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OXER1 mediates testosterone-induced calcium responses in prostate cancer cells.
Panagiotopoulos, AA, Kalyvianaki, K, Serifoglou, B, Konstantinou, E, Notas, G, Castanas, E, Kampa, M
Molecular and cellular endocrinology. 2022;:111487
Abstract
In prostate cancer, calcium homeostasis plays a significant role in the disease's development and progression. Intracellular calcium changes are an important secondary signal, triggered by a variety of extracellular stimuli, that controls many cellular functions. One of the main events affecting calcium is androgen signaling. Indeed, via calcium changes, androgens regulate cell processes like cell growth, differentiation and motility. In the present work we explored the nature of the receptor involved in calcium response induced by membrane-acting testosterone in prostate cancer cells. We report that testosterone, independently of the presence of the classical androgen receptor, can rapidly increase intracellular calcium from calcium stores, through the oxoeicosanoid receptor 1 (OXER1) and a specific signaling cascade that triggers calcium release from the endoplasmic reticulum. These findings reveal for the first time the receptor involved in the rapid calcium changes induced by androgens. Moreover, they further support the notion that androgens, even in the absence of AR, can still exert specific effects that regulate cancer cell fate.
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Differences in sex hormone recovery profile after cessation of 12-week gonadotropin-releasing hormone antagonist versus agonist therapy.
Sasaki, H, Miki, K, Tashiro, K, Mori, K, Urabe, F, Fukuokaya, W, Kimura, T, Sato, S, Takahashi, H, Aoki, M, et al
Andrology. 2022;(2):270-278
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BACKGROUND Pharmacobiological behavior differs between gonadotropin-releasing hormone (GnRH) antagonists and GnRH agonists. However, reliable evidence clarifying the difference between them is limited. OBJECTIVES We aimed to elucidate the difference in recovery profile between GnRH antagonist (degarelix) and GnRH agonist (leuprorelin acetate or goserelin acetate) as short-term (12 weeks) neoadjuvant androgen deprivation therapy (ADT) prior to 125I-transperineal prostate brachytherapy (TPPB) for localized prostate cancer. MATERIALS AND METHODS This study was initially designed as a single-center, prospective, open-label, randomized controlled trial. The primary endpoint was a serum testosterone level above the castration range (>50 ng/dl) after the cessation of 12-week neoadjuvant ADT (GnRH antagonist or GnRH agonists). All patients underwent 12 weeks of neoadjuvant ADT. The recovery profiles of hormones, prostate-specific antigen, total prostate volume (TPV), bone mineral density, and quality of life scores were investigated. RESULTS Testosterone recovery duration after the last injection was significantly longer in the GnRH antagonist arm than in the GnRH agonist arm (median, 27.3 vs. 4.8 weeks, p < 0.001). The serum levels of luteinizing hormone and follicle-stimulating hormone in the GnRH antagonist arm also remained significantly lower than those in the GnRH agonist arm between 16 and 24 weeks (p < 0.01). Meanwhile, reduction in TPV at the time of TPPB was comparable between both arms (p = 0.128). There were also no significant between-arm differences in the International Prostate Symptom Score and the International Index of Erectile Function scores. DISCUSSION AND CONCLUSION The recovery patterns of hormonal profiles after short-term (12 weeks) neoadjuvant ADT differ between GnRH antagonists and GnRH agonists. The choice between these drugs matters and may have a clinical impact depending on the primary objective of ADT.
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Serum Testosterone is Inversely and Sex Hormone-binding Globulin is Directly Associated with All-cause Mortality in Men.
Yeap, BB, Marriott, RJ, Antonio, L, Chan, YX, Raj, S, Dwivedi, G, Reid, CM, Anawalt, BD, Bhasin, S, Dobs, AS, et al
The Journal of clinical endocrinology and metabolism. 2021;(2):e625-e637
Abstract
CONTEXT Serum testosterone concentrations decline with age, while serum sex hormone-binding globulin (SHBG) concentrations increase. OBJECTIVE To analyze associations of baseline serum testosterone and SHBG concentrations, and calculated free testosterone (cFT) values, with all-cause and cause-specific mortality in men. DESIGN, SETTING, AND PARTICIPANTS The UK Biobank prospective cohort study of community-dwelling men aged 40-69 years old, followed for 11 years. MAIN OUTCOME MEASURES All-cause, atherosclerotic cardiovascular disease (CVD) and cancer-related mortality. Cox proportional hazards regression was performed, adjusting for age, waist circumference, medical conditions, and other covariates. Models for testosterone included SHBG and vice versa. RESULTS In a complete case analysis of 149 436 men with 10 053 deaths (1925 CVD and 4927 cancer-related), men with lower testosterone had a higher mortality rate from any cause (lowest vs highest quintile, Q1 vs Q5, fully-adjusted hazard ratio [HR] = 1.14, 95% confidence interval [CI] = 1.06-1.22, overall trend P < 0.001), and cancer (HR = 1.20, CI = 1.09-1.33, P < 0.001), with no association for CVD deaths. Similar results were seen for cFT. Men with lower SHBG had a lower mortality rate from any cause (Q1 vs Q5, HR = 0.68, CI = 0.63-0.73, P < 0.001), CVD (HR = 0.70, CI = 0.59-0.83, P < 0.001), and cancer (HR = 0.80, CI = 0.72-0.89, P < 0.001). A multiply imputed dataset (N = 208 425, 15 914 deaths, 3128 CVD-related and 7468 cancer-related) and analysis excluding deaths within the first 2 years (9261, 1734, and 4534 events) yielded similar results. CONCLUSIONS Lower serum testosterone is independently associated with higher all-cause and cancer-related, but not CVD-related, mortality in middle-aged to older men. Lower SHBG is independently associated with lower all-cause, CVD-related, and cancer-related mortality. Confirmation and determination of causality requires mechanistic studies and prospective trials.
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Clamping Cortisol and Testosterone Mitigates the Development of Insulin Resistance during Sleep Restriction in Men.
Liu, PY, Lawrence-Sidebottom, D, Piotrowska, K, Zhang, W, Iranmanesh, A, Auchus, RJ, Veldhuis, JD, Van Dongen, HPA
The Journal of clinical endocrinology and metabolism. 2021;(9):e3436-e3448
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CONTEXT Sleep loss in men increases cortisol and decreases testosterone, and sleep restriction by 3 to 4 hours/night induces insulin resistance. OBJECTIVE We clamped cortisol and testosterone and determined the effect on insulin resistance. METHODS This was a randomized double-blind, in-laboratory crossover study in which 34 healthy young men underwent 4 nights of sleep restriction of 4 hours/night under 2 treatment conditions in random order: dual hormone clamp (cortisol and testosterone fixed), or matching placebo (cortisol and testosterone not fixed). Fasting blood samples, and an additional 23 samples for a 3-hour oral glucose tolerance test (OGTT), were collected before and after sleep restriction under both treatment conditions. Cytokines and hormones were measured from the fasting samples. Overall insulin sensitivity was determined from the OGTT by combining complementary measures: homeostasis model assessment of insulin resistance of the fasting state; Matsuda index of the absorptive state; and minimal model of both fasting and absorptive states. RESULTS Sleep restriction alone induced hyperinsulinemia, hyperglycemia, and overall insulin resistance (P < 0.001 for each). Clamping cortisol and testosterone alleviated the development of overall insulin resistance (P = 0.046) and hyperinsulinemia (P = 0.014) by 50%. Interleukin-6, high-sensitivity C-reactive protein, peptide YY, and ghrelin did not change, whereas tumor necrosis factor-α and leptin changed in directions that would have mitigated insulin resistance with sleep restriction alone. CONCLUSION Fixing cortisol-testosterone exposure mitigates the development of insulin resistance and hyperinsulinemia, but not hyperglycemia, from sustained sleep restriction in men. The interplay between cortisol and testosterone may be important as a mechanism by which sleep restriction impairs metabolic health.
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Testosterone Replacement Therapy Added to Intensive Lifestyle Intervention in Older Men With Obesity and Hypogonadism.
Barnouin, Y, Armamento-Villareal, R, Celli, A, Jiang, B, Paudyal, A, Nambi, V, Bryant, MS, Marcelli, M, Garcia, JM, Qualls, C, et al
The Journal of clinical endocrinology and metabolism. 2021;(3):e1096-e1110
Abstract
BACKGROUND Obesity and hypogonadism additively contribute to frailty in older men; however, appropriate treatment remains controversial. OBJECTIVE Determine whether testosterone replacement augments the effect of lifestyle therapy on physical function in older men with obesity and hypogonadism. DESIGN Randomized, double-blind, placebo-controlled trial. SETTING VA Medical Center. PARTICIPANTS 83 older (age ≥65 years) men with obesity (body mass index ≥30 kg/m2) and persistently low am testosterone (<10.4 nmol/L) associated with frailty. INTERVENTIONS Participants were randomized to lifestyle therapy (weight management and exercise training) plus either testosterone (LT+Test) or placebo (LT+Pbo) for 6 months. OUTCOME MEASURES Primary outcome was change in Physical Performance Test (PPT) score. Secondary outcomes included other frailty measures, body composition, hip bone mineral density (BMD), physical functions, hematocrit, prostate specific antigen (PSA), and sex hormones. RESULTS PPT score increased similarly in LT+Test and LT+Pbo group (17% vs. 16%; P = 0.58). VO2peak increased more in LT+Test than LT+Pbo (23% vs. 16%; P = 0.03). Despite similar -9% weight loss, lean body mass and thigh muscle volume decreased less in LT+Test than LT+Pbo (-2% vs. -3%; P = 0.01 and -2% vs -4%; P = 0.04). Hip BMD was preserved in LT+Test compared with LT+Pbo (0.5% vs -1.1%; P = 0.003). Strength increased similarly in LT+Test and LT+Pbo (23% vs 22%; P = 0.94). Hematocrit but not PSA increased more in LT+Test than LT+Pbo (5% vs 1%; P < 0.001). Testosterone levels increased more in LT+Test than LT+Pbo (167% vs 27%; P < 0.001). CONCLUSION In older, obese hypogonadal men, adding testosterone for 6 months to lifestyle therapy does not further improve overall physical function. However, our findings suggest that testosterone may attenuate the weight loss-induced reduction in muscle mass and hip BMD and may further improve aerobic capacity.
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Effect of atorvastatin on testosterone levels.
Shawish, MI, Bagheri, B, Musini, VM, Adams, SP, Wright, JM
The Cochrane database of systematic reviews. 2021;(1):CD013211
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Abstract
BACKGROUND Statins are one of the most prescribed classes of drugs worldwide. Atorvastatin, the most prescribed statin, is currently used to treat conditions such as hypercholesterolaemia and dyslipidaemia. By reducing the level of cholesterol, which is the precursor of the steroidogenesis pathway, atorvastatin may cause a reduction in levels of testosterone and other androgens. Testosterone and other androgens play important roles in biological functions. A potential reduction in androgen levels, caused by atorvastatin might cause negative effects in most settings. In contrast, in the setting of polycystic ovary syndrome (PCOS), reducing excessive levels of androgens with atorvastatin could be beneficial. OBJECTIVES Primary objective To quantify the magnitude of the effect of atorvastatin on total testosterone in both males and females, compared to placebo or no treatment. Secondary objectives To quantify the magnitude of the effects of atorvastatin on free testosterone, sex hormone binding globin (SHBG), androstenedione, dehydroepiandrosterone sulphate (DHEAS) concentrations, free androgen index (FAI), and withdrawal due to adverse effects (WDAEs) in both males and females, compared to placebo or no treatment. SEARCH METHODS The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials (RCTs) up to 9 November 2020: the Cochrane Hypertension Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; ;two international trials registries, and the websites of the US Food and Drug Administration, the European Patent Office and the Pfizer pharmaceutical corporation. These searches had no language restrictions. We also contacted authors of relevant articles regarding further published and unpublished work. SELECTION CRITERIA RCTs of daily atorvastatin for at least three weeks, compared with placebo or no treatment, and assessing change in testosterone levels in males or females. DATA COLLECTION AND ANALYSIS Two review authors independently screened the citations, extracted the data and assessed the risk of bias of the included studies. We used the mean difference (MD) with associated 95% confidence intervals (CI) to report the effect size of continuous outcomes,and the risk ratio (RR) to report effect sizes of the sole dichotomous outcome (WDAEs). We used a fixed-effect meta-analytic model to combine effect estimates across studies, and risk ratio to report effect size of the dichotomous outcomes. We used GRADE to assess the certainty of the evidence. MAIN RESULTS We included six RCTs involving 265 participants who completed the study and their data was reported. Participants in two of the studies were male with normal lipid profile or mild dyslipidaemia (N = 140); the mean age of participants was 68 years. Participants in four of the studies were female with PCOS (N = 125); the mean age of participants was 32 years. We found no significant difference in testosterone levels in males between atorvastatin and placebo, MD -0.20 nmol/L (95% CI -0.77 to 0.37). In females, atorvastatin may reduce total testosterone by -0.27 nmol/L (95% CI -0.50 to -0.04), FAI by -2.59 nmol/L (95% CI -3.62 to -1.57), androstenedione by -1.37 nmol/L (95% CI -2.26 to -0.49), and DHEAS by -0.63 μmol/l (95% CI -1.12 to -0.15). Furthermore, compared to placebo, atorvastatin increased SHBG concentrations in females by 3.11 nmol/L (95% CI 0.23 to 5.99). We identified no studies in healthy females (i.e. females with normal testosterone levels) or children (under age 18). Importantly, no study reported on free testosterone levels. AUTHORS' CONCLUSIONS We found no significant difference between atorvastatin and placebo on the levels of total testosterone in males. In females with PCOS, atorvastatin lowered the total testosterone, FAI, androstenedione, and DHEAS. The certainty of evidence ranged from low to very low for both comparisons. More RCTs studying the effect of atorvastatin on testosterone are needed.
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Low testosterone levels and high estradiol to testosterone ratio are associated with hyperinflammatory state and mortality in hospitalized men with COVID-19.
Infante, M, Pieri, M, Lupisella, S, D'Amore, L, Bernardini, S, Fabbri, A, Iannetta, M, Andreoni, M, Morello, M
European review for medical and pharmacological sciences. 2021;(19):5889-5903
Abstract
OBJECTIVE Evidence supports a sex disparity in clinical outcomes of COVID-19 patients, with men exhibiting higher mortality rates compared to women. We aimed to test the correlation between serum levels of sex hormones [total testosterone, estradiol (E2), estradiol to testosterone (E2/T) ratio, progesterone), prolactin and 25-hydroxyvitamin D [25(OH)D] and markers of inflammation, coagulation and sepsis at admission in hospitalized men with COVID-19. PATIENTS AND METHODS We conducted an exploratory retrospective study including symptomatic men with confirmed SARS-CoV-2 infection who were consecutively admitted to our Institution between April 1 and May 31, 2020. RESULTS Patients were divided into survivors (n=20) and non-survivors (n=39). As compared to survivors, non-survivors showed significantly higher median neutrophil-to-lymphocyte ratio (NLR) values, D-dimer and procalcitonin (PCT) levels, along with significantly lower median 25(OH)D levels and total testosterone levels. Non-survivors exhibited significantly higher median values of E2/T ratio (a marker of aromatase activity). Spearman's correlation analysis revealed that total testosterone levels were significantly and inversely correlated with NLR, high-sensitivity C-reactive protein (hsCRP), interleukin-6, D-dimer and PCT. Conversely, E2/T ratio values were significantly and positively correlated with the aforementioned markers and with white blood cell (WBC) count. In a multivariate analysis performed by a logistic regression model after adjusting for major confounders (age, body mass index, hypertension and cardiovascular disease, diabetes mellitus and malignancy), total testosterone levels were significantly and inversely associated with risk of COVID-19-related in-hospital mortality. CONCLUSIONS Low total testosterone levels and elevated E2/T ratio values at admission are associated with hyperinflammatory state in hospitalized men with COVID-19. Low total testosterone levels at admission represent an independent risk factor for in-hospital mortality in such patients. Therefore, total testosterone and E2/T ratio may serve as prognostic markers of disease severity in this population.
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Testosterone, sex hormone-binding globulin, insulin-like growth factor-1 and endometrial cancer risk: observational and Mendelian randomization analyses.
Mullee, A, Dimou, N, Allen, N, O'Mara, T, Gunter, MJ, Murphy, N
British journal of cancer. 2021;(9):1308-1317
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BACKGROUND Dysregulation of endocrine pathways related to steroid and growth hormones may modify endometrial cancer risk; however, prospective data on testosterone, sex hormone-binding globulin (SHBG) and insulin-like growth factor (IGF)-1 are limited. To elucidate the role of these hormones in endometrial cancer risk we conducted complementary observational and Mendelian randomization (MR) analyses. METHODS The observational analyses included 159,702 women (80% postmenopausal) enrolled in the UK Biobank. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. For MR analyses, genetic variants associated with hormone levels were identified and their association with endometrial cancer (12,906 cases/108,979 controls) was examined using two-sample MR. RESULTS In the observational analysis, higher circulating concentrations of total (HR per unit inverse normal scale = 1.38, 95% CI = 1.22-1.57) and free testosterone (HR per unit log scale = 2.07, 95% CI = 1.66-2.58) were associated with higher endometrial cancer risk. An inverse association was found for SHBG (HR per unit inverse normal scale = 0.76, 95% CI = 0.67-0.86). Results for testosterone and SHBG were supported by the MR analyses. No association was found between genetically predicted IGF-1 concentration and endometrial cancer risk. CONCLUSIONS Our results support probable causal associations between circulating concentrations of testosterone and SHBG with endometrial cancer risk.
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Efficacy of testosterone replacement therapy for treating metabolic disturbances in late-onset hypogonadism: a systematic review and meta-analysis.
Kim, SH, Park, JJ, Kim, KH, Yang, HJ, Kim, DS, Lee, CH, Jeon, YS, Shim, SR, Kim, JH
International urology and nephrology. 2021;(9):1733-1746
Abstract
PURPOSE Late onset hypogonadism (LOH) is an age-dependent reduction of testosterone associated with alterations of metabolic profile, including glucose control, insulin sensitivity, and lipid profile. The purpose of this study was to investigate the efficacy of testosterone replacement therapy (TRT) for treating metabolic disturbances through a meta-analysis of randomized clinical trials (RCTs). METHODS A systematic review of literature published from 1964 to November, 2019 was performed using the PubMed/Medline, Embase, and Cochrane databases. Among the 1562 articles screened, 17 articles were selected for qualitative analysis and 16 articles (n = 1373) were included for data synthesis following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). Criteria for final inclusion were RCTs. RESULTS Sixteen studies were finally included (TRT group, n = 709; placebo group, n = 664). Among the metabolic markers, HbA1C [Mean difference (MD) = - 0.172, 95% CI - 0.329, - 0.015], HOMA IR (MD = - 0.514, 95% CI - 0.863, - 0.165), serum insulin (MD = - 12.622, 95% CI - 19.660, - 5.585), and leptin (MD = - 2.381, 95% CI - 2.952, - 1.810) showed significant improvement after TRT versus placebo. Among the lipid profiles, total cholesterol showed significant improvement (MD = - 0.433, 95% CI - 0.761, - 0.105) after TRT. However, HDL showed a decrease (MD = - 0.069, 95% CI - 0.121, - 0.018) after TRT. Among anthropometric markers, waist circumference showed significant improvement (MD = - 0.1640, 95% CI - 2.857, - 0.423). CONCLUSION This study demonstrated greater improvement in metabolic profiles for patients given TRT versus placebo. Further well-designed trials are needed to verify our findings and further elucidate effects of TRT on lipid profiles. This systematic review demonstrates that TRT can exert a net beneficial effect on metabolic profiles.
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Effects of calorie restricted low carbohydrate high fat ketogenic vs. non-ketogenic diet on strength, body-composition, hormonal and lipid profile in trained middle-aged men.
Vidić, V, Ilić, V, Toskić, L, Janković, N, Ugarković, D
Clinical nutrition (Edinburgh, Scotland). 2021;(4):1495-1502
Abstract
BACKGROUND & AIMS The aim of this paper was to investigate and compare the effects of two iso-energetic hypo-caloric ketogenic hyper-ketonemic and non-ketogenic low carbohydrate high fat high cholesterol diets on body-composition, muscle strength and hormonal profile in experienced resistance-trained middle-aged men. METHODS Twenty non-competitive experienced resistance-trained middle-aged men were on the supervised calorie maintenance western diet and resistance-training regimen for 4 weeks and then divided into ketogenic and non-ketogenic groups for 8 weeks period. Keto bodies (β-hydroxybutyrate) levels were measured weekly, testosterone and insulin biweekly, strength and body-composition monthly, lipid profile and blood sugar level at the beginning and at the end of the study. RESULTS Both groups lost a similar amount of lean body mass and fat tissue (from F = 248.665, p < 0.001 to F = 21.943, p = 0.001), but preserved maximal upper and lower body strength (from F = 1.772, p = 0.238 to F = 0.595, p = 0.577). Basal testosterone and free testosterone increased (from F = 37.267, p = 0.001 to F = 16.261, p = 0.005) and insulin levels decreased significantly in both groups (F = 27.609, p = 0.001; F = 54.256, p < 0.001, respectively). No differences in lipid profile and blood sugar level were found (from F = 4.174, p = 0.058, to F = 0.065, p = 0.802). CONCLUSIONS Ketogenic diet with sustained hyper-ketonemia above 1 mol/l has the same impact as low carbohydrate non-ketogenic diet on muscle strength, body-composition, and hormonal and lipid profile in hypo-caloric dietary conditions in strength-trained middle-aged men.