased tissue-specific androgen sensitivity, lower dosages of testosterone replacement therapy are often effective and safer in older men.
Topics: Male; Humans; Aged; Androgens; Testosterone; Aging; Gonadotropin-Releasing Hormone; Hypogonadism
PubMed: 36459352
DOI: 10.1007/s11154-022-09765-2 -
Diabetes & Metabolic Syndrome 2020The coronavirus disease 2019 (COVID-19) pandemic is a global health emergency. According to the findings, male patients with COVID-19 infection are at an increased risk... (Review)
Review
BACKGROUND AND AIM
The coronavirus disease 2019 (COVID-19) pandemic is a global health emergency. According to the findings, male patients with COVID-19 infection are at an increased risk for severe complications than females. The causes of this issue are unknown and are most probably multifactorial. Sexual hormones affect the immune system, so estrogen strengthens the immune system, and testosterone suppresses it. Due to the reports of the high prevalence of androgenic alopecia in hospitalized patients with COVID-19 and a higher risk of respiratory disease and increased use of allergy/asthma medications among patients with polycystic ovary syndrome (PCOS) as a hyperandrogenism condition compared with non-PCOS women, this review aimed to evaluate androgens role in COVID-19.
METHODS
42 related articles from 2008 to 2020 were reviewed with the keywords of androgens, hormonal factors, and hair loss in combination with COVID-19 in medical research databases.
RESULTS
The evidence of transmembrane protease, serine 2 (TMPRSS2) expression in lung tissue, which is an androgen-regulated gene and expressed mainly in the adult prostate may interpret the increased susceptibility of the male gender to severe COVID-19 complications. Moreover, angiotensin-converting enzyme 2 (ACE-2) acts as a functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and male hormones are effective in the ACE-2 passageway and simplify SARS-CoV-2 entry into host cells.
CONCLUSION
Further studies on the severity of symptoms in patients with COVID-19 in other hyperandrogenism conditions compared to the control group are recommended.
Topics: Alopecia; Androgens; Antimalarials; Antiviral Agents; COVID-19; Female; Gonadal Steroid Hormones; Humans; Male; Sex Characteristics; COVID-19 Drug Treatment
PubMed: 33091758
DOI: 10.1016/j.dsx.2020.10.014