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The Role of the EGF Receptor in Sex Differences in Kidney Injury.
Zhang MZ, Sasaki K, Li Y, Li Z, Pan Y, Jin GN, Wang Y, Niu A, Wang S, Fan X, Chen JC, Borza C, Yang H, Pozzi A, Fogo AB, Harris RC
(2019) J Am Soc Nephrol 30: 1659-1673
MeSH Terms: Age Factors, Alleles, Animals, Castration, Cell Line, ErbB Receptors, Erlotinib Hydrochloride, Female, Gain of Function Mutation, Humans, Kidney, Male, Mice, Mice, Inbred C57BL, Middle Aged, Ovariectomy, Podocytes, Protein Kinase Inhibitors, RNA, Messenger, Renal Insufficiency, Chronic, Sex Factors, Testosterone
Show Abstract · Added August 7, 2019
BACKGROUND - Sex differences mediating predisposition to kidney injury are well known, with evidence indicating lower CKD incidence rates and slower decline in renal function in nondiabetic CKD for premenopausal women compared with men. However, signaling pathways involved have not been elucidated to date. The EGF receptor (EGFR) is widely expressed in the kidney in glomeruli and tubules, and persistent and dysregulated EGFR activation mediates progressive renal injury.
METHODS - To investigate the sex differences in response to renal injury, we examined EGFR expression in mice, in human kidney tissue, and in cultured cell lines.
RESULTS - In wild type mice, renal mRNA and protein EGFR levels were comparable in males and females at postnatal day 7 but were significantly lower in age-matched adult females than in adult males. Similar gender differences in renal EGFR expression were detected in normal adult human kidneys. In Dsk5 mutant mice with a gain-of-function allele that increases basal EGFR kinase activity, males had progressive glomerulopathy, albuminuria, loss of podocytes, and tubulointerstitial fibrosis, but female Dsk5 mice had minimal kidney injury. Oophorectomy had no effect on renal EGFR levels in female Dsk5 mice, while castration protected against the kidney injury in male Dsk5 mice, in association with a reduction in EGFR expression to levels seen in females. Conversely, testosterone increased EGFR expression and renal injury in female Dsk5 mice. Testosterone directly stimulated EGFR expression in cultured kidney cells.
CONCLUSIONS - These studies indicate that differential renal EGFR expression plays a role in the sex differences in susceptibility to progressive kidney injury that may be mediated at least in part by testosterone.
Copyright © 2019 by the American Society of Nephrology.
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22 MeSH Terms
Sex Hormone-Binding Globulin Levels in Young Men Are Associated With Nonalcoholic Fatty Liver Disease in Midlife.
Sarkar M, VanWagner LB, Terry JG, Carr JJ, Rinella M, Schreiner PJ, Lewis CE, Terrault N, Coronary Artery Risk Development in Young Adults (CARDIA) Cohort
(2019) Am J Gastroenterol 114: 758-763
MeSH Terms: Adult, Biomarkers, Humans, Intra-Abdominal Fat, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Prevalence, Prospective Studies, Radiography, Abdominal, Risk Factors, Sex Hormone-Binding Globulin, Testosterone, Tomography, X-Ray Computed, United States
Show Abstract · Added April 3, 2019
INTRODUCTION - Cross-sectional data note lower levels of testosterone and sex hormone-binding globulin (SHBG) levels in men with nonalcoholic fatty liver disease (NAFLD). Whether sex hormone levels in young men are predictive of later risk of NAFLD is not known.
METHODS - Among men in the prospective population-based multicenter Coronary Artery Risk Development in Young Adults study (mean age 50; n = 837), we assessed whether testosterone and SHBG levels measured at study year 10 (median age 35 years) were associated with prevalent NAFLD at study year 25. NAFLD was defined using noncontrast abdominal computed tomography (CT) scan after excluding other causes of hepatic steatosis. The association of testosterone and SHBG with prevalent NAFLD was assessed by logistic regression.
RESULTS - Total testosterone levels in young men were inversely associated with subsequent prevalent NAFLD on unadjusted analysis (odds ratio [OR] 0.64, 95% confidence interval 0.53-0.7, P < 0.001), although no longer significant after adjustment for year 10 metabolic covariates as well as change in metabolic covariates from years 10 to 25 (OR 0.99, 95% confidence interval 0.76-1.27). In contrast, there was a significant inverse association of SHBG with prevalent NAFLD, independent of testosterone and metabolic covariates (OR 0.68, OR 0.51-0.92, P = 0.013). On formal mediation testing, visceral adiposity was found to explain ∼41.0% (95% confidence interval 27%-73%) of the association of lower SHBG with prevalent NAFLD.
CONCLUSIONS - Lower levels of SHBG in young men are associated with increase in prevalent NAFLD in middle age, independent of comprehensive metabolic risk factors. SHBG may provide a novel marker of NAFLD risk in young men.
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15 MeSH Terms
Hypogonadism as a Reversible Cause of Torsades de Pointes in Men.
Salem JE, Waintraub X, Courtillot C, Shaffer CM, Gandjbakhch E, Maupain C, Moslehi JJ, Badilini F, Haroche J, Gougis P, Fressart V, Glazer AM, Hidden-Lucet F, Touraine P, Lebrun-Vignes B, Roden DM, Bachelot A, Funck-Brentano C
(2018) Circulation 138: 110-113
MeSH Terms: Adverse Drug Reaction Reporting Systems, Aged, Aged, 80 and over, Androgen Antagonists, Biomarkers, Cross-Sectional Studies, Databases, Factual, Electronic Health Records, Heart Rate, Hormone Replacement Therapy, Humans, Hypogonadism, Male, Middle Aged, Paris, Pharmacovigilance, Prospective Studies, Risk Assessment, Risk Factors, Testosterone, Torsades de Pointes
Added October 1, 2018
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21 MeSH Terms
Androgen excess in pancreatic β cells and neurons predisposes female mice to type 2 diabetes.
Navarro G, Allard C, Morford JJ, Xu W, Liu S, Molinas AJ, Butcher SM, Fine NH, Blandino-Rosano M, Sure VN, Yu S, Zhang R, Münzberg H, Jacobson DA, Katakam PV, Hodson DJ, Bernal-Mizrachi E, Zsombok A, Mauvais-Jarvis F
(2018) JCI Insight 3:
MeSH Terms: Androgens, Animals, Diabetes Mellitus, Type 2, Diet, Western, Dihydrotestosterone, Female, Glucose, Humans, Hyperinsulinism, Hypothalamus, Insulin Resistance, Insulin-Secreting Cells, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Neurons, Receptors, Androgen, Streptozocin
Show Abstract · Added June 28, 2018
Androgen excess predisposes women to type 2 diabetes (T2D), but the mechanism of this is poorly understood. We report that female mice fed a Western diet and exposed to chronic androgen excess using dihydrotestosterone (DHT) exhibit hyperinsulinemia and insulin resistance associated with secondary pancreatic β cell failure, leading to hyperglycemia. These abnormalities are not observed in mice lacking the androgen receptor (AR) in β cells and partially in neurons of the mediobasal hypothalamus (MBH) as well as in mice lacking AR selectively in neurons. Accordingly, i.c.v. infusion of DHT produces hyperinsulinemia and insulin resistance in female WT mice. We observe that acute DHT produces insulin hypersecretion in response to glucose in cultured female mouse and human pancreatic islets in an AR-dependent manner via a cAMP- and mTOR-dependent pathway. Acute DHT exposure increases mitochondrial respiration and oxygen consumption in female cultured islets. As a result, chronic DHT exposure in vivo promotes islet oxidative damage and susceptibility to additional stress induced by streptozotocin via AR in β cells. This study suggests that excess androgen predisposes female mice to T2D following AR activation in neurons, producing peripheral insulin resistance, and in pancreatic β cells, promoting insulin hypersecretion, oxidative injury, and secondary β cell failure.
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19 MeSH Terms
Bone corticalization requires local SOCS3 activity and is promoted by androgen action via interleukin-6.
Cho DC, Brennan HJ, Johnson RW, Poulton IJ, Gooi JH, Tonkin BA, McGregor NE, Walker EC, Handelsman DJ, Martin TJ, Sims NA
(2017) Nat Commun 8: 806
MeSH Terms: Androgens, Animals, Cancellous Bone, Chondrocytes, Dihydrotestosterone, Estradiol, Female, Interleukin-6, Male, Mice, Inbred C57BL, Osteogenesis, Ovariectomy, Suppressor of Cytokine Signaling 3 Protein
Show Abstract · Added March 26, 2019
Long bone strength is determined by its outer shell (cortical bone), which forms by coalescence of thin trabeculae at the metaphysis (corticalization), but the factors that control this process are unknown. Here we show that SOCS3-dependent cytokine expression regulates bone corticalization. Young male and female Dmp1Cre.Socs3 mice, in which SOCS3 has been ablated in osteocytes, have high trabecular bone volume and poorly defined metaphyseal cortices. After puberty, male mice recover, but female corticalization is still impaired, leading to a lasting defect in bone strength. The phenotype depends on sex-steroid hormones: dihydrotestosterone treatment of gonadectomized female Dmp1Cre.Socs3 mice restores normal cortical morphology, whereas in males, estradiol treatment, or IL-6 deletion, recapitulates the female phenotype. This suggests that androgen action promotes metaphyseal corticalization, at least in part, via IL-6 signaling.The strength of long bones is determined by coalescence of trabeculae during corticalization. Here the authors show that this process is regulated by SOCS3 via a mechanism dependent on IL-6 and expression of sex hormones.
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Testosterone Levels in Pre-Menopausal Women are Associated With Nonalcoholic Fatty Liver Disease in Midlife.
Sarkar M, Wellons M, Cedars MI, VanWagner L, Gunderson EP, Ajmera V, Torchen L, Siscovick D, Carr JJ, Terry JG, Rinella M, Lewis CE, Terrault N
(2017) Am J Gastroenterol 112: 755-762
MeSH Terms: Adult, Body Mass Index, Diabetes Mellitus, Follow-Up Studies, Humans, Insulin Resistance, Intra-Abdominal Fat, Lipoproteins, HDL, Middle Aged, Multidetector Computed Tomography, Non-alcoholic Fatty Liver Disease, Premenopause, Prevalence, Risk Factors, Testosterone, Triglycerides, Waist Circumference, Young Adult
Show Abstract · Added September 11, 2017
OBJECTIVES - Young women with hyperandrogenism have high risk of metabolic co-morbidities, including increased risk of nonalcoholic fatty liver disease (NAFLD). Whether testosterone (the predominant androgen) is associated with NAFLD independent of metabolic co-factors is unclear. Additionally, whether testosterone confers increased risk of NAFLD in women without hyperandrogenism is unknown.
METHODS - Among women in the prospective population-based multicenter Coronary Artery Risk Development in Young Adults (CARDIA) study, we assessed whether free testosterone levels measured at Year 2 (1987-1988) were associated with prevalent NAFLD at Year 25 (2010-2011) (n=1052). NAFLD was defined using noncontrast abdominal CT scan with liver attenuation≤40 Hounsfield units after excluding other causes of hepatic fat. The association of free testosterone with prevalent NAFLD was assessed by logistic regression.
RESULTS - Increasing quintiles of free testosterone were associated with prevalent NAFLD at Year 25 (adjusted odds ratio (AOR) 1.25, 95% confidence interval (CI) 1.04-1.50, P=0.015), independent of insulin resistance, body mass index, waist circumference, and serum lipids. Importantly, the association persisted among n=955 women without androgen excess (AOR 1.27, 95% CI 1.05-1.53, P=0.016). Visceral adipose tissue (VAT) volume partially mediated the association of free testosterone with NAFLD (mediating effect 41.0%, 95% CI 22-119%).
CONCLUSIONS - Increasing free testosterone is associated with prevalent NAFLD in middle age, even in women without androgen excess. Visceral adiposity appears to play an important role in the relationship between testosterone and NAFLD in women. Testosterone may provide a potential novel target for NAFLD therapeutics, and future studies in pre-menopausal women should consider the importance of testosterone as a risk factor for NAFLD.
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18 MeSH Terms
NF-κB and androgen receptor variant 7 induce expression of SRD5A isoforms and confer 5ARI resistance.
Austin DC, Strand DW, Love HL, Franco OE, Grabowska MM, Miller NL, Hameed O, Clark PE, Matusik RJ, Jin RJ, Hayward SW
(2016) Prostate 76: 1004-18
MeSH Terms: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase, 5-alpha Reductase Inhibitors, Animals, Apoptosis, Drug Resistance, Gene Expression, Gene Knockdown Techniques, Humans, Isoenzymes, Lower Urinary Tract Symptoms, Male, Membrane Proteins, Mice, Mice, Nude, NF-kappa B, Orchiectomy, Prostate, Prostatic Hyperplasia, Prostatic Neoplasms, Castration-Resistant, Receptors, Androgen, Testosterone, Treatment Failure, Up-Regulation
Show Abstract · Added April 18, 2017
BACKGROUND - Benign prostatic hyperplasia (BPH) is treated with 5α-reductase inhibitors (5ARI). These drugs inhibit the conversion of testosterone to dihydrotestosterone resulting in apoptosis and prostate shrinkage. Most patients initially respond to 5ARIs; however, failure is common especially in inflamed prostates, and often results in surgery. This communication examines a link between activation of NF-κB and increased expression of SRD5A2 as a potential mechanism by which patients fail 5ARI therapy.
METHODS - Tissue was collected from "Surgical" patients, treated specifically for lower urinary tract symptoms secondary to advanced BPH; and, cancer free transition zone from "Incidental" patients treated for low grade, localized peripheral zone prostate cancer. Clinical, molecular and histopathological profiles were analyzed. Human prostatic stromal and epithelial cell lines were genetically modified to regulate NF-κB activity, androgen receptor (AR) full length (AR-FL), and AR variant 7 (AR-V7) expression.
RESULTS - SRD5A2 is upregulated in advanced BPH. SRD5A2 was significantly associated with prostate volume determined by Transrectal Ultrasound (TRUS), and with more severe lower urinary tract symptoms (LUTS) determined by American Urological Association Symptom Score (AUASS). Synthesis of androgens was seen in cells in which NF-κB was activated. AR-FL and AR-V7 expression increased SRD5A2 expression while forced activation of NF-κB increased all three SRD5A isoforms. Knockdown of SRD5A2 in the epithelial cells resulted in significant reduction in proliferation, AR target gene expression, and response to testosterone (T). In tissue recombinants, canonical NF-κB activation in prostatic epithelium elevated all three SRD5A isoforms and resulted in in vivo growth under castrated conditions.
CONCLUSION - Increased BPH severity in patients correlates with SRD5A2 expression. We demonstrate that NF-κB and AR-V7 upregulate SRD5A expression providing a mechanism to explain failure of 5ARI therapy in BPH patients. Prostate 76:1004-1018, 2016. © 2016 Wiley Periodicals, Inc.
© 2016 Wiley Periodicals, Inc.
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Extranuclear Actions of the Androgen Receptor Enhance Glucose-Stimulated Insulin Secretion in the Male.
Navarro G, Xu W, Jacobson DA, Wicksteed B, Allard C, Zhang G, De Gendt K, Kim SH, Wu H, Zhang H, Verhoeven G, Katzenellenbogen JA, Mauvais-Jarvis F
(2016) Cell Metab 23: 837-51
MeSH Terms: Animals, Cell Line, Tumor, Cell Nucleus, Cyclic AMP, Glucose, Glucose Intolerance, Humans, Insulin, Insulin-Secreting Cells, Male, Mice, Knockout, Models, Biological, Receptors, Androgen, Signal Transduction, Testosterone
Show Abstract · Added November 13, 2017
Although men with testosterone deficiency are at increased risk for type 2 diabetes (T2D), previous studies have ignored the role of testosterone and the androgen receptor (AR) in pancreatic β cells. We show that male mice lacking AR in β cells (βARKO) exhibit decreased glucose-stimulated insulin secretion (GSIS), leading to glucose intolerance. The AR agonist dihydrotestosterone (DHT) enhances GSIS in cultured male islets, an effect that is abolished in βARKO(-/y) islets and human islets treated with an AR antagonist. In β cells, DHT-activated AR is predominantly extranuclear and enhances GSIS by increasing islet cAMP and activating the protein kinase A. In mouse and human islets, the insulinotropic effect of DHT depends on activation of the glucagon-like peptide-1 (GLP-1) receptor, and accordingly, DHT amplifies the incretin effect of GLP-1. This study identifies AR as a novel receptor that enhances β cell function, a finding with implications for the prevention of T2D in aging men.
Copyright © 2016 Elsevier Inc. All rights reserved.
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Prepubertal Di-n-Butyl Phthalate Exposure Alters Sertoli and Leydig Cell Function and Lowers Bone Density in Adult Male Mice.
Bielanowicz A, Johnson RW, Goh H, Moody SC, Poulton IJ, Croce N, Loveland KL, Hedger MP, Sims NA, Itman C
(2016) Endocrinology 157: 2595-603
MeSH Terms: Absorptiometry, Photon, Animals, Bone Density, Dibutyl Phthalate, Femur, Leydig Cells, Luteinizing Hormone, Male, Mice, Plasticizers, Sertoli Cells, Testis, Testosterone, X-Ray Microtomography
Show Abstract · Added March 26, 2019
Phthalate exposure impairs testis development and function; however, whether phthalates affect nonreproductive functions is not well understood. To investigate this, C57BL/6J mice were fed 1-500 mg di-n-butyl phthalate (DBP) in corn oil, or vehicle only, daily from 4 to 14 days, after which tissues were collected (prepubertal study). Another group was fed 1-500 mg/kg·d DBP from 4 to 21 days and then maintained untreated until 8 weeks for determination of adult consequences of prepubertal exposure. Bones were assessed by microcomputed tomography and dual-energy X-ray absorptiometry and T by RIA. DBP exposure decreased prepubertal femur length, marrow volume, and mean moment of inertia. Adult animals exposed prepubertally to low DBP doses had lower bone mineral content and bone mineral density and less lean tissue mass than vehicle-treated animals. Altered dynamics of the emerging Leydig population were found in 14-day-old animals fed 100-500 mg/kg·d DBP. Adult mice had variable testicular T and serum T and LH concentrations after prepubertal exposure and a dose-dependent reduction in cytochrome p450, family 11, subfamily A, polypeptide 1. Insulin-like 3 was detected in Sertoli cells of adult mice administered the highest dose of 500 mg/kg·d DBP prepubertally, a finding supported by the induction of insulin-like 3 expression in TM4 cells exposed to 50 μM, but not 5 μM, DBP. We propose that low-dose DBP exposure is detrimental to bone but that normal bone mineral density/bone mineral content after high-dose DBP exposure reflects changes in testicular somatic cells that confer protection to bones. These findings will fuel concerns that low-dose DBP exposure impacts health beyond the reproductive axis.
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Diet-induced obesity in male C57BL/6 mice decreases fertility as a consequence of disrupted blood-testis barrier.
Fan Y, Liu Y, Xue K, Gu G, Fan W, Xu Y, Ding Z
(2015) PLoS One 10: e0120775
MeSH Terms: Animals, Blood-Testis Barrier, Body Weight, Clathrin, Diet, High-Fat, Estradiol, Female, Fertility, Lipids, Male, Mice, Mice, Inbred C57BL, Models, Animal, Obesity, Occludin, Receptors, Androgen, Sertoli Cells, Sperm Motility, Spermatozoa, Testis, Testosterone, Zonula Occludens-1 Protein
Show Abstract · Added December 4, 2020
Obesity is a complex metabolic disease that is a serious detriment to both children and adult health, which induces a variety of diseases, such as cardiovascular disease, type II diabetes, hypertension and cancer. Although adverse effects of obesity on female reproduction or oocyte development have been well recognized, its harmfulness to male fertility is still unclear because of reported conflicting results. The aim of this study was to determine whether diet-induced obesity impairs male fertility and furthermore to uncover its underlying mechanisms. Thus, male C57BL/6 mice fed a high-fat diet (HFD) for 10 weeks served as a model of diet-induced obesity. The results clearly show that the percentage of sperm motility and progressive motility significantly decreased, whereas the proportion of teratozoospermia dramatically increased in HFD mice compared to those in normal diet fed controls. Besides, the sperm acrosome reaction fell accompanied by a decline in testosterone level and an increase in estradiol level in the HFD group. This alteration of sperm function parameters strongly indicated that the fertility of HFD mice was indeed impaired, which was also validated by a low pregnancy rate in their mated normal female. Moreover, testicular morphological analyses revealed that seminiferous epithelia were severely atrophic, and cell adhesions between spermatogenic cells and Sertoli cells were loosely arranged in HFD mice. Meanwhile, the integrity of the blood-testis barrier was severely interrupted consistent with declines in the tight junction related proteins, occludin, ZO-1 and androgen receptor, but instead endocytic vesicle-associated protein, clathrin rose. Taken together, obesity can impair male fertility through declines in the sperm function parameters, sex hormone level, whereas during spermatogenesis damage to the blood-testis barrier (BTB) integrity may be one of the crucial underlying factors accounting for this change.
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