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Liu J, Chin-Yee B, Ho J, Lazo-Langner A, Chin-Yee IH, Iansavitchene A, Hsia CC. Diagnosis, management, and outcomes of drug-induced erythrocytosis: a systematic review. Blood Adv 2025; 9:2108-2118. [PMID: 39913688 PMCID: PMC12051125 DOI: 10.1182/bloodadvances.2024015410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 01/23/2025] [Indexed: 04/25/2025] Open
Abstract
ABSTRACT Secondary erythrocytosis refers to an elevation in hemoglobin or hematocrit due to elevated serum erythropoietin levels. Medications including testosterone and sodium-glucose cotransporter-2 (SGLT-2) inhibitors are increasingly recognized as causes of secondary erythrocytosis. We conducted a systematic review to inform the clinical management of drug-induced erythrocytosis. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we performed a systematic literature search in MEDLINE, EMBASE, CENTRAL (all via Ovid), and Google Scholar. Of the 2036 articles screened for eligibility, 45 studies were included in our review, with 35 studies on testosterone and other androgen use, 5 studies on SGLT-2 inhibitors, 3 studies on antiangiogenic tyrosine kinase inhibitors (TKIs), 1 study on erythropoiesis-stimulating agents, and 1 study on a treatment regimen for multidrug-resistant tuberculosis. Cisgender and transgender men on prescription testosterone had erythrocytosis rates of up to 66.7%, with intramuscular formulations, higher doses, and older age associated with increased risk of erythrocytosis. Up to 2.7% of men on testosterone therapy developed thromboembolic events. Among individuals on SGLT-2 inhibitors, erythrocytosis rates ranged from 2.1% to 22%, with those who discontinued therapy demonstrating improvement or resolution of erythrocytosis. Thromboembolic events were reported in up to 10% of these individuals. Antiangiogenic TKIs were studied in patients with cancer, with erythrocytosis developing in up to 43.5% of patients. Drug-induced erythrocytosis is a heterogeneous condition for which there is no clear consensus among clinicians about its diagnosis and management. We offer recommendations for clinical practice within the scope of this systematic review, although further research is required.
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Affiliation(s)
- Jessica Liu
- Department of Medicine, London Health Sciences Centre, London, ON, Canada
- Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Benjamin Chin-Yee
- Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Division of Hematology, Department of Medicine, London Health Sciences Centre, London, ON, Canada
- Department of History and Philosophy of Science, University of Cambridge, Cambridge, United Kingdom
| | - Jenny Ho
- Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Division of Hematology, Department of Medicine, London Health Sciences Centre, London, ON, Canada
| | - Alejandro Lazo-Langner
- Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Division of Hematology, Department of Medicine, London Health Sciences Centre, London, ON, Canada
| | - Ian H. Chin-Yee
- Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Division of Hematology, Department of Medicine, London Health Sciences Centre, London, ON, Canada
| | - Alla Iansavitchene
- Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Health Science Library, London Health Sciences Centre, London, ON, Canada
| | - Cyrus C. Hsia
- Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Division of Hematology, Department of Medicine, London Health Sciences Centre, London, ON, Canada
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Fink J, Bentzen K, Horie S. Management of hematocrit levels for testosterone replacement patients, a narrative review. Sex Med Rev 2025; 13:229-236. [PMID: 40126900 DOI: 10.1093/sxmrev/qeaf013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 02/01/2025] [Accepted: 02/27/2025] [Indexed: 03/26/2025]
Abstract
INTRODUCTION Testosterone replacement therapy is gaining more and more popularity among hypogonadal men. The positive effects on body composition, metabolic functions, and mental well-being can improve the quality of life of many men. However, testosterone can also trigger several side effects, including increases in hematocrit and hemoglobin levels. Exogenous testosterone tends to increase erythropoiesis. The testosterone-induced increase in red blood cells can increase performance via improved transport of oxygen to the body. However, red blood cell overproduction can cause blood clots and severe sequelae such as heart attack, stroke, or pulmonary embolism. These side effects need to be closely monitored in testosterone replacement therapy (TRT) patients. Traditionally, cessation of TRT was recommended for patients with severe polycythemia. However, cessation of TRT can lead to the recurrence of symptoms experienced before TRT. Fortunately, recent innovations in testosterone preparations allow a treatment with less side effects on hematocrit levels. OBJECTIVES This review focuses on highlighting novel methods to treat hypogonadism while minimizing side effects related to hematocrit levels. METHODS We identified relevant articles using PubMed and Google Scholar searching for specific terms from 2000-2024. RESULTS Elevations in hematocrit levels triggered by testosterone therapy seem to be controversial, some studies advocate noninferior effects as compared to placebo while others found adverse side effects on cardiovascular health. However, the way of administration of testosterone seems to strongly influence the extent of hematocrit increases and can therefore be minimized by choosing the right testosterone preparation. CONCLUSION Depending on the route of administration, testosterone replacement therapy can lead to significant increases in hematocrit and potential cardiovascular incidents. On the other hand, for hypogonadal patients with anemia, testosterone replacement therapy might be beneficial not only for restoring healthy testosterone levels but also red blood cells.
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Affiliation(s)
- Julius Fink
- Department of Urology, Juntendo University, Graduate School of Medicine, Tokyo 113 8421, Japan
- Department of Kinesiology, Occidental College, Los Angeles, CA 90041, United States
| | - Kirk Bentzen
- Department of Kinesiology, Occidental College, Los Angeles, CA 90041, United States
| | - Shigeo Horie
- Department of Urology, Juntendo University, Graduate School of Medicine, Tokyo 113 8421, Japan
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Windfeld-Mathiasen J, Heerfordt IM, Dalhoff KP, Andersen JT, Andersen MA, Johansson KS, Biering-Sørensen T, Olsen FJ, Horwitz H. Cardiovascular Disease in Anabolic Androgenic Steroid Users. Circulation 2025; 151:828-834. [PMID: 39945117 DOI: 10.1161/circulationaha.124.071117] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 01/13/2025] [Indexed: 03/26/2025]
Abstract
BACKGROUND Use of anabolic androgenic steroids (AASs) is associated with increased mortality, and case reports have suggested that some of these deaths are due to cardiovascular disease. However, the epidemiology of cardiovascular disease in AAS users is still relatively unexplored. This study aimed to measure the incidence of cardiovascular disease in male AAS users and to compare these rates with those of a cohort from the general population matched by age and sex. METHODS Men sanctioned in an antidoping program for AAS use in Danish fitness centers between 2006 and 2018 were included and matched for age and sex with 50 times as many controls from the general Danish population. The cohort was followed until June 30, 2023. Using the nationwide registries, we obtained information on admissions, prescriptions, educational length, and occupational status for both the AAS users and controls. This study investigated the incidence of acute myocardial infarction, percutaneous coronary intervention, or coronary artery bypass graft, venous thromboembolism, ischemic stroke, arrhythmia, cardiomyopathy, heart failure, and cardiac arrest during the follow-up period. RESULTS During an average of 11 years of follow-up, AAS users (n=1189) demonstrated a significantly higher incidence of several cardiovascular events compared with controls (n=59 450). Correspondingly, AASs were associated with an increased risk of acute myocardial infarction (adjusted hazard ratio [aHR] 3.00 [95% CI, 1.67-5.39]), percutaneous coronary intervention or coronary artery bypass graft (aHR 2.95 [95% CI, 1.68-5.18]), venous thromboembolism (aHR 2.42 [95% CI, 1.54-3.80]), arrhythmias (aHR 2.26 [95% CI, 1.53-3.32]), cardiomyopathy (aHR 8.90 [95% CI, 4.99-15.88]), and heart failure (aHR 3.63 [95% CI, 2.01-6.55]). Due to the limited number of ischemic stroke and cardiac arrest cases among AAS users, these outcomes were not reportable. CONCLUSIONS AAS use is associated with a substantially increased risk of cardiovascular disease in a large cohort with a long follow-up period.
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Affiliation(s)
- Josefine Windfeld-Mathiasen
- Department of Clinical Pharmacology, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark (J.W.-M., I.M.H., K.P.D., J.T.A., M.A.A., K.S.J., H.H.)
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark (J.W.-M., K.P.D., J.T.A., H.H.)
| | - Ida M Heerfordt
- Department of Clinical Pharmacology, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark (J.W.-M., I.M.H., K.P.D., J.T.A., M.A.A., K.S.J., H.H.)
| | - Kim Peder Dalhoff
- Department of Clinical Pharmacology, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark (J.W.-M., I.M.H., K.P.D., J.T.A., M.A.A., K.S.J., H.H.)
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark (J.W.-M., K.P.D., J.T.A., H.H.)
| | - Jon Trærup Andersen
- Department of Clinical Pharmacology, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark (J.W.-M., I.M.H., K.P.D., J.T.A., M.A.A., K.S.J., H.H.)
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark (J.W.-M., K.P.D., J.T.A., H.H.)
| | - Michael Asger Andersen
- Department of Clinical Pharmacology, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark (J.W.-M., I.M.H., K.P.D., J.T.A., M.A.A., K.S.J., H.H.)
| | - Karl Sebastian Johansson
- Department of Clinical Pharmacology, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark (J.W.-M., I.M.H., K.P.D., J.T.A., M.A.A., K.S.J., H.H.)
| | - Tor Biering-Sørensen
- Center for Translational Cardiology and Pragmatic Randomized Trials, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (T.B.S., F.J.O.)
- Cardiovascular Non-Invasive Imaging Research Laboratory, Department of Cardiology, Copenhagen University Hospital - Herlev and Gentofte, Denmark (T.B.S., F.J.O.)
- Steno Diabetes Center Copenhagen, Copenhagen, Denmark (T.B.S.)
- Department of Cardiology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark (T.B.S.)
| | - Flemming Javier Olsen
- Center for Translational Cardiology and Pragmatic Randomized Trials, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (T.B.S., F.J.O.)
- Cardiovascular Non-Invasive Imaging Research Laboratory, Department of Cardiology, Copenhagen University Hospital - Herlev and Gentofte, Denmark (T.B.S., F.J.O.)
| | - Henrik Horwitz
- Department of Clinical Pharmacology, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark (J.W.-M., I.M.H., K.P.D., J.T.A., M.A.A., K.S.J., H.H.)
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark (J.W.-M., K.P.D., J.T.A., H.H.)
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Lockie AWC, Grice P, Mathur R, Pearce I, Modgil V. Diagnosis and treatment of hypogonadism in men seeking to preserve fertility - what are the options? Int J Impot Res 2025; 37:109-113. [PMID: 38693209 DOI: 10.1038/s41443-024-00897-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 04/05/2024] [Accepted: 04/16/2024] [Indexed: 05/03/2024]
Abstract
Male hypogonadism is a clinical syndrome that results in low testosterone levels and frequently leads to infertility. The syndrome occurs due to disruption at one or more levels of the hypothalamic-pituitary-gonadal axis. Testosterone replacement therapy (TRT) is the most common treatment utilised for male hypogonadism. However, long-acting forms of TRT leads to infertility and so is inappropriate for patients wishing to conceive. For patients who wish to remain fertile, nasal TRT, clomiphene citrate, exogenous gonadotropins, gonadotropin releasing hormone and aromatase inhibitors have been used as alternative treatment options with different degrees of success. A review of the literature was performed to identify the safety and efficacy of alternative treatment options. Gonadotropin releasing hormone can successfully induce spermatogenesis but is impractical to administer. Likewise, aromatase inhibitors have limited use due to inducing osteopenia. Nasal TRT may be a good treatment option for these patients, but its efficacy has so far only been demonstrated in small sample sizes. However, clomiphene citrate and exogenous gonadotropins are safe, offer good symptom control and can successfully induce fertility in hypogonadism patients.
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Affiliation(s)
| | - Peter Grice
- Northampton General Hospital, Northampton, UK
| | - Raj Mathur
- Manchester Royal Infirmary, Manchester, UK
| | - Ian Pearce
- Manchester Royal Infirmary, Manchester, UK
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Virtanen N, Pesonen E, Saarela U, Hurskainen E, Arffman RK, Koivunen P, Piltonen T. Association of hemoglobin levels with metabolic traits in women with PCOS. Acta Obstet Gynecol Scand 2025; 104:357-367. [PMID: 39740096 PMCID: PMC11782057 DOI: 10.1111/aogs.15047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 12/14/2024] [Accepted: 12/18/2024] [Indexed: 01/02/2025]
Abstract
INTRODUCTION Within normal variation, higher hemoglobin (Hb) levels are associated with poorer metabolic profile in population cohorts, underlying the link between oxygen delivery and cell metabolism. Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women and is commonly accompanied by metabolic derangements. In this study we sought to investigate Hb levels, and their metabolic associations, in women with PCOS. MATERIAL AND METHODS We used data from Northern Finland Birth Cohort 1966 to evaluate Hb levels in women with or without PCOS at the ages of 31 and 46 years. Linear regression models were used to investigate associations between Hb levels and essential metabolic parameters in both groups. RESULTS Women with PCOS had higher Hb levels than controls at the age of 31 years but not at the age of 46 years. Hb levels were associated positively with most of the metabolic parameters tested (body mass index, waist circumference, fasting insulin, homeostatic model assessment-insulin resistance (HOMA-IR), blood pressure, inflammatory markers, and blood lipids), with stronger associations in women with PCOS than in non-PCOS controls. There were fewer associations at the age of 46 than at 31 years, and body mass index seemed to explain many, though not all, differences between the PCOS and non-PCOS groups. CONCLUSIONS Women with PCOS have higher Hb levels at the age of 31 years. In both women with and without PCOS, Hb levels associate with poorer metabolic profile.
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Affiliation(s)
- Nikke Virtanen
- Department of Obstetrics and Gynecology, Medical Research Centre, Research Unit of Clinical MedicineUniversity of Oulu, Oulu University HospitalOuluFinland
- Faculty of Biochemistry and Molecular MedicineUniversity of OuluOuluFinland
| | - Emilia Pesonen
- Department of Obstetrics and Gynecology, Medical Research Centre, Research Unit of Clinical MedicineUniversity of Oulu, Oulu University HospitalOuluFinland
| | - Ulla Saarela
- Department of Obstetrics and Gynecology, Medical Research Centre, Research Unit of Clinical MedicineUniversity of Oulu, Oulu University HospitalOuluFinland
| | - Elisa Hurskainen
- Department of Obstetrics and Gynecology, Medical Research Centre, Research Unit of Clinical MedicineUniversity of Oulu, Oulu University HospitalOuluFinland
| | - Riikka K. Arffman
- Department of Obstetrics and Gynecology, Medical Research Centre, Research Unit of Clinical MedicineUniversity of Oulu, Oulu University HospitalOuluFinland
| | - Peppi Koivunen
- Faculty of Biochemistry and Molecular MedicineUniversity of OuluOuluFinland
| | - Terhi Piltonen
- Department of Obstetrics and Gynecology, Medical Research Centre, Research Unit of Clinical MedicineUniversity of Oulu, Oulu University HospitalOuluFinland
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Neidhart A, von Wyl V, Käslin B, Henzen C, Fischli S. Prevalence and predictive factors of testosterone-induced erythrocytosis: a retrospective single center study. Front Endocrinol (Lausanne) 2025; 15:1496906. [PMID: 39882268 PMCID: PMC11774685 DOI: 10.3389/fendo.2024.1496906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Accepted: 12/26/2024] [Indexed: 01/31/2025] Open
Abstract
Aim This study analyzes the prevalence and predictive factors of testosterone-induced erythrocytosis (TIE) in patients receiving testosterone replacement therapy (TRT). Methods Retrospective single-center observational study. Results 247 patients were included; median age was 47.0 years (interquartile range (IQR) 32-60) and median follow-up years 2.9 (1.0-5.5). The most common indication for TRT was central hypogonadism (51%) followed by primary hypogonadism (26%). TRT was carried out with testosterone undecanoate (TU) n=194, testosterone enanthate (TE) n=18 and testosterone gel (n=35). Compared to baseline, hematocrit (HCT) values at last follow-up (LFU) increased significantly by +0.04 (95% confidence interval (CI) [0.027, 0.050], p=<0.0001) in all patients (n=92) and +0.06 (95%CI [0.031, 0.057], p<0.0001) in the TU group (n=71). 57% of the patients reached an HCT value>0.46, 23% >0.5 and 5%>0.54. 46% of the patients who have reached an HCT value >0.46 have had their highest HCT measurement within the first year of TRT application. Logistic regression analysis indicated that body mass index (BMI) was significantly associated with the development of an HCT ≥0.5 (p=0.013) and HCT ≥0.46 (p=0.008). There was an association between the baseline HCT measurement and the outcome of a HCT measurement ≥0.46 (p=0.025), patients with high starting values were more likely to develop TIE. Conclusions TIE appears to be frequent and does not only present within the first year of therapy which indicates a close follow-up of laboratory values within the first year followed by annual controls. Baseline BMI and baseline HCT measurement should be considered in risk stratification of TIE development.
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Affiliation(s)
- Anina Neidhart
- Department of Internal Medicine, Division of Endocrinology, Diabetes and Clinical Nutrition, Luzerner Kantonsspital, Lucerne, Switzerland
| | - Viktor von Wyl
- Institute for Implementation Science in Healthcare, University of Zurich, Zurich, Switzerland
- Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland
| | - Benno Käslin
- Control & Simulation Department, Faculty of Aerospace Engineering, Delft University of Technology, Delft, Netherlands
| | - Christoph Henzen
- Department of Internal Medicine, Division of Endocrinology, Diabetes and Clinical Nutrition, Luzerner Kantonsspital, Lucerne, Switzerland
| | - Stefan Fischli
- Department of Internal Medicine, Division of Endocrinology, Diabetes and Clinical Nutrition, Luzerner Kantonsspital, Lucerne, Switzerland
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McMartin MC, Savkovic S, Romano A, Lim S, Muir CA, Jayadev V, Conway AJ, Seccombe L, Handelsman DJ. Testosterone and Erythrocyte Lifespan. J Clin Endocrinol Metab 2024; 110:114-122. [PMID: 38912796 DOI: 10.1210/clinem/dgae434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 06/18/2024] [Accepted: 06/20/2024] [Indexed: 06/25/2024]
Abstract
CONTEXT Endogenous and exogenous androgens increase circulating erythrocytes and hemoglobin but their effects on erythrocyte lifespan is not known. OBJECTIVE To investigate androgen effects on immature and mature erythrocyte lifespan in humans and mice using novel nonradioactive minimally invasive methods. DESIGN Human erythrocyte lifespan was estimated using alveolar carbon monoxide concentration and blood hemoglobin in Levitt's formula in hypogonadal or transgender men before and up to 18 weeks after commencing testosterone (T) treatment. Erythrocyte lifespan was estimated in androgen receptor knockout and wild-type mice after T or DHT treatment of intact females or orchidectomized males using in vivo biotin labelling of erythrocyte surface epitopes for reticulocytes (Ter119+CD71+) and 2 markers of erythrocytes (CD45-, Ter119+CD71-) monitoring their blood disappearance rate by flow cytometry. RESULTS Before treatment, hypogonadal and transgender men had marked reduction in erythrocyte lifespan compared with controls. T treatment increased erythrocyte lifespan at 6 weeks but returned to pretreatment levels at 18 weeks, whereas serum T and blood hemoglobin were increased by T treatment remaining elevated at 18 weeks. In mice, T and DHT treatment had higher erythrocyte (but not reticulocyte) lifespan but neither orchidectomy nor androgen receptor inactivation significantly influenced erythrocyte or reticulocyte lifespan. CONCLUSION We conclude that hypogonadal men have reduced erythrocyte lifespan and acute androgen-induced increase in circulating erythrocyte lifespan may contribute to the well-known erythropoietic effects of androgens, but longer term effects require further investigation to determine how much they contribute to androgen-induced increases in circulating hemoglobin.
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Affiliation(s)
- Melissa C McMartin
- ANZAC Research Institute, University of Sydney, Concord Repatriation General Hospital, Concord Hospital, Sydney, NSW 2139, Australia
| | - Sasha Savkovic
- Andrology, Concord Repatriation General Hospital Concord Hospital, Sydney, NSW 2139, Australia
| | - Adelina Romano
- ANZAC Research Institute, University of Sydney, Concord Repatriation General Hospital, Concord Hospital, Sydney, NSW 2139, Australia
| | - Sarina Lim
- Andrology, Concord Repatriation General Hospital Concord Hospital, Sydney, NSW 2139, Australia
| | - Christopher A Muir
- Andrology, Concord Repatriation General Hospital Concord Hospital, Sydney, NSW 2139, Australia
| | - Veena Jayadev
- Andrology, Concord Repatriation General Hospital Concord Hospital, Sydney, NSW 2139, Australia
| | - Ann J Conway
- ANZAC Research Institute, University of Sydney, Concord Repatriation General Hospital, Concord Hospital, Sydney, NSW 2139, Australia
- Andrology, Concord Repatriation General Hospital Concord Hospital, Sydney, NSW 2139, Australia
| | - Leigh Seccombe
- Respiratory Medicine Department, Concord Repatriation General Hospital Concord Hospital, Sydney, NSW 2139, Australia
| | - David J Handelsman
- ANZAC Research Institute, University of Sydney, Concord Repatriation General Hospital, Concord Hospital, Sydney, NSW 2139, Australia
- Andrology, Concord Repatriation General Hospital Concord Hospital, Sydney, NSW 2139, Australia
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King H, Kelley TP, Shatzel JJ. Gender-affirming hormone therapy in the transgender patient: influence on thrombotic risk. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2024; 2024:652-663. [PMID: 39644058 DOI: 10.1182/hematology.2024000592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/09/2024]
Abstract
Research regarding the hematologic sequelae of estrogen and testosterone therapy for transgender people is an emerging area. While estrogen therapy has been widely studied in cisgender women, studies in transgender individuals are limited, revealing variable adverse effects influenced by the dose and formulation of estrogen used. Thrombotic risk factors in transgender and gender-diverse individuals are multifactorial, involving both modifiable and nonmodifiable factors. Management of venous thromboembolism (VTE) in individuals receiving gender-affirming estrogen entails standard anticoagulation therapy alongside shared decision-making regarding hormone continuation and risk factor modification. While data and guidance from cisgender women can offer a reference for managing thrombotic risk in transgender individuals on hormone therapy, fully applying these insights can be challenging. The benefits of gender-affirming hormone therapy include significantly reducing the risk of suicide and depression, highlighting the importance of a contemplative approach to the management of hormonal therapy after a VTE event. Although limited, the available data in the literature indicate a low thrombotic risk for transgender individuals undergoing gender-affirming testosterone therapy. However, polycythemia is a common adverse effect necessitating monitoring and, occasionally, adjustments to hormonal therapy. Additionally, iron deficiency may arise due to the physiological effects of testosterone or health care providers' use of phlebotomy, an aspect that remains unstudied in this population. In conclusion, while the set of clinical data is expanding, further research remains vital to refine management strategies and improve hematologic outcomes for transgender individuals undergoing gender-affirming hormone therapy.
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Affiliation(s)
- Hannah King
- Department of Internal Medicine, Oregon Health & Science University, Portland, OR
| | | | - Joseph J Shatzel
- Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR
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9
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Wittert G, Umapathysivam MM. Testosterone and the prevention of type 2 diabetes mellitus: therapeutic implications from recent trials. Curr Opin Endocrinol Diabetes Obes 2024; 31:243-248. [PMID: 39285839 DOI: 10.1097/med.0000000000000884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2024]
Abstract
PURPOSE OF REVIEW Type 2 diabetes (T2D) is increasing to epidemic proportions and frequently associated with obesity and a low serum testosterone concentration in men. This review valuates recent randomized controlled trials (RCTs) investigating the effect of testosterone treatment on glycemic control and T2D prevention. RECENT FINDINGS The 2-year Testosterone for the Prevention of Type 2 diabetes Trial (T4DM) study showed that in men aged 50 years and over with visceral obesity and impaired glucose tolerance, testosterone treatment on the background of a lifestyle intervention reduced T2D risk by 40%. The Testosterone Effects on Atherosclerosis Progression in Aging Men and Testosterone Trials demonstrated modest improvements in insulin sensitivity and body composition. However, the Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy Response in Hypogonadal Men trial found no significant glycemic benefits over 2 years. Recent data from the Diabetes Prevention Program Outcome Study support the cost efficacy and durability of metformin. SUMMARY In men at high risk of T2D, treatment with testosterone prevents the disease; however, there are caveats to its use and other approaches may be more applicable. Differences in trial designs, age groups, and outcome measures contribute to varying results. HbA1C is a suboptimal outcome measure. Future research should explore potential synergies between testosterone and GLP-1 receptor agonists in T2D management, while considering cost-effectiveness.
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Affiliation(s)
- Gary Wittert
- Freemasons Centre for Male Health and Wellbeing, South Australian Health and Medical Research Institute, University of Adelaide, Adelaide
| | - Mahesh M Umapathysivam
- Freemasons Centre for Male Health and Wellbeing, South Australian Health and Medical Research Institute, University of Adelaide, Adelaide
- Southern Adelaide Diabetes and Endocrine Service, Adelaide, South Australia, Australia
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Miller C, Madden-Doyle L, Jayasena C, McIlroy M, Sherlock M, O'Reilly MW. Mechanisms in endocrinology: hypogonadism and metabolic health in men-novel insights into pathophysiology. Eur J Endocrinol 2024; 191:R1-R17. [PMID: 39344641 DOI: 10.1093/ejendo/lvae128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 08/30/2024] [Accepted: 09/26/2024] [Indexed: 10/01/2024]
Abstract
Hypogonadism in men is associated with an adverse metabolic phenotype and increased mortality. Reciprocally, obesity and insulin resistance can suppress the hypothalamic-pituitary-gonadal axis in the absence of structural organic disease, further perpetuating a cycle of metabolic dysfunction and low testosterone. The mechanisms underpinning this bidirectional association are complex as hypogonadism is a heterogenous syndrome, and obesity is associated with metabolic perturbations in glucose and lipid metabolism even in the presence of normal testicular function. However, distinct molecular defects specific to testosterone deficiency have been identified in pathways relating to glucose and lipid metabolism in target metabolic depots such as adipose tissue and skeletal muscle. This review discusses the etiology and prevalence of metabolic disease in male hypogonadism, with a specific focus on both disease mechanisms and novel potential approaches to enhance our understanding.
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Affiliation(s)
- Clare Miller
- Academic Department of Endocrinology, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin, Ireland
- Department of Endocrinology, Beaumont Hospital, Dublin, Ireland
| | - Lauren Madden-Doyle
- Academic Department of Endocrinology, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin, Ireland
- Department of Endocrinology, Beaumont Hospital, Dublin, Ireland
| | - Channa Jayasena
- Department of Metabolism, Digestion and Reproduction, Imperial College, London, United Kingdom
| | - Marie McIlroy
- Academic Department of Endocrinology, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin, Ireland
| | - Mark Sherlock
- Academic Department of Endocrinology, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin, Ireland
- Department of Endocrinology, Beaumont Hospital, Dublin, Ireland
| | - Michael W O'Reilly
- Academic Department of Endocrinology, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin, Ireland
- Department of Endocrinology, Beaumont Hospital, Dublin, Ireland
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11
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Lanzi V, Indirli R, Tripodi A, Clerici M, Bonomi M, Cangiano B, Petria I, Arosio M, Mantovani G, Ferrante E. Testosterone Therapy Does Not Affect Coagulation in Male Hypogonadism: A Longitudinal Study Based on Thrombin Generation. J Clin Endocrinol Metab 2024; 109:3186-3195. [PMID: 38717871 PMCID: PMC11570389 DOI: 10.1210/clinem/dgae317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Indexed: 11/19/2024]
Abstract
CONTEXT Testosterone therapy has been variably associated with increased thrombotic risk but investigations of global coagulation in this setting are lacking. OBJECTIVE This work aimed to compare global coagulation of hypogonadal men before (T0) and 6 months after (T1) starting testosterone replacement therapy (TRT), and healthy controls (HCs). METHODS An observational prospective cohort study was conducted at 2 tertiary endocrinological ambulatory care centers. Patients included 38 men with hypogonadism (mean age 55 years, SD 13) and 38 age-matched HCs. Thrombin generation assay (TGA) was performed at T0 and T1 in hypogonadal men and in HCs. TGA is an in vitro procedure based on the continuous registration of thrombin generation and decay under conditions mimicking the process that occurs in vivo. The following TGA parameters were recorded: lag time; thrombin-peak concentration; time-to-reach peak, velocity index, and endogenous thrombin potential (ETP), the latter representing the total amount of thrombin generated under the driving forces of procoagulants opposed by the anticoagulants. Protein C, antithrombin, factor (F) VIII, and fibrinogen were assessed. RESULTS No changes in TGA parameters were observed between T0 and T1. Hypogonadal men displayed significantly higher ETP, fibrinogen, and significantly lower antithrombin levels both at T0 and T1 compared to HCs. Thrombin peak of hypogonadal men was significantly higher than HCs at T0 but not at T1. ETP and antithrombin were correlated with testosterone levels. CONCLUSION Hypogonadal men display a procoagulant imbalance detected by increased thrombin generation. Short-term TRT does not worsen global coagulation, suggesting that the treatment can be safely prescribed to men diagnosed with hypogonadism.
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Affiliation(s)
- Valeria Lanzi
- Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
| | - Rita Indirli
- Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
| | - Armando Tripodi
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Fondazione Luigi Villa, 20122 Milan, Italy
| | - Marigrazia Clerici
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Marco Bonomi
- Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, 20133 Milan, Italy
| | - Biagio Cangiano
- Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, 20133 Milan, Italy
| | - Iulia Petria
- Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
| | - Maura Arosio
- Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
| | - Giovanna Mantovani
- Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
| | - Emanuele Ferrante
- Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
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12
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De Silva NL, Papanikolaou N, Grossmann M, Antonio L, Quinton R, Anawalt BD, Jayasena CN. Male hypogonadism: pathogenesis, diagnosis, and management. Lancet Diabetes Endocrinol 2024; 12:761-774. [PMID: 39159641 DOI: 10.1016/s2213-8587(24)00199-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 07/09/2024] [Accepted: 07/09/2024] [Indexed: 08/21/2024]
Abstract
Organic male hypogonadism due to irreversible hypothalamic-pituitary-testicular (HPT) pathology is easily diagnosed and treated with testosterone-replacement therapy. However, controversy surrounds the global practice of prescribing testosterone to symptomatic men with low testosterone and non-gonadal factors reducing health status, such as obesity, type 2 diabetes, and ageing (ie, functional hypogonadism), but without identifiable HPT axis pathology. Health optimisation remains the gold-standard management strategy. Nevertheless, in the last decade large clinical trials and an individual patient data meta-analysis of smaller clinical trials confirmed that testosterone therapy induces modest, yet statistically significant, improvements in sexual function without increasing short-term to medium-term cardiovascular or prostate cancer risks in men with functional hypogonadism. Although testosterone improves bone mineral density and insulin sensitivity in these men, trials from the last decade suggest insufficient evidence to determine the safety and effectiveness of use of this hormone for the prevention of fractures or type 2 diabetes. This Review discusses the pathogenesis and diagnosis of male hypogonadism and appraises the evidence underpinning the management of this condition.
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Affiliation(s)
- Nipun Lakshitha De Silva
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK; Faculty of Medicine, General Sir John Kotelawala Defence University, Colombo, Sri Lanka
| | - Nikoleta Papanikolaou
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Mathis Grossmann
- Department of Medicine (Austin Health), The University of Melbourne, Melbourne, VIC, Australia; Department of Endocrinology, Austin Health, Heidelberg, VIC, Australia
| | - Leen Antonio
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium; Department of Endocrinology, University Hospitals Leuven, Leuven, Belgium
| | - Richard Quinton
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK; Northern Regional Gender Dysphoria Service, Cumbria Northumberland Tyne & Wear NHS Foundation Trust, Newcastle-upon-Tyne, UK
| | - Bradley David Anawalt
- Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
| | - Channa N Jayasena
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
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13
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Wu FCW, Lo K. Initiating male contraception methods. Andrology 2024; 12:1529-1534. [PMID: 39073522 DOI: 10.1111/andr.13694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 06/12/2024] [Accepted: 06/29/2024] [Indexed: 07/30/2024]
Abstract
Non-surgical (reversible) male contraception methods, when approved for general clinical application, should be made available to all interested men aged 18 50 years in good general health regardless of their semen parameters. In the preliminary workup, a complete personal and family history aimed at identifying specific conditions that may potentially increase the risks for adverse effects (associated with testosterone replacement) is advisable but a general or andrological examination is not required, unless indicated by the history. Baseline body weight, blood pressure and haemoglobin should be recorded for the purpose of future monitoring. While risks and benefits of vasectomy have been well established, appropriately nuanced patient counselling and assessment are essential for ensuring a satisfactory outcome of vasectomy.
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Affiliation(s)
- Frederick C W Wu
- Division of Endocrinology, Diabetes and Gastroenterology, Faculty of Biology, Medicine and Health, School of Medical Sciences, University of Manchester, Manchester, UK
| | - Kirk Lo
- Division of Urology, Department of Surgery, University of Toronto, Toronto, Canada
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14
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Bond P, Verdegaal T, Smit DL. Testosterone therapy-induced erythrocytosis: can phlebotomy be justified? Endocr Connect 2024; 13:e240283. [PMID: 39212549 PMCID: PMC11466264 DOI: 10.1530/ec-24-0283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 08/30/2024] [Indexed: 09/04/2024]
Abstract
Erythrocytosis, or elevated hematocrit, is a common side effect of testosterone therapy (TTh) in male hypogonadism. Testosterone stimulates erythropoiesis through an initial rise in erythropoietin (EPO), the establishment of a new EPO/hemoglobin 'set point', and a parallel decrease in the master iron regulator protein hepcidin, as well as several other potential mechanisms. Evidence shows an increased thrombotic risk associated with TTh-induced erythrocytosis. Several guidelines by endocrine organizations for the treatment of male hypogonadism recommend against starting TTh in patients presenting with elevated hematocrit at baseline or stopping TTh when its levels cannot be controlled. Besides dose adjustments, therapeutic phlebotomy or venesection is mentioned as a means of reducing hematocrit in these patients. However, evidence supporting the efficacy or safety of therapeutic phlebotomy in lowering hematocrit in TTh-induced erythrocytosis is lacking. In light of this dearth of evidence, the recommendation to lower hematocrit using therapeutic phlebotomy is notable, as phlebotomy lowers tissue oxygen partial pressure (pO2) and eventually depletes iron stores, thereby triggering various biological pathways which might increase thrombotic risk. The potential pros and cons should therefore be carefully weighed against each other, and shared decision-making is recommended for initiating therapeutic phlebotomy as a treatment in patients on TTh who present with increased hematocrit.
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Affiliation(s)
- Peter Bond
- Department of Internal Medicine, Elisabeth TweeSteden Hospital, Tilburg, the Netherlands
- Department of Performance and Image-enhancing Drugs Research, Android Health Clinic, Utrecht, the Netherlands
| | - Tijs Verdegaal
- Department of Internal Medicine, Elisabeth TweeSteden Hospital, Tilburg, the Netherlands
- Department of Internal Medicine, Spaarne Gasthuis, Haarlem, the Netherlands
| | - Diederik L Smit
- Department of Internal Medicine, Elisabeth TweeSteden Hospital, Tilburg, the Netherlands
- Department of Performance and Image-enhancing Drugs Research, Android Health Clinic, Utrecht, the Netherlands
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15
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de Silva NL, Grant B, Minhas S, Jayasena CN. Cardiovascular disease and testosterone therapy in male hypogonadism. Ann N Y Acad Sci 2024; 1540:121-132. [PMID: 39243393 DOI: 10.1111/nyas.15211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/09/2024]
Abstract
This review assesses the evidence of the physiological effects of testosterone on cardiovascular health, the association between male hypogonadism and cardiovascular health, and the effects of testosterone therapy on cardiovascular health in male hypogonadism. Preclinical studies suggest complex effects of testosterone on cardiovascular risk by acting on skeletal muscle, cardiomyocytes, vasculature, adipocytes, insulin action, and erythropoiesis. Furthermore, low testosterone has a bi-directional association with cardiometabolic risk. Observational studies have reported worse metabolic profiles in men with organic hypogonadism. However, a consistent association between major cardiovascular events and male hypogonadism has not been established. Hematocrit increases with testosterone therapy; however, most studies do not report an increase in venous thromboembolism risk. Although some observational studies and a small randomized controlled study reported an increased risk of cardiovascular disease, recent data confirm the medium-term cardiovascular safety of testosterone therapy in middle-aged and older men with low testosterone.
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Affiliation(s)
- Nipun Lakshitha de Silva
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- Faculty of Medicine, General Sir John Kotelawala Defence University, Colombo, Sri Lanka
| | - Bonnie Grant
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Suks Minhas
- Department of Urology, Imperial College Healthcare NHS Trust, London, UK
| | - Channa N Jayasena
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
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16
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Poopuangpairoj T, Sirisopana K, Ketsuwan C, Kongchareonsombat W, Phengsalae Y, Matang W, Sangkum P. Impact of Testosterone Therapy on Major Cardiovascular Risk in Erectile Dysfunction Patients with Testosterone Deficiency. Res Rep Urol 2024; 16:195-203. [PMID: 39310218 PMCID: PMC11416101 DOI: 10.2147/rru.s476804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 09/06/2024] [Indexed: 09/25/2024] Open
Abstract
Objective The objective of this study was to evaluate major adverse cardiovascular events in erectile dysfunction (ED) patients who received testosterone replacement therapy (TRT) compared with those who did not. Materials and Methods From January 2012 to October 2021, we collected the retrospective data of patients with ED at Ramathibodi Hospital. We divided the patients into two groups: those who received TRT (TRT group) and those with normal testosterone levels and therefore not requiring TRT (non-TRT group). The patients' baseline clinicodemographic data were collected. Major adverse cardiovascular events, including cardiovascular death, ST- and non-ST-elevation myocardial infarction, hospitalization from congestive heart failure, transient ischemic attack, and ischemic stroke, were collected and analyzed within 2 years after treatment in all groups. Results Of the 221 patients, 111 were in the TRT group and 110 were in the non-TRT group. In the non-TRT group, one event each of the following occurred: myocardial infarction, transient ischemic attack, and stroke. In the TRT group, no major cardiovascular event occurred during the 2-year follow-up period. However, no significant difference in major cardiovascular events was noted between the two groups (p = 0.314). Conclusion TRT in ED patients with testosterone deficiency does not increase adverse cardiovascular events when compared with ED patients with normal testosterone level.
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Affiliation(s)
- Tanawin Poopuangpairoj
- Division of Urology, Department of Surgery, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Kun Sirisopana
- Division of Urology, Department of Surgery, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Chinnakhet Ketsuwan
- Division of Urology, Department of Surgery, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Wisoot Kongchareonsombat
- Division of Urology, Department of Surgery, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Yada Phengsalae
- Division of Urology, Department of Surgery, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Wijittra Matang
- Division of Urology, Department of Surgery, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Premsant Sangkum
- Division of Urology, Department of Surgery, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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17
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Pan X, Köberle M, Ghashghaeinia M. Vitamin C-Dependent Uptake of Non-Heme Iron by Enterocytes, Its Impact on Erythropoiesis and Redox Capacity of Human Erythrocytes. Antioxidants (Basel) 2024; 13:968. [PMID: 39199214 PMCID: PMC11352176 DOI: 10.3390/antiox13080968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 08/06/2024] [Accepted: 08/07/2024] [Indexed: 09/01/2024] Open
Abstract
In the small intestine, nutrients from ingested food are absorbed and broken down by enterocytes, which constitute over 95% of the intestinal epithelium. Enterocytes demonstrate diet- and segment-dependent metabolic flexibility, enabling them to take up large amounts of glutamine and glucose to meet their energy needs and transfer these nutrients into the bloodstream. During glycolysis, ATP, lactate, and H+ ions are produced within the enterocytes. Based on extensive but incomplete glutamine oxidation large amounts of alanine or lactate are produced. Lactate, in turn, promotes hypoxia-inducible factor-1α (Hif-1α) activation and Hif-1α-dependent transcription of various proton channels and exchangers, which extrude cytoplasmic H+-ions into the intestinal lumen. In parallel, the vitamin C-dependent and duodenal cytochrome b-mediated conversion of ferric iron into ferrous iron progresses. Finally, the generated electrochemical gradient is utilized by the divalent metal transporter 1 for H+-coupled uptake of non-heme Fe2+-ions. Iron efflux from enterocytes, subsequent binding to the plasma protein transferrin, and systemic distribution supply a wide range of cells with iron, including erythroid precursors essential for erythropoiesis. In this review, we discuss the impact of vitamin C on the redox capacity of human erythrocytes and connect enterocyte function with iron metabolism, highlighting its effects on erythropoiesis.
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Affiliation(s)
- Xia Pan
- Physiological Institute, Department of Vegetative and Clinical Physiology, Eberhard Karls University of Tübingen, 72074 Tübingen, Germany
| | - Martin Köberle
- Department of Dermatology and Allergology, School of Medicine and Health, Technical University of Munich, Biedersteinerstr. 29, 80802 München, Germany
| | - Mehrdad Ghashghaeinia
- Physiological Institute, Department of Vegetative and Clinical Physiology, Eberhard Karls University of Tübingen, 72074 Tübingen, Germany
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18
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Talbot JS, Perkins DR, Dawkins TG, Lord RN, Oliver JL, Lloyd RS, McManus AM, Stembridge M, Pugh CJA. Flow-mediated dilation is modified by exercise training status during childhood and adolescence: preliminary evidence of the youth athlete's artery. Am J Physiol Heart Circ Physiol 2024; 327:H331-H339. [PMID: 38847760 DOI: 10.1152/ajpheart.00287.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 06/04/2024] [Accepted: 06/04/2024] [Indexed: 07/17/2024]
Abstract
Chronic exercise training is associated with an "athlete's artery" phenotype in young adults and an attenuated age-related decline in endothelium-dependent arterial function. Adolescence is associated with an influx of sex-specific hormones that may exert divergent effects on endothelial function, but whether training adaptations interact with biological maturation to produce a "youth athlete's artery" has not been explored. We investigated the influence of exercise-training status on endothelium-dependent arterial function during childhood and adolescence. Brachial artery flow-mediated dilation (FMD) was assessed in n = 102 exercise-trained (males, n = 25; females, n = 29) and untrained (males, n = 23; females, n = 25) youths, characterized as pre (males, n = 25; females, n = 26)- or post (males, n = 23; females, n = 28)-predicted age at peak height velocity (PHV). Baseline brachial artery diameter was larger in post- compared with pre-PHV youths (P ≤ 0.001), males compared with females (P ≤ 0.001), and trained compared with untrained youths (3.26 ± 0.51 vs. 3.11 ± 0.42 mm; P = 0.041). Brachial FMD was similar in pre- and post-PHV youths (P = 0.298), and males and females (P = 0.946). However, exercise-trained youths demonstrated higher FMD when compared with untrained counterparts (5.3 ± 3.3 vs. 3.0 ± 2.6%; P ≤ 0.001). Furthermore, brachial artery diameter (r2 = 0.142; P = 0.007 vs. r2 = 0.004; P = 0.652) and FMD (r2 = 0.138; P = 0.008 vs. r2 = 0.003; P = 0.706) were positively associated with cardiorespiratory fitness in post-, but not pre-PHV youths, respectively. Collectively, our data indicate that exercise training is associated with brachial artery remodeling and enhanced endothelial function during youth. However, arterial remodeling and endothelium-dependent function are only associated with elevated cardiorespiratory fitness during later stages of adolescence.NEW & NOTEWORTHY We report preliminary evidence of the "youth athlete's artery," characterized by training-related arterial remodeling and elevated endothelium-dependent arterial function in children and adolescents. However, training-related adaptations in brachial artery diameter and flow-mediated dilation (FMD) were associated with cardiorespiratory fitness in adolescents, but not in children. Our findings indicate that endothelium-dependent arterial function is modifiable with chronic exercise training during childhood, but the association between FMD and elevated cardiorespiratory fitness is only apparent during later stages of adolescence.
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Affiliation(s)
- Jack S Talbot
- Cardiff School of Sport and Health Sciences, Cardiff Metropolitan University, Cardiff, United Kingdom
- Centre for Health, Activity and Wellbeing Research, Cardiff Metropolitan University, Cardiff, United Kingdom
- Cardiometabolic Health and Exercise Physiology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Dean R Perkins
- Department of Sport Science, University of Innsbruck, Innsbruck, Austria
| | - Tony G Dawkins
- Centre for Heart, Lung and Vascular Health, School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, British Columbia, Canada
| | - Rachel N Lord
- Cardiff School of Sport and Health Sciences, Cardiff Metropolitan University, Cardiff, United Kingdom
- Centre for Health, Activity and Wellbeing Research, Cardiff Metropolitan University, Cardiff, United Kingdom
| | - Jon L Oliver
- Youth Physical Development Centre, Cardiff Metropolitan University, Cardiff, United Kingdom
- Sports Performance Research Institute New Zealand, AUT University, Auckland, New Zealand
| | - Rhodri S Lloyd
- Youth Physical Development Centre, Cardiff Metropolitan University, Cardiff, United Kingdom
- Sports Performance Research Institute New Zealand, AUT University, Auckland, New Zealand
- Centre for Sport Science and Human Performance, Waikato Institute of Technology, Waikato, New Zealand
| | - Ali M McManus
- Centre for Heart, Lung and Vascular Health, School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, British Columbia, Canada
| | - Mike Stembridge
- Cardiff School of Sport and Health Sciences, Cardiff Metropolitan University, Cardiff, United Kingdom
- Youth Physical Development Centre, Cardiff Metropolitan University, Cardiff, United Kingdom
| | - Christopher J A Pugh
- Cardiff School of Sport and Health Sciences, Cardiff Metropolitan University, Cardiff, United Kingdom
- Centre for Health, Activity and Wellbeing Research, Cardiff Metropolitan University, Cardiff, United Kingdom
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19
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Chitrakar A, Bean SWM, Kanias T, Thomas KA. Stored platelet hemostatic phenotype and function is not altered when donors are on testosterone replacement therapy. Transfusion 2024; 64:1520-1532. [PMID: 38994922 PMCID: PMC11326535 DOI: 10.1111/trf.17926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 04/22/2024] [Accepted: 06/02/2024] [Indexed: 07/13/2024]
Abstract
BACKGROUND Critical shortages in the national blood supply have led to a re-evaluation of previously overlooked donor sources for blood products. As a part of that effort, red blood cells collected from therapeutic phlebotomy of donors on testosterone replacement therapy (TRT) have been conditionally approved for transfusion. However, platelets from TRT donors are not currently approved for use due to limited data on effects of supraphysiologic testosterone on recipient safety and platelet function. The objective of this study was to provide a comprehensive profile of phenotype and function in platelets from TRT and control donors. STUDY DESIGN AND METHODS Platelets in plasma were collected from TRT and control donors (N = 10 per group; age- and sex-matched) and stored at room temperature for 7 days. On storage Day 1 (D1) and Day 7 (D7), platelet products were analyzed for platelet count, metabolic parameters (i.e., glucose, lactate, mitochondrial function), surface receptor expression, aggregation, thrombin generation, and thrombus formation under physiological flow conditions. RESULTS TRT donor platelets were not significantly different than control donor platelets in terms of count, surface phenotype, metabolic function, ability to aggregate, thrombin generation, or ability to form occlusive thrombus under arterial flow regimes. Both groups were similar to each other by D7, but had significantly lost hemostatic function compared to D1. DISCUSSION Platelets derived from donors undergoing TRT have similar phenotypic and functional profiles compared to those derived from control donors. This suggests that therapeutic phlebotomy of TRT donors may provide a useful source for platelet products.
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Affiliation(s)
| | | | - Tamir Kanias
- Vitalant Research Institute, Denver, Colorado, USA
- Department of Pathology, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA
| | - Kimberly A Thomas
- Vitalant Research Institute, Denver, Colorado, USA
- Department of Pathology, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA
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20
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Scala A, Graziani A, Vianello F, Ferlin A, Garolla A. Risk of erythrocytosis in transgender individuals undergoing testosterone therapy: a systematic review. Minerva Endocrinol (Torino) 2024; 49:205-216. [PMID: 39028210 DOI: 10.23736/s2724-6507.24.04171-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/20/2024]
Abstract
INTRODUCTION In transgender individuals assigned female at birth, testosterone therapy is employed for body masculinization. Guidelines recommend close monitoring for potential side effects of hormonal therapy, especially during the first year. Erythrocytosis is a common finding during testosterone therapy and has been associated with a potential risk of thrombotic and cardiovascular events. Currently, the hematologic effects of testosterone therapy are understudied, with existing data primarily derived from the cisgender male population. The aim of this study was to comprehensively examine the hematological changes induced by testosterone therapy in the transgender population. EVIDENCE ACQUISITION A systematic search was conducted using the electronic database PubMed. EVIDENCE SYNTHESIS Thirty-six manuscripts were retrieved. After screening for original studies, 19 articles were included. Selected articles were published between 2005 and 2023. CONCLUSIONS In our systematic review, the prevalence of erythrocytosis varied from 0% to 29.3%, with severe erythrocytosis ranging from 0.5% to 2.3%. Testosterone therapy was associated with an increase in hemoglobin and hematocrit, particularly within the first year of therapy. Factors such as serum testosterone levels, along with the duration, doses, and formulation of testosterone therapy, were found to be associated with the development of erythrocytosis. Further research is crucial to provide specific recommendations for clinical practice.
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Affiliation(s)
- Alberto Scala
- Department of Medicine, University of Padua, Padua, Italy
- Unit of Andrology and Reproductive Medicine, University Hospital of Padua, Padua, Italy
- Unit of Hematology, Department of Medicine, University of Padua, Padua, Italy
- Regional Reference Center for Gender Incongruence (CRRIG), Padua, Italy
| | - Andrea Graziani
- Department of Medicine, University of Padua, Padua, Italy
- Unit of Andrology and Reproductive Medicine, University Hospital of Padua, Padua, Italy
| | - Fabrizio Vianello
- Department of Medicine, University of Padua, Padua, Italy
- Unit of Hematology, Department of Medicine, University of Padua, Padua, Italy
- Regional Reference Center for Gender Incongruence (CRRIG), Padua, Italy
| | - Alberto Ferlin
- Department of Medicine, University of Padua, Padua, Italy
- Unit of Andrology and Reproductive Medicine, University Hospital of Padua, Padua, Italy
- Regional Reference Center for Gender Incongruence (CRRIG), Padua, Italy
| | - Andrea Garolla
- Department of Medicine, University of Padua, Padua, Italy -
- Unit of Andrology and Reproductive Medicine, University Hospital of Padua, Padua, Italy
- Regional Reference Center for Gender Incongruence (CRRIG), Padua, Italy
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21
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Krishnamurthy N, Slack DJ, Kyweluk M, Cullen O, Kirkley J, Safer JD. Erythrocytosis Is Rare With Exogenous Testosterone in Gender-Affirming Hormone Therapy. J Clin Endocrinol Metab 2024; 109:1285-1290. [PMID: 38011684 DOI: 10.1210/clinem/dgad651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Indexed: 11/29/2023]
Abstract
CONTEXT Studies have found a variable incidence of erythrocytosis among people using testosterone as part of gender-affirming hormone therapy (GAHT). OBJECTIVE To examine the effect of using exogenous testosterone as GAHT on hematocrit in a large North American cohort. METHODS We conducted a cross-sectional analysis of testosterone and hematocrit laboratory values in 6670 patients who were prescribed testosterone through Plume, a national provider of GAHT. The prevalence of erythrocytosis, the mean hematocrit at predetermined testosterone thresholds and with varying routes of testosterone administration were assessed. RESULTS Among 6670 individuals, 560 (8.4%) had a hematocrit ≥50%, 182 ≥ 52% (2.7%), and 60 ≥ 54% (0.9%). There was significant variation (P < .001) in hematocrit between different clinically relevant testosterone thresholds (T < 50 vs T 50-299 vs T 300-999 vs T ≥ 1000 ng/dL) and when comparing serum testosterone in increments of 50 ng/dL within the target range for males (300-1000 ng/dL) (P < .001). Mean hematocrit ranged from 41.84% (T < 50 ng/dL) to 45.68% (T 900-949 ng/dL). Patients on intramuscular testosterone had a higher mean hematocrit than those on transdermal testosterone (44.96% vs 43.41%, P < .001). Both route of administration (P < .001) and testosterone level (P < .001) had statistically significant associations with hematocrit when controlling for each other. CONCLUSION While the magnitude of change in hematocrit with serum level and route of administration of testosterone was statistically significant, the absolute levels were within the normal range, unlikely to be clinically meaningful. These findings, along with the low prevalence of erythrocytosis, should help allay concerns about the use of testosterone as GAHT.
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Affiliation(s)
| | - Daniel J Slack
- Division of Endocrinology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA
| | - Moira Kyweluk
- Clinical Research Division, Plume Health, Denver, CO 80209, USA
| | - Olivia Cullen
- Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA
| | - Jerrica Kirkley
- Clinical Research Division, Plume Health, Denver, CO 80209, USA
| | - Joshua D Safer
- Center for Transgender Medicine and Surgery, Mount Sinai Health System, New York, NY 10029-6574, USA
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22
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Green DJ, Chasland LC, Yeap BB, Naylor LH. Comparing the Impacts of Testosterone and Exercise on Lean Body Mass, Strength and Aerobic Fitness in Aging Men. SPORTS MEDICINE - OPEN 2024; 10:30. [PMID: 38563849 PMCID: PMC10987448 DOI: 10.1186/s40798-024-00703-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 03/20/2024] [Indexed: 04/04/2024]
Abstract
BACKGROUND Based on the largely untested premise that it is a restorative hormone that may reverse the detrimental impacts of aging, prescription of testosterone (T) has increased in recent decades despite no new clinical indications. It is apparent that middle-aged and older men with low-normal serum T levels are considering T supplementation as an anti-aging strategy. At the same time, there is evidence that physical activity (PA) is at historical lows in the Western world. In this review, we compare the impacts of T treatment aimed at achieving physiological T concentrations in middle-aged and older men, alongside the impacts of ecologically relevant forms of exercise training. The independent, and possible combined, effects of T and exercise therapy on physiological outcomes such as aerobic fitness, body composition and muscular strength are addressed. MAIN BODY Our findings suggest that both T treatment and exercise improve lean body mass in healthy older men. If improvement in lean body mass is the primary aim, then T treatment could be considered, and the combination of T and exercise may be more beneficial than either in isolation. In terms of muscle strength in older age, an exercise program is likely to be more beneficial than T treatment (where the dose is aimed at achieving physiological concentrations), and the addition of such T treatment does not provide further benefit beyond that of exercise alone. For aerobic fitness, T at doses aimed at achieving physiological concentrations has relatively modest impacts, particularly in comparison to exercise training, and there is limited evidence as to additive effects. Whilst higher doses of T, particularly by intramuscular injection, may have larger impacts on lean body mass and strength, this must be balanced against potential risks. CONCLUSION Knowing the impacts of T treatment and exercise on variables such as body composition, strength and aerobic fitness extends our understanding of the relative benefits of physiological and pharmacological interventions in aging men. Our review suggests that T has impacts on strength, body composition and aerobic fitness outcomes that are dependent upon dose, route of administration, and formulation. T treatment aimed at achieving physiological T concentrations in middle-aged and older men can improve lean body mass, whilst exercise training enhances lean body mass, aerobic fitness and strength. Men who are physically able to exercise safely should be encouraged to do so, not only in terms of building lean body mass, strength and aerobic fitness, but for the myriad health benefits that exercise training confers.
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Affiliation(s)
- Daniel J Green
- School of Human Sciences (Exercise and Sport Science), The University of Western Australia, Perth, WA, 6009, Australia.
| | - Lauren C Chasland
- School of Human Sciences (Exercise and Sport Science), The University of Western Australia, Perth, WA, 6009, Australia
- Allied Health Department, Fiona Stanley Hospital, Perth, WA, Australia
| | - Bu B Yeap
- Medical School, University of Western Australia, Perth, WA, Australia
- Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, WA, Australia
| | - Louise H Naylor
- School of Human Sciences (Exercise and Sport Science), The University of Western Australia, Perth, WA, 6009, Australia
- Allied Health Department, Fiona Stanley Hospital, Perth, WA, Australia
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23
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Schluessel S, Bidlingmaier M, Martini S, Reincke M, Reisch N, Schaupp A, Stalla G, Teupser D, Schmidmaier R, Drey M. Hypogonadism is frequent in very old men with multimorbidity and is associated with anemia and sarcopenia. Z Gerontol Geriatr 2024; 57:43-49. [PMID: 37674061 PMCID: PMC10827893 DOI: 10.1007/s00391-023-02235-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/07/2023] [Indexed: 09/08/2023]
Abstract
BACKGROUND Clinical data regarding hypogonadism in very old men with multimorbidity are rare. Hypogonadism can contribute to osteoporosis, anemia and sarcopenia and is therefore a relevant problem for geriatric patients. METHODS A total of 167 men aged 65-96 years (mean 81 ± 7 years) admitted to an acute geriatric ward were included in a cross-sectional study. Body composition derived from dual-energy X‑ray absorptiometry, bone mineral density, handgrip strength, multimorbidity, polypharmacy and laboratory values were obtained from the routine electronic clinical patient file. RESULTS Hypogonadism was present in 62% (n = 104) of the study participants, of whom 83% showed clinical manifestation of hypogonadism (hypogonadism in combination with anemia, sarcopenia and/or low T‑score). The subgroups showed a distribution of 52% primary and 48% secondary hypogonadism. Compared to the eugonadal patients, hypogonadal patients had reduced handgrip strength (p = 0.031) and lower hemoglobin levels (p = 0.043), even after adjustment for age, body mass index and glomerular filtration rate. CONCLUSION Hypogonadism is common in geriatric patients. If chronic anemia, sarcopenia, or osteoporosis are diagnosed, testosterone levels should be determined in geriatric settings.
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Affiliation(s)
- Sabine Schluessel
- Medizinische Klinik und Poliklinik IV, Department of Geriatrics, LMU Klinikum, Ludwig-Maximilians-Universität München, Munich, Germany.
- , Ziemssenstraße 5, 80336, Munich, Germany.
| | - Martin Bidlingmaier
- Medizinische Klinik und Poliklinik IV, Department of Endocrinology, LMU Klinikum, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Sebastian Martini
- Medizinische Klinik und Poliklinik IV, Department of Geriatrics, LMU Klinikum, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Martin Reincke
- Medizinische Klinik und Poliklinik IV, Department of Endocrinology, LMU Klinikum, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Nicole Reisch
- Medizinische Klinik und Poliklinik IV, Department of Endocrinology, LMU Klinikum, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Anna Schaupp
- Medizinische Klinik und Poliklinik IV, Department of Geriatrics, LMU Klinikum, Ludwig-Maximilians-Universität München, Munich, Germany
| | | | - Daniel Teupser
- Institute of Laboratory Medicine, LMU Klinikum, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Ralf Schmidmaier
- Medizinische Klinik und Poliklinik IV, Department of Endocrinology, LMU Klinikum, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Michael Drey
- Medizinische Klinik und Poliklinik IV, Department of Geriatrics, LMU Klinikum, Ludwig-Maximilians-Universität München, Munich, Germany
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24
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Nackeeran S, Ramasamy R. Re: Cardiovascular Safety of Testosterone-Replacement Therapy. Eur Urol 2024; 85:181. [PMID: 37802684 DOI: 10.1016/j.eururo.2023.09.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 09/11/2023] [Indexed: 10/08/2023]
Affiliation(s)
- Sirpi Nackeeran
- Department of Urology, University of California-San Diego, San Diego, CA, USA
| | - Ranjith Ramasamy
- Desai Sethi Urology Institute, University of Miami, Miami, FL, USA.
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25
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Płoszczyca K, Czuba M, Zakrzeska A, Gajda R. The Effects of Six-Gram D-Aspartic Acid Supplementation on the Testosterone, Cortisol, and Hematological Responses of Male Boxers Subjected to 11 Days of Nocturnal Exposure to Normobaric Hypoxia. Nutrients 2023; 16:76. [PMID: 38201906 PMCID: PMC10780457 DOI: 10.3390/nu16010076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 12/22/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
The aim of this study was to evaluate the effects of D-aspartic acid (DAA) supplementation during a simulated altitude protocol on the hormonal and hematological responses in athletes. We hypothesized that DAA supplementation would contribute to an increase in the luteinizing hormone (LH), free, and testosterone and a greater increase in hematological variables. Sixteen male boxers participated; they were randomly assigned to an experimental group (DAA) or a control group (C) and underwent 14 days of supplementation, 6 g/day of DAA. Both DAA and C participants were exposed to normobaric hypoxia (FiO2 = 15.5%; 2500 m) for 10-12 h a day over a period of 11 days. The results showed that DAA had no significant effect on resting, LH, or the testosterone/cortisol ratio during the training camp. Hypoxic exposure significantly (p < 0.05) increased red blood cell and reticulocyte counts as well as hemoglobin and hematocrit concentrations in both groups, but DAA had no significant effect on these changes. In conclusion, we found that DAA supplementation at a dose of 6 g/day for 14 days does not affect the testosterone, cortisol, or hematological responses of athletes during.
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Affiliation(s)
- Kamila Płoszczyca
- Department of Kinesiology, Institute of Sport, 01-982 Warsaw, Poland
| | - Miłosz Czuba
- Faculty of Rehabilitation, Józef Piłsudski University of Physical Education in Warsaw, Marymoncka 34, 00-968 Warsaw, Poland;
| | - Agnieszka Zakrzeska
- Department of Biotechnology, University of Medical Science in Bialystok, 15-875 Białystok, Poland (R.G.)
| | - Robert Gajda
- Department of Biotechnology, University of Medical Science in Bialystok, 15-875 Białystok, Poland (R.G.)
- Center for Sports Cardiology, Gajda-Med Medical Center, 06-100 Pultusk, Poland
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26
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Cheng K, Skolnick A. Testosterone Pellet Use in Transgender Men. Transgend Health 2023; 8:494-499. [PMID: 38130978 PMCID: PMC10732158 DOI: 10.1089/trgh.2021.0205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Purpose We assessed the efficacy and short-term adverse effects of testosterone pellet use in transgender men to broaden therapeutic options. Methods We conducted a retrospective study of 30 transgender men who started testosterone pellets between 2018 and 2020. Results Testosterone pellets were started at dosages 675-825 mg per cycle and dose was adjusted according to testosterone levels obtained 1 to 6 months post-testosterone pellet insertion. Pharmacokinetics of testosterone pellet in transgender men was similar to those in cisgender men. Total testosterone levels reached a peak in 1 month and remained in the therapeutic range for ∼4 months in the range of 300-800 ng/dL. After switching over to testosterone pellets, 100% of patients continued to achieve amenorrhea and deepening of their voice. Most of the patients noticed increased hair growth in androgen-dependent regions (96.3%) and improved libido (70%). Adverse events were notable for a rate of polycythemia that was unexpectedly high at 46.67%. Pellet extrusion was found in 13.33% of patients. There was a low rate of pellet site hematoma (6.67%) and cellulitis (3.33%). No thromboembolic or cardiovascular events occurred in any of the patients. Conclusion This study reveals that testosterone pellets are a reasonable alternative to other testosterone modalities in transgender men but would use caution in patients with a history of polycythemia or higher risk for thromboembolic events.
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Affiliation(s)
- Kwan Cheng
- Department of Endocrinology, Diabetes and Metabolism, Northwell Health, New Hyde Park, New York, USA
| | - Aren Skolnick
- Department of Endocrinology, Diabetes and Metabolism, Northwell Health, New Hyde Park, New York, USA
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27
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Pencina KM, Travison TG, Artz AS, Lincoff AM, Nissen SE, Flevaris P, Chan A, Li X, Diegel SA, Wannemuehler K, Bhasin S. Efficacy of Testosterone Replacement Therapy in Correcting Anemia in Men With Hypogonadism: A Randomized Clinical Trial. JAMA Netw Open 2023; 6:e2340030. [PMID: 37889486 PMCID: PMC10611996 DOI: 10.1001/jamanetworkopen.2023.40030] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Accepted: 09/08/2023] [Indexed: 10/28/2023] Open
Abstract
Importance Testosterone deficiency causes mild anemia. Whether testosterone replacement therapy (TRT) can correct anemia or prevent the development of anemia in men with hypogonadism remains incompletely understood. Objective To assess the efficacy of TRT in correcting anemia in men with hypogonadism and anemia, and reducing the risk of developing anemia in those without anemia. Design, Setting, and Participants This randomized, placebo-controlled trial included men with hypogonadism at 316 US sites enrolled between May 2018 and February 2022. This study was nested within the Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) Study, which evaluated the effect of TRT on major adverse cardiovascular events in middle-aged and older men with hypogonadism. Eligible participants were aged 45 to 80 years, with 2 testosterone concentration results below 300 ng/dL, hypogonadal symptoms, and cardiovascular disease (CVD) or increased CVD risk. The last study visit took place in January 2023. Data were analyzed between March and August 2023. Intervention Participants were randomized with stratification for preexisting CVD to 1.62% testosterone gel or placebo gel daily for the study duration. Main Outcomes and Measures Proportion of participants with anemia (hemoglobin below 12.7 g/dL) whose anemia remitted (hemoglobin 12.7 g/dL or above) over the study duration. Secondary end points included incidence of anemia among men who were not anemic. Binary end points were analyzed using repeated-measures log-binomial regression. Results A total of 5204 men were included, 815 with anemia (mean [SD] age, 64.8 [7.7] years; 247 Black [30.3%], 544 White [66.7%], 24 other [2.9%]) and 4379 without anemia (mean [SD] age, 63.0 [7.9] years; 629 Black [14.4%], 3603 White [82.3%], 147 other [3.4%]). Anemia corrected in a significantly greater proportion of testosterone-treated than placebo-treated men at 6 months (143 of 349 [41.0%] vs 103 of 375 [27.5%]), 12 months (152 of 338 [45.0%] vs 122 of 360 [33.9%]), 24 months (124 of 290 [42.8%] vs 95 of 307 [30.9%]), 36 months (94 of 216 [43.5%] vs 76 of 229 [33.2%]), and 48 months (41 of 92 [44.6%] vs 38 of 97 [39.2%]) (P = .002). Among participants without anemia, a significantly smaller proportion of testosterone-treated men developed anemia than placebo-treated men. Changes in hemoglobin were associated with changes in energy level. Conclusions and Relevance In middle-aged and older men with hypogonadism and anemia, TRT was more efficacious than placebo in correcting anemia. Among men who were not anemic, a smaller proportion of testosterone-treated men developed anemia than placebo-treated men. Trial Registration ClinicalTrials.gov Identifier: NCT03518034.
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Affiliation(s)
- Karol M. Pencina
- Research Program in Men’s Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Thomas G. Travison
- Marcus Institute for Aging Research, Hebrew Senior Life; Division of Gerontology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Andrew S. Artz
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, Duarte, California
| | - A. Michael Lincoff
- Cleveland Clinic Coordinating Center for Clinical Research (C5Research), Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
| | - Steven E. Nissen
- Cleveland Clinic Coordinating Center for Clinical Research (C5Research), Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
| | | | | | - Xue Li
- AbbVie Inc, North Chicago, Illinois
| | - Scott A. Diegel
- Department of Biostatistics and Medical Informatics, Statistical Data Analysis Center, University of Wisconsin, Madison
| | - Kathleen Wannemuehler
- Department of Biostatistics and Medical Informatics, Statistical Data Analysis Center, University of Wisconsin, Madison
| | - Shalender Bhasin
- Research Program in Men’s Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
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28
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Banyeh M, Kangkpi T, Bani SB, Zogli KE, Tanko MM, Atuahene PE, Iddrisu AY, Ekor C, Akoto EO, Amidu N. Are sex differences in blood cell count and hemoglobin moderated by the 2D:4D ratio? A cross-sectional study in a Ghanaian population. Health Sci Rep 2023; 6:e1547. [PMID: 37670848 PMCID: PMC10476464 DOI: 10.1002/hsr2.1547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 08/02/2023] [Accepted: 08/22/2023] [Indexed: 09/07/2023] Open
Abstract
Background and Aims There are sex differences in blood cell count and hemoglobin (HGB) in adulthood due to differences in the levels of circulating sex hormones. The second-to-fourth digit ratio (2D:4D) is the putative marker of prenatal hormone exposure. The 2D:4D or the right-left difference (Dr-l) are sexually dimorphic and are correlates of sex hormones in adulthood. The study sought to determine whether sex differences in adult blood cell count and HGB can be partly explained by the 2D:4D or Dr-l. Methods The study was cross-sectional between June and December 2021 at the University for Development Studies. The study involved 207 healthy participants (females = 113) aged from 18 to 32 years. The right-hand (2D:4DR), and the left-hand (2D:4DL) digit ratio and their difference (Dr-l) were measured using Computer-assisted analysis. Blood cell count, HGB, testosterone, and estradiol were measured from venous blood samples using an automated HGB analyzer and ELIZA technique. Results The platelet count was inversely related to the 2D:4DR in the total sample with the 2D:4DR accounting for about 0.2% (adjR 2 = 0.002) of the variability in platelet count. However, there was a sex difference as indicated by the significant interaction between sex and the 2D:4DR on platelet count (p = 0.03). The relationship between platelet count and the 2D:4DR was negative in females but positive in males. Also, there was a positive relationship between HGB concentration and the Dr-l in the total study sample, where the Dr-l accounted for about 0.6% (adjR 2 = 0.006) of the variability in HGB concentration. Sex interacted significantly with the Dr-l on HGB concentration (p = 0.01) such that the relationship between HGB and the Dr-l was positive in females but negative in males. Conclusion Prenatal hormone exposure, as indexed by the 2D:4D ratio, may partly account for the observed sex differences in platelet count and HGB levels in adulthood.
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Affiliation(s)
- Moses Banyeh
- Department of Biomedical Laboratory ScienceUniversity for Development StudiesTamaleGhana
| | - Thea Kangkpi
- Department of Biomedical Laboratory ScienceUniversity for Development StudiesTamaleGhana
| | - Simon B. Bani
- Department of Biomedical Laboratory ScienceUniversity for Development StudiesTamaleGhana
| | - Kervin Edinam Zogli
- Department of Biomedical Laboratory ScienceUniversity for Development StudiesTamaleGhana
| | - Muniru Mohammed Tanko
- Department of Biomedical Laboratory ScienceUniversity for Development StudiesTamaleGhana
| | - Peter Eugene Atuahene
- Department of Biomedical Laboratory ScienceUniversity for Development StudiesTamaleGhana
| | - Aisha Yaaba Iddrisu
- Department of Biomedical Laboratory ScienceUniversity for Development StudiesTamaleGhana
| | - Christine Ekor
- Department of Biomedical Laboratory ScienceUniversity for Development StudiesTamaleGhana
| | - Emmanuel Osei Akoto
- Department of Biomedical Laboratory ScienceUniversity for Development StudiesTamaleGhana
| | - Nafiu Amidu
- Department of Biomedical Laboratory ScienceUniversity for Development StudiesTamaleGhana
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Corona G, Sparano C, Rastrelli G, Vignozzi L, Maggi M. Developments and challenges for new and emergent preparations for male hypogonadism treatment. Expert Opin Investig Drugs 2023; 32:1071-1084. [PMID: 37943011 DOI: 10.1080/13543784.2023.2276760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 10/24/2023] [Indexed: 11/10/2023]
Abstract
INTRODUCTION The specific role of testosterone (T) replacement therapy in patients with late onset hypogonadism is still conflicting. Several available preparations have been developed to restore either fertility and normal testosterone (T) levels (secondary hypogonadism) or just T levels (primary hypogonadism). AREAS COVERED Advantages and limitations related to available new treatments will be discussed in detail. In addition, possible news related to preparations in the pipeline will be discussed. EXPERT OPINION The selection of a specific T preparation should be adequately discussed with each subject. Transdermal T preparations are those that can preserve, after a unique morning administration, the circadian rhythmicity of T secretion. Conversely, short-acting preparations (such as oral or intranasal) need two- or three-times daily administration, potentially reducing patient compliance. Long acting T preparations, such as injectable T undecanoate have the advantage of bimestrial or trimestral administration, reducing the required number of administrations. The use of non-steroidal selective androgen receptor modulators (SARM), a heterogeneous class of compounds selectively acting on androgen receptor targets, remains investigational due to the lack of the full spectrum of T's action and the possible risk of side effects, despite their potential use in the treatment of muscle wasting and osteoporosis.
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Affiliation(s)
- Giovanni Corona
- Endocrinology Unit, Maggiore Hospital, Azienda AUSL Bologna, Bolognas, Italy
| | - Clotilde Sparano
- Endocrinology Unit, Department of Experimental, Clinical and Biomedical Sciences, University of Florence, Florence, Italy
| | - Giulia Rastrelli
- Andrology, Female Endocrinology and Gender Incongruence Unit Department of Experimental, Clinical and Biomedical Sciences, University of Florence, Florence, Italy
| | - Linda Vignozzi
- Andrology, Female Endocrinology and Gender Incongruence Unit Department of Experimental, Clinical and Biomedical Sciences, University of Florence, Florence, Italy
| | - Mario Maggi
- Endocrinology Unit, Department of Experimental, Clinical and Biomedical Sciences, University of Florence, Florence, Italy
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30
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Pavey H, Polkey MI, Bolton CE, Cheriyan J, McEniery CM, Wilkinson I, Mohan D, Casaburi R, Miller BE, Tal-Singer R, Fisk M. Circulating testosterone levels and health outcomes in chronic obstructive pulmonary disease: results from ECLIPSE and ERICA. BMJ Open Respir Res 2023; 10:e001601. [PMID: 37316306 PMCID: PMC10277522 DOI: 10.1136/bmjresp-2022-001601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 05/30/2023] [Indexed: 06/16/2023] Open
Abstract
The relationship of circulating testosterone levels with health outcomes in people with chronic obstructive pulmonary disease (COPD) is unknown. AIM To determine whether serum testosterone levels predict hospitalised acute exacerbations of COPD (H-AECOPD), cardiovascular disease outcome, and mortality in people with COPD. METHODS Separate analyses were carried out on two observational, multicentre COPD cohorts, Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) and Evaluation of the Role of Inflammation in Chronic Airways Disease (ERICA), both of which had serum testosterone measured using a validated liquid chromatography assay at the same laboratory. Data from 1296 male participants in ECLIPSE and 386 male, 239 female participants in ERICA were analysed. All analyses were sex-specific. Multivariate logistic regression was used to determine associations with H-AECOPD during follow-up (3 years ECLIPSE, 4.5 years ERICA), a composite endpoint of cardiovascular hospitalisation and cardiovascular death, and all-cause mortality. RESULTS Mean (SD) testosterone levels were consistent across cohorts; 459 (197) and 455 (200) ng/dL for males in ECLIPSE and ERICA, respectively, and in ERICA females: 28 (56) ng/dL. Testosterone was not associated with H-AECOPD (ECLIPSE: OR: 0.76, p=0.329, ERICA males: OR (95% CI): 1.06 (0.73 to 1.56), p=0.779, ERICA females: OR: 0.77 (0.52 to 1.12), p=0.178) or cardiovascular hospitalisation and death. Testosterone was associated with all-cause mortality in Global Initiative for Obstructive Lung Disease (GOLD) stage 2 male patients only, in ECLIPSE (OR: 0.25, p=0.007) and ERICA (OR: (95% CI): 0.56 (0.32 to 0.95), p=0.030). CONCLUSIONS Testosterone levels do not relate to H-AECOPD or cardiovascular outcome in COPD, but are associated with all-cause mortality in GOLD stage 2 COPD male patients, although the clinical significance of this finding is uncertain.
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Affiliation(s)
- Holly Pavey
- Division of Experimental Medicine and Immunotherapeutics, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Michael I Polkey
- Department of Respiratory Medicine, Royal Brompton Hospital, London, UK
| | - Charlotte E Bolton
- Centre for Respiratory Research, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK
- NIHR Nottingham Biomedical Research Centre, Nottingham, UK
| | - Joseph Cheriyan
- Division of Experimental Medicine and Immunotherapeutics, Department of Medicine, University of Cambridge, Cambridge, UK
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Carmel M McEniery
- Division of Experimental Medicine and Immunotherapeutics, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Ian Wilkinson
- Division of Experimental Medicine and Immunotherapeutics, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Divya Mohan
- Former employee of GSK, Collegeville, Pennsylvania, USA
| | - Richard Casaburi
- Rehabilitation Clinical Trials Center, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA
| | | | | | - Marie Fisk
- Division of Experimental Medicine and Immunotherapeutics, Department of Medicine, University of Cambridge, Cambridge, UK
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31
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Abstract
Recent publications of well-conducted population studies have informed us that the syndromic prevalence of age-related low testosterone, also known as late-onset hypogonadism, is quite low. Several well-conducted trials in middle-aged and older men with age-related decline in testosterone levels have revealed that efficacy of testosterone therapy is modest with improvement in sexual function, mood, volumetric bone density, and anemia. Although select older men might benefit from testosterone therapy, its effect on prostate cancer risk and major adverse cardiovascular events remains unclear. The results of the ongoing TRAVERSE trial will likely provide important insights into these risks.
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Affiliation(s)
- Maria Gabriela Figueiredo
- Division of Endocrinology and Metabolism, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, BLI 541, Boston, MA 02115, USA; Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Thiago Gagliano-Jucá
- Division of Endocrinology and Metabolism, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, BLI 541, Boston, MA 02115, USA; Northwestern Medicine McHenry Hospital, Chicago Medical School, Rosalind Franklin University of Medicine and Science, McHenry, IL, USA
| | - Shehzad Basaria
- Division of Endocrinology and Metabolism, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, BLI 541, Boston, MA 02115, USA.
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Chen J, Rees A, Coughlan CH, Goodison W, Murphy E, Chandratheva A. Ischaemic stroke with multi-focal venous and arterial thrombosis due to hyperhomocysteinemia: anabolic androgenic steroid use and MTHFR c.667 C > T variant - a case report. BMC Neurol 2023; 23:167. [PMID: 37101129 PMCID: PMC10131300 DOI: 10.1186/s12883-023-03197-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 04/03/2023] [Indexed: 04/28/2023] Open
Abstract
BACKGROUND Severely elevated serum homocysteine is a rare cause of ischaemic stroke and extra-cranial arterial and venous thrombosis. Several factors can lead to mild elevation of homocysteine including dietary folate and B12 deficiency, and genetic variants of the methylenetetrahydrofolate reductase (MTHFR) enzyme. The use of Anabolic androgenic steroid (AAS) is under-reported, but increasingly linked to ischaemic stroke and can raise homocysteine levels. CASE REPORT We present a case of a man in his 40s with a large left middle cerebral artery (MCA) territory ischaemic stroke and combined multifocal, extracranial venous, and arterial thrombosis. His past medical history was significant for Crohn's disease and covert use of AAS. A young stroke screen was negative except for a severely elevated total homocysteine concentration, folate and B12 deficiencies. Further tests revealed he was homozygous for the methylenetetrahydrofolate reductase enzyme thermolabile variant (MTHFR c.667 C > T). The etiology of this stroke was a hypercoagulable state induced by raised plasma homocysteine. Raised homocysteine in this case was likely multifactorial and related to chronic AAS use in combination with the homozygous MTHFR c.677 C > T thermolabile variant, folate deficiency and, vitamin B12 deficiency. CONCLUSION In summary, hyperhomocysteinemia is an important potential cause of ischaemic stroke and may result from genetic, dietary, and social factors. Anabolic androgenic steroid use is an important risk factor for clinicians to consider, particularly in cases of young stroke with elevated serum homocysteine. Testing for MFTHR variants in stroke patients with raised homocysteine may be useful to guide secondary stroke prevention through adequate vitamin supplementation. Further studies looking into primary and secondary stroke prevention in the high-risk MTHFR variant cohort are necessary.
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Affiliation(s)
- Jpk Chen
- National Hospital for Neurology and Neurosurgery, London, UK.
| | - A Rees
- National Hospital for Neurology and Neurosurgery, London, UK
| | - C H Coughlan
- University College London Hospitals NHS Foundation Trust, London, UK
| | - W Goodison
- National Hospital for Neurology and Neurosurgery, London, UK
| | - E Murphy
- University College London Hospitals NHS Foundation Trust, London, UK
| | - A Chandratheva
- University College London Hospitals NHS Foundation Trust, London, UK
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Menakuru SR, Atta M, Dhillon VS, Salih A. Testosterone Usage Leading to Pulmonary Embolisms and Deep Vein Thrombosis: A Case Report and Review of the Literature. Hematol Rep 2023; 15:290-297. [PMID: 37218821 DOI: 10.3390/hematolrep15020029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 03/30/2023] [Accepted: 04/19/2023] [Indexed: 05/24/2023] Open
Abstract
Androgen usage has widely increased in recent times via prescribed and unprescribed means. Testosterone is a popular androgen taken by both athletes and the general population. While there is some evidence of androgens being thrombogenic, we report on a 19-year-old male who presented to the hospital after the usage of testosterone for one month, leading to the development of multiple pulmonary emboli and deep vein thrombosis. The authors hope to elucidate the relationship between testosterone usage and thrombosis formation.
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Affiliation(s)
- Sasmith R Menakuru
- Department of Internal Medicine, Indiana University School of Medicine, Muncie, IN 47306, USA
| | - Mona Atta
- Department of Internal Medicine, Indiana University School of Medicine, Muncie, IN 47306, USA
| | - Vijaypal S Dhillon
- Department of Internal Medicine, Indiana University School of Medicine, Muncie, IN 47306, USA
| | - Ahmed Salih
- Department of Internal Medicine, Indiana University School of Medicine, Muncie, IN 47306, USA
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Margolis LM, Marlatt KL, Berryman CE, Howard EE, Murphy NE, Carrigan CT, Harris MN, Beyl RA, Ravussin E, Pasiakos SM, Rood JC. Metabolic Adaptations and Substrate Oxidation are Unaffected by Exogenous Testosterone Administration during Energy Deficit in Men. Med Sci Sports Exerc 2023; 55:661-669. [PMID: 36563086 PMCID: PMC11801180 DOI: 10.1249/mss.0000000000003089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION/PURPOSE The effects of testosterone on energy and substrate metabolism during energy deficit are unknown. The objective of this study was to determine the effects of weekly testosterone enanthate (TEST; 200 mg·wk -1 ) injections on energy expenditure, energy substrate oxidation, and related gene expression during 28 d of energy deficit compared with placebo (PLA). METHODS After a 14-d energy balance phase, healthy men were randomly assigned to TEST ( n = 24) or PLA ( n = 26) for a 28-d controlled diet- and exercise-induced energy deficit (55% below total energy needs by reducing energy intake and increasing physical activity). Whole-room indirect calorimetry and 24-h urine collections were used to measure energy expenditure and energy substrate oxidation during balance and deficit. Transcriptional regulation of energy and substrate metabolism was assessed using quantitative reverse transcription-polymerase chain reaction from rested/fasted muscle biopsy samples collected during balance and deficit. RESULTS Per protocol design, 24-h energy expenditure increased ( P < 0.05) and energy intake decreased ( P < 0.05) in TEST and PLA during deficit compared with balance. Carbohydrate oxidation decreased ( P < 0.05), whereas protein and fat oxidation increased ( P < 0.05) in TEST and PLA during deficit compared with balance. Change (∆; deficit minus balance) in 24-h energy expenditure was associated with ∆activity factor ( r = 0.595), but not ∆fat-free mass ( r = 0.147). Energy sensing (PRKAB1 and TP53), mitochondria (TFAM and COXIV), fatty acid metabolism (CD36/FAT, FABP, CPT1b, and ACOX1) and storage (FASN), and amino acid metabolism (BCAT2 and BCKHDA) genes were increased ( P < 0.05) during deficit compared with balance, independent of treatment. CONCLUSIONS These data demonstrate that increased physical activity and not exogenous testosterone administration is the primary determinate of whole-body and skeletal muscle metabolic adaptations during diet- and exercise-induced energy deficit.
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Affiliation(s)
- Lee M Margolis
- Military Nutrition Division, US Army Research Institute of Environmental Medicine, Natick, MA
| | | | | | - Emily E Howard
- Military Nutrition Division, US Army Research Institute of Environmental Medicine, Natick, MA
| | - Nancy E Murphy
- Military Nutrition Division, US Army Research Institute of Environmental Medicine, Natick, MA
| | - Christopher T Carrigan
- Military Nutrition Division, US Army Research Institute of Environmental Medicine, Natick, MA
| | | | - Robbie A Beyl
- Pennington Biomedical Research Center, Baton Rouge, LA
| | - Eric Ravussin
- Pennington Biomedical Research Center, Baton Rouge, LA
| | - Stefan M Pasiakos
- Military Performance Division, US Army Research Institute of Environmental Medicine, Natick, MA
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Ide H, Akehi Y, Fukuhara S, Ohira S, Ogawa S, Kataoka T, Kumagai H, Kobayashi K, Komiya A, Shigehara K, Syuto T, Soh J, Tanabe M, Taniguchi H, Chiba K, Matsushita K, Mitsui Y, Yoneyama T, Shirakawa T, Fujii Y, Kumano H, Ueshiba H, Amano T, Sasaki H, Maeda S, Mizokami A, Suzuki K, Horie S. Summary of the clinical practice manual for late-onset hypogonadism. Int J Urol 2023; 30:422-430. [PMID: 36757880 DOI: 10.1111/iju.15160] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 01/15/2023] [Indexed: 02/10/2023]
Abstract
Testosterone plays an important role in maintaining both physical and mental function. Age-related testosterone depletion contributes to the development of angina, arteriosclerosis, obesity, metabolic syndrome, dementia, frailty, and a range of other conditions. A condition involving age-related testosterone depletion and the associated clinical symptoms is defined as late-onset hypogonadism (LOH). LOH is treated by testosterone replacement therapy. Indications for testosterone replacement therapy are determined by evaluating symptoms and signs.
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Affiliation(s)
- Hisamitsu Ide
- Department of Urology, Dokkyo Medical University, Saitama Medical Center, Saitama, Japan
| | - Yuko Akehi
- Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
| | - Shinichiro Fukuhara
- Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Shin Ohira
- Department of Urology, Kawasaki Medical School, Okayama, Japan
| | - Sumito Ogawa
- Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tomoya Kataoka
- Department of Clinical Pharmaceutics, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Aichi, Japan
| | - Hiroshi Kumagai
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, USA
| | - Ko Kobayashi
- Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Akira Komiya
- Department of Urology, Kameda Medical Center, Chiba, Japan
| | - Kazuyoshi Shigehara
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan
| | - Takahiro Syuto
- Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Jintetu Soh
- Department of Urology, Japanese Red Cross Society Kyoto Daini, Kyoto, Japan
| | - Makito Tanabe
- Department of Endocrinology and Diabetes Mellitus, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Hisanori Taniguchi
- Department of Urology and Andrology, Kansai Medical University, Hirakata, Osaka, Japan
| | - Koji Chiba
- Department of Urology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Kazuhito Matsushita
- Department of Urology, Juntendo University, Graduate School of Medicine, Tokyo, Japan
| | - Yozo Mitsui
- Department of Urology, Toho University School of Medicine, Tokyo, Japan
| | - Takahiro Yoneyama
- Department of Advanced Transplant and Regenerative Medicine, Hirosaki University Graduate School of Medicine, Aomori, Japan
| | - Tomoya Shirakawa
- Department of Urology, Juntendo University, Graduate School of Medicine, Tokyo, Japan
| | - Yasuhisa Fujii
- Department of Urology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroaki Kumano
- Faculty of Human Sciences, Waseda University, Saitama, Japan
| | - Hajime Ueshiba
- Division of Diabetes, Metabolism and Endocrinology, Toho University Ohashi Medical Center, Tokyo, Japan
| | - Toshiyasu Amano
- Department of Urology, Nagano Red Cross Hospital, Nagano, Japan
| | - Haruaki Sasaki
- Department of Urology, Showa University Fujigaoka Hospital, Kanagawa, Japan
| | - Seiji Maeda
- Faculty of Sport Sciences, Waseda University, Saitama, Japan
| | - Atsushi Mizokami
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan
| | - Kazuhiro Suzuki
- Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Shigeo Horie
- Department of Urology, Juntendo University, Graduate School of Medicine, Tokyo, Japan
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36
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Testosterone Therapy in Oncologic Patients. CURRENT SEXUAL HEALTH REPORTS 2023. [DOI: 10.1007/s11930-022-00351-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
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Turco F, Di Prima L, Pisano C, Poletto S, De Filippis M, Crespi V, Farinea G, Cani M, Calabrese M, Saporita I, Di Stefano RF, Tucci M, Buttigliero C. How to Improve the Quality of Life of Patients with Prostate Cancer Treated with Hormone Therapy? Res Rep Urol 2023; 15:9-26. [PMID: 36698681 PMCID: PMC9869701 DOI: 10.2147/rru.s350793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 01/07/2023] [Indexed: 01/19/2023] Open
Abstract
Prostate cancer (PC) is a hormone-sensitive tumor. Androgen deprivation therapy (ADT) is the cornerstone of systemic therapy for patients with intermediate or high-risk localized, recurrent, and metastatic prostate cancer. Although generally well tolerated, ADT can lead to short- and long-term adverse events that can worsen the quality of life of patients with PC. In the last decade, the introduction of novel generation androgen receptor pathway inhibitors (ARPI) has resulted in an improvement in the prognosis of patients with metastatic PC when used in combination with ADT. The use of ARPI in increasingly early stages of the disease determines a longer exposure of patients to these treatments. Although ARPIs are normally well-tolerated drugs, they generally cause an increase in toxicity compared to ADT alone, being able to worsen some adverse events already induced by ADT or leading to the development of specific side effects. Although there are no specific treatments for all the adverse events induced by hormonal therapies, it is essential to know the possible toxicities induced by the different treatments and to start procedures to prevent and/or recognize and consequently treat them early in order to not compromise the quality of life of the patients with PC. The aim of this review is to describe the adverse events induced by hormonal therapies. We will first describe the side effects induced by both ADT and ARPI and then the specific adverse events of the different ARPIs. Furthermore, we will try to highlight the possible therapeutic options to prevent or mitigate the toxicity induced by hormone therapies in order to improve the quality of life of the patients with PC.
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Affiliation(s)
- Fabio Turco
- Department of Oncology, University of Turin, at Division of Medical Oncology, San Luigi Gonzaga Hospital, Turin, Italy
| | - Lavinia Di Prima
- Department of Oncology, University of Turin, at Division of Medical Oncology, San Luigi Gonzaga Hospital, Turin, Italy
| | - Chiara Pisano
- Department of Oncology, University of Turin, at Division of Medical Oncology, San Luigi Gonzaga Hospital, Turin, Italy
| | - Stefano Poletto
- Department of Oncology, University of Turin, at Division of Medical Oncology, San Luigi Gonzaga Hospital, Turin, Italy
| | - Marco De Filippis
- Department of Oncology, University of Turin, at Division of Medical Oncology, San Luigi Gonzaga Hospital, Turin, Italy
| | - Veronica Crespi
- Department of Oncology, University of Turin, at Division of Medical Oncology, San Luigi Gonzaga Hospital, Turin, Italy
| | - Giovanni Farinea
- Department of Oncology, University of Turin, at Division of Medical Oncology, San Luigi Gonzaga Hospital, Turin, Italy
| | - Massimiliano Cani
- Department of Oncology, University of Turin, at Division of Medical Oncology, San Luigi Gonzaga Hospital, Turin, Italy
| | - Mariangela Calabrese
- Department of Oncology, University of Turin, at Division of Medical Oncology, San Luigi Gonzaga Hospital, Turin, Italy
| | - Isabella Saporita
- Department of Oncology, University of Turin, at Division of Medical Oncology, San Luigi Gonzaga Hospital, Turin, Italy
| | - Rosario Francesco Di Stefano
- Department of Oncology, University of Turin, at Division of Medical Oncology, San Luigi Gonzaga Hospital, Turin, Italy
| | - Marcello Tucci
- Department of Medical Oncology, Cardinal Massaia Hospital, Asti, Italy
| | - Consuelo Buttigliero
- Department of Oncology, University of Turin, at Division of Medical Oncology, San Luigi Gonzaga Hospital, Turin, Italy
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Bond P, Smit DL, de Ronde W. Anabolic-androgenic steroids: How do they work and what are the risks? Front Endocrinol (Lausanne) 2022; 13:1059473. [PMID: 36644692 PMCID: PMC9837614 DOI: 10.3389/fendo.2022.1059473] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 11/28/2022] [Indexed: 12/23/2022] Open
Abstract
Anabolic-androgenic steroids (AAS) are a class of hormones that are widely abused for their muscle-building and strength-increasing properties in high, nontherapeutic, dosages. This review provides an up-to-date and comprehensive overview on how these hormones work and what side effects they might elicit. We discuss how AAS are absorbed into the circulation after intramuscular injection or oral ingestion and how they are subsequently transported to the tissues, where they will move into the extravascular compartment and diffuse into their target cells. Inside these cells, AAS can biotransform into different metabolites or bind to their cognate receptor: the androgen receptor. AAS and their metabolites can cause side effects such as acne vulgaris, hypertension, hepatotoxicity, dyslipidemia, testosterone deficiency, erectile dysfunction, gynecomastia, and cardiomyopathy. Where applicable, we mention treatment options and self-medication practices of AAS users to counteract these side effects. Clinicians may use this review as a guide for understanding how AAS use can impact health and to assist in patient education and, in some cases, the management of side effects.
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Affiliation(s)
| | - Diederik L. Smit
- Department of Internal Medicine, Elisabeth-TweeSteden Hospital, Tilburg, Netherlands
| | - Willem de Ronde
- Department of Internal Medicine, Spaarne Gasthuis, Haarlem, Netherlands
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Abstract
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.
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Affiliation(s)
- Bradley D Anawalt
- Department of Medicine, University of Washington School of Medicine, Department of Medicine, 1959 NE Pacific Avenue, Box 356420, Seattle, WA, 98195, USA.
| | - Alvin M Matsumoto
- Department of Medicine, University of Washington School of Medicine, Department of Medicine, 1959 NE Pacific Avenue, Box 356420, Seattle, WA, 98195, USA
- Geriatric Research, Education and Clinical Center VA Puget Sound Health Care System, 1660 South Columbian Way (S-182-GRECC), Seattle, WA, 98118, USA
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Gattu AK, Goldman AL, Guzelce EC, Galbiati F, Bhasin S. The anabolic applications of androgens in older adults with functional limitations. Rev Endocr Metab Disord 2022; 23:1209-1220. [PMID: 36355323 DOI: 10.1007/s11154-022-09766-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/20/2022] [Indexed: 11/11/2022]
Abstract
Aging is associated with a progressive decrease in skeletal muscle mass, strength and power and impairment of physical function. Serum testosterone concentrations in men decrease with advancing age due to defects at all levels of the hypothalamic-pituitary-testicular axis. Testosterone administration increases skeletal muscle mass, strength and power in older men with low or low normal testosterone levels, but the effects on performance-based measures of physical function have been inconsistent. Adequately powered randomized trials are needed to determine the long-term safety and efficacy of testosterone in improving physical function and quality of life in older adults with functional limitations.
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Affiliation(s)
- Arijeet K Gattu
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, RFB-2, Boston, MA, 02115, USA
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, RFB-2, Boston, MA, 02115, USA
- Brigham and Women's Hospital, Research Program in Men's Health: Aging and Metabolism, Boston, MA, USA
| | - Anna L Goldman
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, RFB-2, Boston, MA, 02115, USA
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, RFB-2, Boston, MA, 02115, USA
- Brigham and Women's Hospital, Research Program in Men's Health: Aging and Metabolism, Boston, MA, USA
| | - Ezgi Caliskan Guzelce
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, RFB-2, Boston, MA, 02115, USA
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, RFB-2, Boston, MA, 02115, USA
| | - Francesca Galbiati
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, RFB-2, Boston, MA, 02115, USA
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, RFB-2, Boston, MA, 02115, USA
| | - Shalender Bhasin
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, RFB-2, Boston, MA, 02115, USA.
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, RFB-2, Boston, MA, 02115, USA.
- Brigham and Women's Hospital, Research Program in Men's Health: Aging and Metabolism, Boston, MA, USA.
- Boston Claude D. Pepper Older Americans Independence Center, Boston, MA, USA.
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Anderson DJ, Vazirnia P, Loehr C, Sternfels W, Hasoon J, Viswanath O, Kaye AD, Urits I. Testosterone Replacement Therapy in the Treatment of Depression. Health Psychol Res 2022; 10:38956. [PMID: 36452903 PMCID: PMC9704723 DOI: 10.52965/001c.38956] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/12/2024] Open
Abstract
BACKGROUND Depression is a common disorder that affects millions globally and is linked to reduced quality of life and mortality. Its pathophysiology is complex and there are several forms of treatment proposed in the literature with differing side effect profiles. Many patients do not respond to treatment which warrants augmentation with other treatments and the investigation of novel treatments. One of these treatments includes testosterone therapy which evidence suggests might improve depressed mood in older patients with low levels of testosterone and helps restore physical impairments caused by age-related hormonal changes. OBJECTIVE The objective of this review is to synthesize information regarding clinical depression, its treatment options, and the efficacy and safety of testosterone treatment for the treatment of depression. METHODS This review utilized comprehensive secondary and tertiary data analysis across many academic databases and published work pertaining to the topic of interest. RESULTS Within some subpopulations such as men with dysthymic disorder, treatment resistant depression, or low testosterone levels, testosterone administration yielded positive results in the treatment of depression. Additionally, rodent models have shown that administering testosterone to gonadectomized male animals reduces symptoms of depression. Conversely, some studies have found no difference in depressive symptoms after treatment with testosterone when compared with placebo. It was also noted that over administration of testosterone is associated with multiple adverse effects and complications. CONCLUSION The current evidence provides mixed conclusions on the effectiveness of testosterone therapy for treating depression. More research is needed in adult men to see if declining testosterone levels directly influence the development of depression.
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Affiliation(s)
| | | | - Catherine Loehr
- School of Medicine, Louisiana State University Health Sciences Center
| | - Whitney Sternfels
- School of Medicine, Louisiana State University Health Sciences Center
| | - Jamal Hasoon
- Department of Anesthesia, Critical Care, and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School
| | - Omar Viswanath
- Department of Anesthesia, Critical Care, and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School; Valley Anesthesiology and Pain Consultants, Envision Physician Services; Department of Anesthesiology, University of Arizona College of Medicine Phoenix; Department of Anesthesiology, Creighton University School of Medicine
| | - Alan D Kaye
- Department of Anesthesiology, Louisiana State University Health Sciences Center
| | - Ivan Urits
- Department of Anesthesia, Critical Care, and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School; Department of Anesthesiology, Louisiana State University Health Shreveport
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Thirumalai A, Anawalt BD. Androgenic Steroids Use and Abuse. Urol Clin North Am 2022; 49:645-663. [DOI: 10.1016/j.ucl.2022.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Galbiati FF, Goldman AL, Gattu A, Guzelce EC, Bhasin S. Benefits and Risks of Testosterone Treatment of Older Men with Hypogonadism. Urol Clin North Am 2022; 49:593-602. [DOI: 10.1016/j.ucl.2022.07.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
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Aguilar-Castro J, Cervantes-Candelas LA, Buendía-González FO, Fernández-Rivera O, Nolasco-Pérez TDJ, López-Padilla MS, Chavira-Ramírez DR, Cervantes-Sandoval A, Legorreta-Herrera M. Testosterone induces sexual dimorphism during infection with Plasmodium berghei ANKA. Front Cell Infect Microbiol 2022; 12:968325. [PMID: 36237427 PMCID: PMC9551224 DOI: 10.3389/fcimb.2022.968325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 09/05/2022] [Indexed: 11/13/2022] Open
Abstract
Malaria is the most lethal parasitic disease worldwide; men exhibit higher mortality and more severe symptomatology than women; however, in most studies of immune response in malaria, sex is not considered a variable. Sex hormones 17β-oestradiol and testosterone are responsible for the main physiological differences between sexes. When interacting with their receptors on different immune cells, they modify the expression of genes that modulate cell proliferation, differentiation, and synthesis of cytokines. The immunosuppressive activity of testosterone is well accepted; however, its participation in the sexual dimorphism of the immune response to malaria has not been studied. In this work, we analysed whether altering the concentration of testosterone, through increasing the concentration of this hormone for exogenous administration for three weeks, or gonadectomy before infection with Plasmodium berghei ANKA affects different cells of the immune response necessary for parasite clearance. We also assessed the concentration of pro-and anti-inflammatory cytokines in male and female CBA/Ca mice infected or not with the parasite. Our results show that testosterone changes affect females more than males, resulting in sex-associated patterns. Testosterone administration increased parasitaemia in intact males while reducing it in intact females leading to a dimorphic pattern. In addition, gonadectomy increased parasitaemia in both sexes. Moreover, testosterone administration prevented both weight loss caused by the infection in females and hypothermia in gonadectomized mice of both sexes. Boosting testosterone concentration increased CD3+ and CD8+ populations but decreased the B220+ cells exclusively in females. Additionally, testosterone reduced IFN-γ concentration and increased IL-6 levels only in females, while in males, testosterone increased the number of NK cells. Finally, gonadectomy decreased TNF-α concentration in both sexes. Our results demonstrate that testosterone induces different patterns depending on sex and testosterone concentration. The results of this work contribute to understanding the impact of modifying testosterone concentration on the immune response specific against Plasmodium and the participation of this hormone in sexual dimorphism in malaria.
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Affiliation(s)
- Jesús Aguilar-Castro
- Unidad de Investigación Química Computacional, Síntesis y Farmacología de Moléculas de Interés Biológico. Laboratorio de Inmunología Molecular, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, Mexico
- Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Luis Antonio Cervantes-Candelas
- Unidad de Investigación Química Computacional, Síntesis y Farmacología de Moléculas de Interés Biológico. Laboratorio de Inmunología Molecular, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, Mexico
- Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Fidel Orlando Buendía-González
- Unidad de Investigación Química Computacional, Síntesis y Farmacología de Moléculas de Interés Biológico. Laboratorio de Inmunología Molecular, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, Mexico
- Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Omar Fernández-Rivera
- Unidad de Investigación Química Computacional, Síntesis y Farmacología de Moléculas de Interés Biológico. Laboratorio de Inmunología Molecular, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, Mexico
- Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Teresita de Jesús Nolasco-Pérez
- Unidad de Investigación Química Computacional, Síntesis y Farmacología de Moléculas de Interés Biológico. Laboratorio de Inmunología Molecular, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, Mexico
- Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Monserrat Sofía López-Padilla
- Unidad de Investigación Química Computacional, Síntesis y Farmacología de Moléculas de Interés Biológico. Laboratorio de Inmunología Molecular, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, Mexico
| | - David Roberto Chavira-Ramírez
- Departamento de Biología de la Reproducción, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, Mexico
| | - Armando Cervantes-Sandoval
- Laboratorio de Aplicaciones Computacionales, Facultad de Estudios Superiores Zaragoza, UNAM, Ciudad de México, Mexico
| | - Martha Legorreta-Herrera
- Unidad de Investigación Química Computacional, Síntesis y Farmacología de Moléculas de Interés Biológico. Laboratorio de Inmunología Molecular, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, Mexico
- *Correspondence: Martha Legorreta-Herrera,
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Abstract
In this review, we discuss the effects on androgens on the haemopoietic system, focussing largely on the effects of testosterone on erythropoiesis. Stimulation of erythropoiesis is one of the most consistent effects of testosterone treatment observed in clinical trials. In men with anaemia this effect can be beneficial. Conversely, erythrocytosis is one of the most common adverse effects of testosterone treatment with a relative risk of 8.14 (95% CI: 1.87-35.40) estimated by a recent meta-analysis of randomised placebo controlled clinical trials. A reduction in haemoglobin is commonly seen in men receiving androgen deprivation therapy for prostate cancer, and in transwomen receiving gender affirming therapy to reduce serum testosterone. While mechanisms by which androgens regulate erythropoiesis are not fully understood, it is likely that effects on erythropoietic progenitor cells and erythropoietin are involved, with secondary effects on iron metabolism. In contrast, whether androgens exert clinically relevant effects on white blood cells and on platelets requires further study.
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Affiliation(s)
- Annabelle M Warren
- Department of Endocrinology, Austin Health and University of Melbourne, Australia.
| | - Mathis Grossmann
- Department of Endocrinology, Austin Health and University of Melbourne, Australia.
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Testosterone Deficiency as One of the Major Endocrine Disorders in Chronic Kidney Disease. Nutrients 2022; 14:nu14163438. [PMID: 36014945 PMCID: PMC9415930 DOI: 10.3390/nu14163438] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/11/2022] [Accepted: 08/19/2022] [Indexed: 11/28/2022] Open
Abstract
Reduced testosterone concentration is nowadays thought to be one of the main endocrine disorders in chronic kidney disease (CKD). It is caused by the dysfunction of the hypothalamic-pituitary-gonadal axis. The role of testosterone is multifactorial. Testosterone is responsible not only for reproductive processes, but it is a hormone which increases bone and muscle mass, improves lipid profile, insulin sensitivity, erythropoiesis, reduces blood pressure, and ameliorates mood and perception. The implications of hypogonadism in CKD are infertility and loss of libido, reduction of muscle mass and strength, disorders in bone mineralization, the development of sarcopenia and protein energy wasting (PEW), progression of atherosclerosis, increased visceral adiposity, insulin resistance, and anaemia. Reduced testosterone serum concentrations in CKD are associated with increased mortality rate. Testosterone supplementation improves sexual functions, reduces the level of inflammatory markers and blood pressure, stimulates muscle protein synthesis, improves insulin sensitivity and lipid profile, and increases muscle mass, bone mineral density, and haemoglobin concentration. It positively affects mood and well-being. The modes of testosterone supplementation are intramuscular injections, subcutaneous pellets, and percutaneous methods—patches and gels. Successful kidney transplantation may improve gonadal function and testosterone production, however, half of men with low testosterone concentrations before kidney transplantation do not restore hormonal function.
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Sex differences in normal and malignant hematopoiesis. BLOOD SCIENCE 2022; 4:185-191. [PMID: 36311819 PMCID: PMC9592170 DOI: 10.1097/bs9.0000000000000133] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 07/10/2022] [Indexed: 12/09/2022] Open
Abstract
Hematopoiesis is a continuous and well-regulated process requiring both the capacity for self-renewal and the potential for differentiation of hematopoietic stem cells. Multiple studies indicate that sex hormones exert significant effects on not only hematopoietic stem and progenitor cells, but also the development of hematopoietic lineages, resulting in sexual dimorphisms in normal hematopoiesis. Hematologic malignancies comprise a wide variety of cancers affecting the blood, bone marrow, and lymphatic system, such as leukemia, lymphoma, myeloma, myelodysplastic syndrome, and myeloproliferative diseases. Overall, males are at greater risk and have worse prognosis for most of these malignancies compared with females. A better understanding of the differences between male and female could be of substantial value in research as well as clinical management.
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Fernández-Lázaro D, Fernandez-Lazaro CI, Seco-Calvo J, Garrosa E, Adams DP, Mielgo-Ayuso J. Effects of Tribulus terrestris L. on Sport and Health Biomarkers in Physically Active Adult Males: A Systematic Review. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19159533. [PMID: 35954909 PMCID: PMC9368143 DOI: 10.3390/ijerph19159533] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/18/2022] [Accepted: 07/26/2022] [Indexed: 11/16/2022]
Abstract
Tribulus terrestris L. (TT) is a plant used in traditional Chinese medicine, Ayurvedic medicine, and sports nutrition to improve health and performance. However, no conclusive evidence exists about the potential beneficial effects of TT on sport and health biomarkers in physically active adults. Based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the modified McMaster Critical Review Form for methodological quality assessment, we systematically reviewed studies indexed in Web of Science, Scopus, and PubMed, to assess the effects of TT on immunological, hematological, biochemical, renal, lipidic, hormonal behavior, and anti-inflammatory response in physically active adult males. Among 340 records identified in the search, a total of 7 studies met the inclusion and exclusion criteria. Overall, participants supplemented with TT displayed significant improvements in lipid profile. Inflammatory and hematological biomarkers showed moderate beneficial effects with no significant changes on renal biomarkers. No positive effects were observed on the immune system response. Additionally, no TT-induced toxicity was reported. In conclusion, there was no clear evidence of the beneficial effects of TT supplementation on muscle damage markers and hormonal behavior. More studies are needed to confirm the benefits of TT due to the limited number of studies available in the current literature.
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Affiliation(s)
- Diego Fernández-Lázaro
- Department of Cellular Biology, Genetics, Histology and Pharmacology, Faculty of Health Sciences, University of Valladolid, Campus of Soria, 42003 Soria, Spain
- Neurobiology Research Group, Faculty of Medicine, University of Valladolid, 47005 Valladolid, Spain
- Correspondence: (D.F.-L.); (C.I.F.-L.)
| | - Cesar I. Fernandez-Lazaro
- Department of Preventive Medicine and Public Health, School of Medicine, University of Navarra, Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain
- Correspondence: (D.F.-L.); (C.I.F.-L.)
| | - Jesús Seco-Calvo
- Institute of Biomedicine (IBIOMED), Physiotherapy Department, University of Leon, Campus de Vegazana, 24071 Leon, Spain;
- Psychology Department, Faculty of Medicine, Basque Country University, 48900 Leioa, Spain
| | - Evelina Garrosa
- Department of Cellular Biology, Genetics, Histology and Pharmacology, Faculty of Medicine, and Institute of Neurosciences of Castile and Leon (INCYL), University of Valladolid, 47005 Valladolid, Spain;
| | - David P. Adams
- Dual Credit Enrollment Program, Point University, Savannah, GA 31419, USA;
| | - Juan Mielgo-Ayuso
- Department of Health Sciences, Faculty of Health Sciences, University of Burgos, 09001 Burgos, Spain;
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Transwoman Elite Athletes: Their Extra Percentage Relative to Female Physiology. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19159103. [PMID: 35897465 PMCID: PMC9331831 DOI: 10.3390/ijerph19159103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 06/28/2022] [Accepted: 07/07/2022] [Indexed: 12/03/2022]
Abstract
There is increasing debate as to whether transwoman athletes should be included in the elite female competition. Most elite sports are divided into male and female divisions because of the greater athletic performance displayed by males. Without the sex division, females would have little chance of winning because males are faster, stronger, and have greater endurance capacity. Male physiology underpins their better athletic performance including increased muscle mass and strength, stronger bones, different skeletal structure, better adapted cardiorespiratory systems, and early developmental effects on brain networks that wires males to be inherently more competitive and aggressive. Testosterone secreted before birth, postnatally, and then after puberty is the major factor that drives these physiological sex differences, and as adults, testosterone levels are ten to fifteen times higher in males than females. The non-overlapping ranges of testosterone between the sexes has led sports regulators, such as the International Olympic Committee, to use 10 nmol/L testosterone as a sole physiological parameter to divide the male and female sporting divisions. Using testosterone levels as a basis for separating female and male elite athletes is arguably flawed. Male physiology cannot be reformatted by estrogen therapy in transwoman athletes because testosterone has driven permanent effects through early life exposure. This descriptive critical review discusses the inherent male physiological advantages that lead to superior athletic performance and then addresses how estrogen therapy fails to create a female-like physiology in the male. Ultimately, the former male physiology of transwoman athletes provides them with a physiological advantage over the cis-female athlete.
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Bhattad PB, Roumia M. Building Body With Anabolics Is Weakening the Heart: Anabolic Steroid Induced Cardiomyopathy. Cureus 2022; 14:e26579. [PMID: 35936132 PMCID: PMC9352142 DOI: 10.7759/cureus.26579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/05/2022] [Indexed: 11/21/2022] Open
Abstract
Anabolic steroid (AS) use is common in young males, with several reports of various adverse cardiovascular events in the users of AS. We present a unique case of a young male with no other risk factors who developed dilated cardiomyopathy secondary to abuse of AS. The exact mechanism by which AS leads to cardiomyopathy is not very well understood. No specific guidelines have been developed yet with regard to the management of AS-induced cardiomyopathy currently. Adverse events from AS must be promoted to increase awareness in the general and medical population.
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