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McMahon A, Fantus RJ. Testosterone Replacement Therapy for Testosterone Deficiency in Older Men. Clin Geriatr Med 2025; 41:163-173. [PMID: 40345771 DOI: 10.1016/j.cger.2025.01.002] [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] [Indexed: 05/11/2025]
Abstract
This review explores the increasing use of testosterone therapy in aging men, driven by the need to address age-related symptoms like decreased libido, muscle weakness, and anemia. Studies such as the Testosterone Trials and Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men trial show that testosterone therapy can offer benefits in sexual function, physical performance, and bone density, with no significant increase in risks for cardiovascular events or prostate cancer. However, conflicting data suggest that careful, individualized treatment is necessary, especially in older men with existing health conditions.
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Affiliation(s)
- Amber McMahon
- Department of Urology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
| | - Richard J Fantus
- Department of Urology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.
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Augusto S, Kaelber DC, Tang WHW. Testosterone therapy in patients with heart failure and protein-calorie malnutrition: Insights from a propensity-matched cohort study. Curr Probl Cardiol 2025; 50:103070. [PMID: 40311854 DOI: 10.1016/j.cpcardiol.2025.103070] [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: 04/19/2025] [Accepted: 04/28/2025] [Indexed: 05/03/2025]
Abstract
INTRODUCTION Testosterone therapy may improve physical capacity and mood in men with chronic heart failure. However, recent findings have raised concerns that testosterone therapy could also increase the risk of atrial fibrillation, pulmonary embolism, and acute kidney injury. METHODS Leveraging data from the TriNetX platform from January 1, 2014, to December 01, 2024, we conducted a propensity-matched analysis of two cohorts of patients with heart failure with protein-calorie malnutrition, where the only difference between cohorts was testosterone therapy. The primary outcomes were all-cause mortality and the incidence of acute heart failure, with secondary outcomes including major adverse cardiovascular events as well as cardiovascular, kidney, and thrombotic diseases. RESULTS After propensity matching, 577 patients were compared across the two cohorts. The findings indicated that testosterone therapy reduced the risk of all-cause mortality (hazard ratio [HR] 0.56, 95 % confidence interval [CI] 0.46-0.68), acute heart failure (HR 0.62, 95 % CI 0.49-0.78), and major adverse cardiovascular events (HR 0.77, 95 % CI 0.61-0.97). Additionally, incident peripheral arterial disease (HR 0.52, 95 % CI 0.30-0.91), coronary arterial disease (HR 0.83, 95 % CI 0.69-1.00), acute myocardial infarction (HR 0.65, 95 % CI 0.48-0.89), and atrial fibrillation (HR 0.79, 95 % CI 0.66-0.95) also favored the testosterone-treated cohort. There was a trend toward an increased risk of venous thromboembolism (HR 1.14, 95 % CI 1.03-1.27) and stroke (HR 1.12, 95 % CI 0.81-1.54) associated with testosterone therapy. CONCLUSION These hypothesis-generating findings support potential beneficial effects of testosterone therapy in patients with heart failure and protein-calorie malnutrition.
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Affiliation(s)
- SilvioNunes Augusto
- Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland OH, USA; The Center for Clinical Informatics Research and Education, The MetroHealth System, Cleveland OH, USA
| | - David C Kaelber
- The Center for Clinical Informatics Research and Education, The MetroHealth System, Cleveland OH, USA; The Departments of Internal Medicine, Pediatrics, and Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland OH, USA
| | - W H Wilson Tang
- Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland OH, USA; Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland OH, USA; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland OH, , USA.
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Groti Antonič K, Zitzmann M. Novel perspectives of testosterone therapy in men with functional hypogonadism: traversing the gaps of knowledge. Aging Male 2024; 27:2296460. [PMID: 38149634 DOI: 10.1080/13685538.2023.2296460] [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: 10/16/2023] [Accepted: 12/13/2023] [Indexed: 12/28/2023] Open
Abstract
INTRODUCTION In the past decade, there has been a significant augmentation in the corpus of evidence pertaining to functional hypogonadism. Despite this, prevailing clinical guidelines continue to advise against the universal screening for hypogonadism in middle-aged and elderly males. FINDINGS Numerous randomized controlled trials have scrutinized the effects of testosterone therapy in males afflicted with type 2 diabetes and/or obesity. However, these guidelines uniformly assert that lifestyle modifications and weight reduction should be the primary intervention strategies in overweight and obese males, relegating testosterone therapy to a secondary, selective option. It is extensively documented that testosterone therapy can yield substantial improvements in various metabolic parameters as well as ameliorate symptoms of erectile dysfunction. Moreover, recent studies have demonstrated the potential of testosterone therapy in reversing type 2 diabetes in males with low-normal testosterone levels who are at elevated risk for this condition, in comparison to the outcomes achievable through lifestyle modifications alone. CONCLUSION This focused review article aims to present a comprehensive update on the latest data concerning the innovative aspects of testosterone therapy in males with functional hypogonadism, particularly in the context of type 2 diabetes and/or obesity. Additionally, it will delve into the cardiovascular safety of such interventions within this high-risk demographic, with a special emphasis on insights gleaned from the TRAVERSE trial.
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Affiliation(s)
- Kristina Groti Antonič
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Michael Zitzmann
- Centre for Reproductive Medicine and Andrology, Münster University Hospital, Münster, Germany
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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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Morgentaler A, Dhindsa S, Dobs AS, Hackett G, Jones TH, Kloner RA, Miner M, Zitzmann M, Traish AM. Androgen Society Position Paper on Cardiovascular Risk With Testosterone Therapy. Mayo Clin Proc 2024; 99:1785-1801. [PMID: 39436329 DOI: 10.1016/j.mayocp.2024.08.008] [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: 04/09/2024] [Revised: 07/13/2024] [Accepted: 08/06/2024] [Indexed: 10/23/2024]
Abstract
The Androgen Society is an international, multidisciplinary medical organization committed to advancing research and education in the field of testosterone deficiency and testosterone therapy (TTh). This position paper is written in response to results of the TRAVERSE study, published in June 2023, which reported no increased risk of major adverse cardiovascular events (MACE) in men who received TTh compared with placebo. In 2013-2014, 2 observational studies reported increased cardiovascular (CV) risks with TTh and received wide media attention. Despite strong criticism of those 2 studies, in 2015, the Food and Drug Administration added a CV warning to testosterone product labels and required pharmaceutical companies to perform a CV safety study, which became the TRAVERSE trial. TRAVERSE enrolled 5246 men at high risk for MACE based on existing heart disease or multiple risk factors. Participants were randomized to daily testosterone gel or placebo gel, with a mean follow-up of 33 months. Results revealed no greater risk of MACE (myocardial infarction, stroke, or CV death) or venothrombotic events in men who received TTh compared with placebo. Review of the prior literature reveals near uniformity of studies reporting no increased MACE with TTh. This includes 2 additional large randomized controlled trials, multiple smaller randomized controlled trials, several large observational studies, and 19 meta-analyses. In view of these findings, it is the position of the Androgen Society that it has now been conclusively determined that TTh is not associated with increased risks of heart attack, stroke, or CV death.
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Affiliation(s)
- Abraham Morgentaler
- Division of Urology, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
| | - Sandeep Dhindsa
- Division of Endocrinology and Metabolism, St Louis University, St Louis, MO
| | - Adrian S Dobs
- Division of Endocrinology, Diabetes and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Geoff Hackett
- Aston University Medical School, Birmingham, United Kingdom
| | - T Hugh Jones
- Department of Endocrinology, Barnsley Hospital, Barnsley, UK; Department of Biochemistry, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Robert A Kloner
- Cardiovascular Division, Department of Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA
| | - Martin Miner
- Departments of Family Medicine and Urology, Warren Alpert School of Medicine, Brown University, Providence, RI
| | - Michael Zitzmann
- Department of Clinical and Surgical Andrology, Centre of Reproductive Medicine and Andrology, Münster University Hospital, Münster, Germany
| | - Abdulmaged M Traish
- Departments of Biochemistry and Urology, Boston University School of Medicine, Boston, MA
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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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Donald DM, McDonnell T, O'Reilly MW, Sherlock M. Replacement with sex steroids in hypopituitary men and women: implications for gender differences in morbidities and mortality. Rev Endocr Metab Disord 2024; 25:839-854. [PMID: 39370498 PMCID: PMC11470859 DOI: 10.1007/s11154-024-09897-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/17/2024] [Indexed: 10/08/2024]
Abstract
Hypopituitarism is a heterogenous disorder characterised by a deficiency in one or more anterior pituitary hormones. There are marked sex disparities in the morbidity and mortality experienced by patients with hypopituitarism. In women with hypopituitarism, the prevalence of many cardiovascular risk factors, myocardial infarction, stroke and mortality are significantly elevated compared to the general population, however in men, they approach that of the general population. The hypothalamic-pituitary-gonadal axis (HPG) is the most sexually dimorphic pituitary hormone axis. Gonadotropin deficiency is caused by a deficiency of either hypothalamic gonadotropin-releasing hormone (GnRH) or pituitary gonadotropins, namely follicle-stimulating hormone (FSH) and luteinising hormone (LH). HPG axis dysfunction results in oestrogen and testosterone deficiency in women and men, respectively. Replacement of deficient sex hormones is the mainstay of treatment in individuals not seeking fertility. Oestrogen and testosterone replacement in women and men, respectively, have numerous beneficial health impacts. These benefits include improved body composition, enhanced insulin sensitivity, improved atherogenic lipid profiles and increased bone mineral density. Oestrogen replacement in women also reduces the risk of developing type 2 diabetes mellitus. When women and men are considered together, untreated gonadotropin deficiency is independently associated with an increased mortality risk. However, treatment with sex hormone replacement reduces the mortality risk comparable to those with an intact gonadal axis. The reasons for the sex disparities in mortality remain poorly understood. Potential explanations include the reversal of women's natural survival advantage over men, premature loss of oestrogen's cardioprotective effect, less aggressive cardiovascular risk factor modification and inadequate oestrogen replacement in women with gonadotropin deficiency. Regrettably, historical inertia and unfounded concerns about the safety of oestrogen replacement in women of reproductive age have impeded the treatment of gonadotropin deficiency.
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Affiliation(s)
- Darran Mc Donald
- Department of Endocrinology, Beaumont Hospital, Royal College of Surgeons of Ireland, Dublin 9, Dublin, Ireland
- Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Tara McDonnell
- Department of Endocrinology, Beaumont Hospital, Royal College of Surgeons of Ireland, Dublin 9, Dublin, Ireland
- Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Michael W O'Reilly
- Department of Endocrinology, Beaumont Hospital, Royal College of Surgeons of Ireland, Dublin 9, Dublin, Ireland
- Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Mark Sherlock
- Department of Endocrinology, Beaumont Hospital, Royal College of Surgeons of Ireland, Dublin 9, Dublin, Ireland.
- Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.
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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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Abildgaard J, Bang AK, Nordkap L, Priskorn L, Jørgensen N. The influence of body composition on the response to dynamic stimulation of the endocrine pituitary-testis axis. Int J Obes (Lond) 2024; 48:1216-1222. [PMID: 38609526 PMCID: PMC11347364 DOI: 10.1038/s41366-024-01518-2] [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: 01/09/2024] [Revised: 03/27/2024] [Accepted: 04/02/2024] [Indexed: 04/14/2024]
Abstract
BACKGROUND Testosterone treatment is generally not recommended in men with obesity induced low serum testosterone. However, distinguishing this condition from overt testosterone deficiency in men with obesity where treatment should be initiated is a diagnostic challenge and tools to differentiate these conditions are scarce but could be of important clinical relevance. OBJECTIVES To investigate the association between body composition and dynamic responses of the pituitary-testis axis in men. METHODS Single-center cross-sectional study including 112 healthy men. Participants went through a full biochemical assessment of the pituitary-testis axis, and dynamic stimulatory tests of luteinizing hormone (LH) secretion (gonadotropin-releasing hormone (GnRH)-test) and testosterone secretion (choriogonadotropin (hCG)-test). A subset (N = 78) further had a DXA-scan performed. RESULTS A higher body mass index (BMI) was associated with lower basal serum LH (BU = -0.44, 95% CI: -0.88--0.01, p = 0.04). The GnRH-stimulated LH increase was not significantly associated with BMI (BU = -0.10, 95% CI: -0.72-0.51, p = 0.74). Furthermore, a high BMI was associated with low basal testosterone (BU -0.02, 95% CI: -0.03--0.02, p < 0.001), and free testosterone (BU -15.0, 95% CI: -19.9--10.0, p < 0.001) and men with overweight and obesity had significantly lower testosterone (9%, p = 0.003 and 24%, p < 0.001) and free testosterone (25%, p = 0.006 and 50%, p < 0.001) concentrations compared to men with normal weight. The HCG-stimulated testosterone increase was significantly less dependent on BMI compared to the influence of BMI on basal testosterone concentrations (p = 0.04 for the interaction). CONCLUSIONS Dynamic sex hormone responses following pituitary-testis axis stimulation were less dependent on BMI, compared to the influence of BMI on basal hormone concentrations and could potentially assist clinical decision making in patients with obesity suspected of testosterone deficiency.
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Affiliation(s)
- Julie Abildgaard
- Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
- The Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Anne Kirstine Bang
- Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Loa Nordkap
- Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Lærke Priskorn
- Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Niels Jørgensen
- Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
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Grossmann M, Wittert GA. Testosterone in prevention and treatment of type 2 diabetes in men: Focus on recent randomized controlled trials. Ann N Y Acad Sci 2024; 1538:45-55. [PMID: 39039746 DOI: 10.1111/nyas.15188] [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] [Indexed: 07/24/2024]
Abstract
In epidemiological studies, lowered serum testosterone concentrations are common in men with obesity, prediabetes, and established type 2 diabetes (T2D). In men with prediabetes, lowered serum testosterone also predicts a future risk of T2D in men. Administration of testosterone consistently reduces fat mass and increases skeletal muscle mass-body compositional changes expected to be metabolically favorable. In men with established T2D, the effects of testosterone treatment on glycemic measures are inconsistent. Irrespective of baseline serum testosterone concentration in men with prediabetes or newly diagnosed early-onset T2D, testosterone treatment prescribed in conjunction with a lifestyle program has been reported to reduce the risk of T2D by 40% after 2 years, suggesting that either a lifestyle program is required to facilitate the glycemic benefit of testosterone treatment and/or that testosterone treatment has more favorable effects on glycemia in men early in the evolution or onset of the disease. The durability of the benefit and longer-term safety of testosterone treatment have not been established. Therefore, more studies are required before testosterone treatment can be recommended for the prevention and/or treatment of men with or at elevated risk of T2D who do not have hypogonadism due to an established disease of the hypothalamic-pituitary-testicular axis.
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Affiliation(s)
- Mathis Grossmann
- Department of Medicine, Austin Health, The University of Melbourne, Melbourne, Victoria, Australia
- Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia
| | - Gary A Wittert
- Freemasons Centre for Male Health and Well-being, South Australia Health and Medical Research Centre, University of Adelaide, Adelaide, South Australia, Australia
- Endocrine Unit, Royal Adelaide Hospital, Parkville, Victoria, Australia
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Xega V, Liu JL. Beyond reproduction: unraveling the impact of sex hormones on cardiometabolic health. MEDICAL REVIEW (2021) 2024; 4:284-300. [PMID: 39135604 PMCID: PMC11317208 DOI: 10.1515/mr-2024-0012] [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: 02/01/2024] [Accepted: 05/07/2024] [Indexed: 08/15/2024]
Abstract
This review thoroughly explores the multifaceted roles of sexual hormones, emphasizing their impact beyond reproductive functions and underscoring their significant influence on cardiometabolic regulation. It analyzes the broader physiological implications of estrogen, testosterone, and progesterone, highlighting their effects on metabolic syndrome, lipid metabolism, glucose homeostasis, and cardiovascular health. Drawing from diverse molecular, clinical, and therapeutic studies, the paper delves into the intricate interplay between these hormones and cardiometabolic processes. By presenting a comprehensive analysis that goes beyond traditional perspectives, and recognizing sexual hormones as more than reproductive agents, the review sheds light on their broader significance in health and disease management, advocating for holistic and personalized medical approaches.
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Affiliation(s)
- Viktoria Xega
- MeDiC Program, The Research Institute of McGill University Health Centre, Montreal, Canada
| | - Jun-Li Liu
- Division of Endocrinology and Metabolism, Department of Medicine, McGill University, Montreal, Canada
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Cruickshank M, Hudson J, Hernández R, Aceves-Martins M, Quinton R, Gillies K, Aucott LS, Kennedy C, Manson P, Oliver N, Wu F, Bhattacharya S, Dhillo WS, Jayasena CN, Brazzelli M. The effects and safety of testosterone replacement therapy for men with hypogonadism: the TestES evidence synthesis and economic evaluation. Health Technol Assess 2024; 28:1-210. [PMID: 39248210 PMCID: PMC11404359 DOI: 10.3310/jryt3981] [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] [Indexed: 09/10/2024] Open
Abstract
Background Low levels of testosterone cause male hypogonadism, which is associated with sexual dysfunction, tiredness and reduced muscle strength and quality of life. Testosterone replacement therapy is commonly used for ameliorating symptoms of male hypogonadism, but there is uncertainty about the magnitude of its effects and its cardiovascular and cerebrovascular safety. Aims of the research The primary aim was to evaluate the safety of testosterone replacement therapy. We also assessed the clinical and cost-effectiveness of testosterone replacement therapy for men with male hypogonadism, and the existing qualitative evidence on men's experience and acceptability of testosterone replacement therapy. Design Evidence synthesis and individual participant data meta-analysis of effectiveness and safety, qualitative evidence synthesis and model-based cost-utility analysis. Data sources Major electronic databases were searched from 1992 to February 2021 and were restricted to English-language publications. Methods We conducted a systematic review with meta-analysis of individual participant data according to current methodological standards. Evidence was considered from placebo-controlled randomised controlled trials assessing the effects of any formulation of testosterone replacement therapy in men with male hypogonadism. Primary outcomes were mortality and cardiovascular and cerebrovascular events. Data were extracted by one reviewer and cross-checked by a second reviewer. The risk of bias was assessed using the Cochrane Risk of Bias tool. We performed one-stage meta-analyses using the acquired individual participant data and two-stage meta-analyses to integrate the individual participant data with data extracted from eligible studies that did not provide individual participant data. A decision-analytic Markov model was developed to evaluate the cost per quality-adjusted life-years of the use of testosterone replacement therapy in cohorts of patients of different starting ages. Results We identified 35 trials (5601 randomised participants). Of these, 17 trials (3431 participants) provided individual participant data. There were too few deaths to assess mortality. There was no difference between the testosterone replacement therapy group (120/1601, 7.5%) and placebo group (110/1519, 7.2%) in the incidence of cardiovascular and/or cerebrovascular events (13 studies, odds ratio 1.07, 95% confidence interval 0.81 to 1.42; p = 0.62). Testosterone replacement therapy improved quality of life and sexual function in almost all patient subgroups. In the testosterone replacement therapy group, serum testosterone was higher while serum cholesterol, triglycerides, haemoglobin and haematocrit were all lower. We identified several themes from five qualitative studies showing how symptoms of low testosterone affect men's lives and their experience of treatment. The cost-effectiveness of testosterone replacement therapy was dependent on whether uncertain effects on all-cause mortality were included in the model, and on the approach used to estimate the health state utility increment associated with testosterone replacement therapy, which might have been driven by improvements in symptoms such as sexual dysfunction and low mood. Limitations A meaningful evaluation of mortality was hampered by the limited number of defined events. Definition and reporting of cardiovascular and cerebrovascular events and methods for testosterone measurement varied across trials. Conclusions Our findings do not support a relationship between testosterone replacement therapy and cardiovascular/cerebrovascular events in the short-to-medium term. Testosterone replacement therapy improves sexual function and quality of life without adverse effects on blood pressure, serum lipids or glycaemic markers. Future work Rigorous long-term evidence assessing the safety of testosterone replacement therapy and subgroups most benefiting from treatment is needed. Study registration The study is registered as PROSPERO CRD42018111005. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/68/01) and is published in full in Health Technology Assessment; Vol. 28, No. 43. See the NIHR Funding and Awards website for further award information.
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Affiliation(s)
| | - Jemma Hudson
- Health Services Research Unit, University of Aberdeen, Aberdeen, UK
| | - Rodolfo Hernández
- Health Economics Research Unit, University of Aberdeen, Aberdeen, UK
| | | | - Richard Quinton
- Department of Endocrinology, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
| | - Katie Gillies
- Health Services Research Unit, University of Aberdeen, Aberdeen, UK
| | - Lorna S Aucott
- Health Services Research Unit, University of Aberdeen, Aberdeen, UK
| | - Charlotte Kennedy
- Health Economics Research Unit, University of Aberdeen, Aberdeen, UK
| | - Paul Manson
- Health Services Research Unit, University of Aberdeen, Aberdeen, UK
| | | | - Frederick Wu
- Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, UK
| | - Siladitya Bhattacharya
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK
| | | | | | - Miriam Brazzelli
- Health Services Research Unit, University of Aberdeen, Aberdeen, UK
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Jaiswal V, Sawhney A, Nebuwa C, Borra V, Deb N, Halder A, Rajak K, Jha M, Wajid Z, Thachil R, Bandyopadhyay D, Mattumpuram J, Lavie CJ. Association between testosterone replacement therapy and cardiovascular outcomes: A meta-analysis of 30 randomized controlled trials. Prog Cardiovasc Dis 2024; 85:45-53. [PMID: 38589271 DOI: 10.1016/j.pcad.2024.04.001] [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: 04/01/2024] [Accepted: 04/01/2024] [Indexed: 04/10/2024]
Abstract
BACKGROUND The Cardiovascular safety of testosterone replacement therapy (TRT) among men with hypogonadism is not well established to date. Hence, we sought to evaluate the cardiovascular disease (CVD) outcomes among patients receiving testosterone therapy by using all recently published randomized controlled trials. METHODS We performed a systematic literature search on PubMed, EMBASE, and Clinicaltrial.gov for relevant randomized controlled trials (RCTs) from inception until September 30th, 2023. RESULTS A total of 30 randomized trials with 11,502 patients were included in the final analysis. The mean age was ranging from 61.61 to 61.82 years. Pooled analysis of primary and secondary outcomes showed that the incidence of any CVD events (OR, 1.12 (95%CI: 0.77-1.62), P = 0.55), stroke (OR, 1.01 (95%CI: 0.68-1.51), P = 0.94), myocardial infarction (OR, 1.05 (95%CI: 0.76-1.45), P = 0.77), all-cause mortality (OR, 0.94 (95%CI: 0.76-1.17), P = 0.57), and CVD mortality (OR, 0.87 (95%CI: 0.65-1.15), P = 0.31) was comparable between TRT and placebo groups. CONCLUSION Our analysis indicates that for patients with hypogonadism, testosterone replacement therapy does not increase the CVD risk and all-cause mortality.
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Affiliation(s)
- Vikash Jaiswal
- Department of Cardiovascular Research, Larkin Community Hospital, South Miami, FL, USA.
| | - Aanchal Sawhney
- Department of Internal Medicine, Crozer Chester Medical Center, Upland, PA, USA
| | - Chikodili Nebuwa
- Department of Internal Medicine, Nuvance Health, Poughkeepsie, NY, USA
| | - Vamsikalyan Borra
- Department of Internal Medicine, University of Texas Rio Grande Valley, Weslaco, TX, USA
| | - Novonil Deb
- North Bengal Medical College and Hospital, India
| | - Anupam Halder
- Department of Internal Medicine, UPMC, Harrisburg, PA, USA
| | - Kripa Rajak
- Department of Internal Medicine, UPMC, Harrisburg, PA, USA
| | - Mayank Jha
- Department of Medicine, Government Medical College, Surat, India
| | - Zarghoona Wajid
- Department of Internal Medicine, Wayne State University School of Medicine, USA
| | - Rosy Thachil
- Division of Cardiology, Elmhurst Hospital Center, Mount Sinai School of Medicine, New York, USA
| | | | - Jishanth Mattumpuram
- Division of Cardiology, University of Louisville School of Medicine, KY 40202, United States
| | - Carl J Lavie
- Department of Cardiovascular Disease, John Ochsner Heart and Vascular Institute, New Orleans, LA, USA.
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14
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Seipone ID, Mendham AE, Storbeck KH, Oestlund I, Kufe CN, Chikowore T, Masemola M, Crowther NJ, Kengne AP, Norris S, Olsson T, Brown T, Micklesfield LK, Goedecke JH. SHBG, Free Testosterone, and Type 2 Diabetes Risk in Middle-aged African Men: A Longitudinal Study. J Endocr Soc 2024; 8:bvae129. [PMID: 39055720 PMCID: PMC11272087 DOI: 10.1210/jendso/bvae129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Indexed: 07/27/2024] Open
Abstract
Objectives To investigate longitudinal changes in SHBG and free testosterone (free T) levels among Black middle-aged African men, with and without coexistent HIV, and explore associations with incident dysglycaemia and measures of glucose metabolism. Design This longitudinal study enrolled 407 Black South African middle-aged men, comprising primarily 322 men living without HIV (MLWOH) and 85 men living with HIV (MLWH), with normal fasting glucose at enrollment. Follow-up assessments were conducted after 3.1 ± 1.5 years. Methods At baseline and follow-up, SHBG, albumin, and total testosterone were measured and free T was calculated. An oral glucose tolerance test at follow-up determined dysglycaemia (impaired fasting glucose, impaired glucose tolerance, type 2 diabetes) and glucose metabolism parameters including insulin sensitivity (Matsuda index), insulin resistance (homeostasis model assessment of insulin resistance), and beta(β)-cell function (disposition index). The primary analysis focussed on MLWOH, with a subanalysis on MLWH to explore whether associations in MLWOH differed from MLWH. Results The prevalence of dysglycaemia at follow-up was 17% (n = 55) in MLWOH. Higher baseline SHBG was associated with a lower risk of incident dysglycaemia (odds ratio 0.966; 95% confidence interval 0.945-0.987) and positively associated with insulin sensitivity (β = 0.124, P < .001) and β-cell function (β = 0.194, P = .001) at follow-up. Free T did not predict dysglycaemia. In MLWH, dysglycaemia prevalence at follow-up was 12% (n = 10). Neither baseline SHBG nor free T were associated with incident dysglycaemia and glucose metabolism parameters in MLWH. Conclusion SHBG levels predict the development of dysglycaemia in middle-aged African men but do not exhibit the same predictive value in MLWH.
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Affiliation(s)
- Ikanyeng D Seipone
- Biomedical Research Innovation Platform, South African Medical Research Council, Cape Town 7505, South Africa
| | - Amy E Mendham
- Riverland Academy of Clinical Excellence, Riverland Mallee Coorong Local Health Network, South Australia Health, Berri, SA 5343, Australiacountry
- South African Medical Research Council/WITS Developmental Pathways for Health Research Unit, Department of Paediatrics, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa
- Health through Physical Activity, Lifestyle and Sport Research Centre, FIMS International Collaborating Centre of Sports Medicine, Division of Physiological Sciences, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town 7701, South Africa
| | - Karl-Heinz Storbeck
- Department of Biochemistry, Stellenbosch University, Stellenbosch 7602, South Africa
| | - Imken Oestlund
- Department of Biochemistry, Stellenbosch University, Stellenbosch 7602, South Africa
| | - Clement N Kufe
- South African Medical Research Council/WITS Developmental Pathways for Health Research Unit, Department of Paediatrics, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa
| | - Tinashe Chikowore
- South African Medical Research Council/WITS Developmental Pathways for Health Research Unit, Department of Paediatrics, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa
| | - Maphoko Masemola
- South African Medical Research Council/WITS Developmental Pathways for Health Research Unit, Department of Paediatrics, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa
| | - Nigel J Crowther
- Department of Chemical Pathology, National Health Laboratory Service and University of the Witwatersrand Faculty of Health Sciences, Johannesburg 2000, South Africa
| | - Andre Pascal Kengne
- Non-Communicable Diseases Research Unit, South African Medical Research Council, Cape Town 7505, South Africa
| | - Shane Norris
- South African Medical Research Council/WITS Developmental Pathways for Health Research Unit, Department of Paediatrics, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa
| | - Tommy Olsson
- Department of Public Health and Clinical Medicine, Umeå University, Umeå 90187, Sweden
| | - Todd Brown
- Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA
| | - Lisa K Micklesfield
- South African Medical Research Council/WITS Developmental Pathways for Health Research Unit, Department of Paediatrics, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa
| | - Julia H Goedecke
- Biomedical Research Innovation Platform, South African Medical Research Council, Cape Town 7505, South Africa
- South African Medical Research Council/WITS Developmental Pathways for Health Research Unit, Department of Paediatrics, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa
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15
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Shenoy MT, Mondal S, Fernandez CJ, Pappachan JM. Management of male obesity-related secondary hypogonadism: A clinical update. World J Exp Med 2024; 14:93689. [PMID: 38948417 PMCID: PMC11212738 DOI: 10.5493/wjem.v14.i2.93689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 04/22/2024] [Accepted: 05/15/2024] [Indexed: 06/19/2024] Open
Abstract
The global obesity pandemic has resulted in a rise in the prevalence of male obesity-related secondary hypogonadism (MOSH) with emerging evidence on the role of testosterone therapy. We aim to provide an updated and practical approach towards its management. We did a comprehensive literature search across MEDLINE (via PubMed), Scopus, and Google Scholar databases using the keywords "MOSH" OR "Obesity-related hypogonadism" OR "Testosterone replacement therapy" OR "Selective estrogen receptor modulator" OR "SERM" OR "Guidelines on male hypogonadism" as well as a manual search of references within the articles. A narrative review based on available evidence, recommendations and their practical implications was done. Although weight loss is the ideal therapeutic strategy for patients with MOSH, achievement of significant weight reduction is usually difficult with lifestyle changes alone in real-world practice. Therefore, androgen administration is often necessary in the management of hypogonadism in patients with MOSH which also improves many other comorbidities related to obesity. However, there is conflicting evidence for the appropriate use of testosterone replacement therapy (TRT), and it can also be associated with complications. This evidence-based review updates the available evidence including the very recently published results of the TRAVERSE trial and provides comprehensive clinical practice pearls for the management of patients with MOSH. Before starting testosterone replacement in functional hypogonadism of obesity, it would be desirable to initiate lifestyle modification to ensure weight reduction. TRT should be coupled with the management of other comorbidities related to obesity in MOSH patients. Balancing the risks and benefits of TRT should be considered in every patient before and during long-term management.
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Affiliation(s)
- Mohan T Shenoy
- Department of Endocrinology, Sree Gokulam Medical College, and Research Foundation, Trivandrum 695607, Kerala, India
| | - Sunetra Mondal
- Department of Endocrinology, NRS Medical College and Hospital, Kolkata 700014, West Bengal, India
| | - Cornelius James Fernandez
- Department of Endocrinology & Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, United Kingdom
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
- Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M13 9PL, United Kingdom
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Ravi H, Das S, Devi Rajeswari V, Venkatraman G, Choudhury AA, Chakraborty S, Ramanathan G. Hormonal regulation in diabetes: Special emphasis on sex hormones and metabolic traits. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2024; 142:257-291. [PMID: 39059988 DOI: 10.1016/bs.apcsb.2023.12.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/28/2024]
Abstract
Diabetes constitutes a significant global public health challenge that is rapidly reaching epidemic proportions. Among the non-communicable diseases, the incidence of diabetes is rising at an alarming rate. The International Diabetes Federation has documented a 9.09% prevalence of diabetes among individuals aged between 20 and 79 years. The interplay of gonadal hormones and gender differences is critical in regulating insulin sensitivity and glucose tolerance, and this dynamic is particularly crucial because of the escalating incidence of diabetes. Variations in insulin sensitivity are observed across genders, levels of adiposity, and age groups. Both estrogen and testosterone are seen to influence glucose metabolism and insulin sensitivity. This chapter surveys the present knowledge of sex differences, sex hormones, and chromosomes on insulin imbalance and diabetes development. It further highlights the influence of metabolic traits in diabetes and changes in sex hormones during diabetic pregnancy. Notably, even stressful lifestyles have been acknowledged to induce hormonal imbalances. Furthermore, it discusses the potential of hormonal therapy to help stabilize sex hormones in diabetic individuals and focuses on the most recent research investigating the correlation between sex hormones and diabetes.
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Affiliation(s)
- Harini Ravi
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Soumik Das
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - V Devi Rajeswari
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Ganesh Venkatraman
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Abbas Alam Choudhury
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Shreya Chakraborty
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Gnanasambandan Ramanathan
- Department of Bio-Medical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India.
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Tishova Y, Kalinchenko S, Mskhalaya G, Hackett G, Livingston M, König C, Strange R, Zitzmann M, Mann A, Maarouf A, Ramachandran S. Testosterone therapy reduces insulin resistance in men with adult-onset testosterone deficiency and metabolic syndrome. Results from the Moscow Study, a randomized controlled trial with an open-label phase. Diabetes Obes Metab 2024; 26:2147-2157. [PMID: 38433502 DOI: 10.1111/dom.15520] [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: 12/18/2023] [Revised: 02/01/2024] [Accepted: 02/11/2024] [Indexed: 03/05/2024]
Abstract
AIMS To describe changes in homeostasis model assessment of insulin resistance index (HOMA-IR) following testosterone therapy in men with hypogonadism and metabolic syndrome (MetS). MATERIALS AND METHODS A randomized, placebo-controlled, double-blind randomized controlled trial (RCT) comprising 184 men with MetS and hypogonadism (testosterone undecanoate [TU]: 113 men, placebo: 71 men) was conducted. This was followed by an open-label phase in which all men were given TU. We focused on men who were not receiving antiglycaemic agents (TU: 81 men; placebo: 54 men) as these could affect HOMA-IR. Inter-group comparison of HOMA-IR was restricted to the RCT (30 weeks), whilst intra-group comparison was carried out on men provided TU during the RCT and open-label phases (study cohort) and men given placebo during the RCT and then switched to TU during the open-label phase (confirmatory cohort). Regression analysis was performed to identify factors associated with change in HOMA-IR (∆HOMA-IR). RESULTS The median HOMA-IR was significantly reduced at almost every time point (after 18 weeks) compared to baseline in men receiving TU in both the study and confirmatory cohorts. There was a significant decrease in median values of fasting glucose (30 weeks: -2.1%; 138 weeks: -4.9%) and insulin (30 weeks: -10.5%; 138 weeks: -35.5%) after TU treatment. Placebo was not associated with significant ∆HOMA-IR. The only consistent predictor of HOMA-IR decrease following TU treatment was baseline HOMA-IR (r2 ≥ 0.64). CONCLUSIONS Baseline HOMA-IR predicted ΔHOMA-IR, with a greater percentage change in insulin than in fasting glucose. In men with MetS/type 2 diabetes (T2DM) not on antiglycaemic therapy, improvements in HOMA-IR may be greater than suggested by change in fasting glucose. Our results suggest that hypogonadism screening be included in the management of men with MetS/T2DM.
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Affiliation(s)
- Yuliya Tishova
- Department of Endocrinology, Medical Clinic K-medicine, Moscow, Russia
| | - Svetlana Kalinchenko
- Department of Endocrinology, People's Friendship University of Russia, Moscow, Russia
| | - George Mskhalaya
- Department of Preventive Medicine, European Medical Center, Moscow, Russia
| | - Geoffrey Hackett
- School of Health and Life Sciences, Aston University, Birmingham, UK
| | - Mark Livingston
- Department of Clinical Biochemistry, Black Country Pathology Services, Walsall Manor Hospital, UK
- School of Medicine and Clinical Practice, Faculty of Science and Engineering, The University of Wolverhampton, Wolverhampton, UK
| | - Carola König
- Department of Mechanical and Aerospace Engineering, Brunel University, London, UK
| | - Richard Strange
- School of Pharmacy and Bioengineering, Keele University, Staffordshire, UK
| | - Michael Zitzmann
- Department of Clinical and Surgical Andrology, Centre of Reproductive Medicine and Andrology, Munster University Hospital, Munster, Germany
| | - Amar Mann
- Department of Clinical Biochemistry, University Hospitals Birmingham NHS Foundation Trust, West Midlands, UK
| | - Amro Maarouf
- Department of Clinical Biochemistry, University Hospitals Birmingham NHS Foundation Trust, West Midlands, UK
| | - Sudarshan Ramachandran
- Department of Mechanical and Aerospace Engineering, Brunel University, London, UK
- School of Pharmacy and Bioengineering, Keele University, Staffordshire, UK
- Department of Clinical Biochemistry, University Hospitals Birmingham NHS Foundation Trust, West Midlands, UK
- Department of Clinical Biochemistry, University Hospitals of North Midlands NHS Foundation Trust, Staffordshire, UK
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18
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Corona G, Rastrelli G, Sparano C, Carinci V, Casella G, Vignozzi L, Sforza A, Maggi M. Cardiovascular safety of testosterone replacement therapy in men: an updated systematic review and meta-analysis. Expert Opin Drug Saf 2024; 23:565-579. [PMID: 38553429 DOI: 10.1080/14740338.2024.2337741] [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: 12/29/2023] [Accepted: 03/28/2023] [Indexed: 05/07/2024]
Abstract
INTRODUCTION The cardiovascular (CV) safety of testosterone (T) replacement therapy (TRT) is still conflicting. Recent data suggested a TRT-related increased risk of atrial fibrillation (AF). The aim of this study was to systematic review and meta-analyze CV risk related to TRT as derived from placebo controlled randomized trials (RCTs). AREAS COVERED An extensive Medline, Embase, and Cochrane search was performed. All placebo-controlled RCTs reporting data on TRT-related CV safety were considered. To better analyze the role of T on AF, population-based studies investigating the relationship between endogenous circulating T levels and AF incidence were also included and analyzed. EXPERT OPINION Out of 3.615, 106 studies were considered, including 8.126 subjects treated with TRT and 7.310 patients allocated to placebo. No difference between TRT and placebo was observed when major adverse CV events were considered. Whereas the incidence of non-fatal arrhythmias and AF was increased in the only trial considering CV safety as the primary endpoint, this was not confirmed when all other studies were considered (MH-OR 1.61[0.84;3.08] and 1.44[0.46;4.46]). Similarly, no relationship between endogenous T levels and AF incidence was observed after the adjustment for confounders Available data confirm that TRT is safe and it is not related to an increased CV risk.
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Affiliation(s)
- Giovanni Corona
- Endocrinology Unit, Azienda AUSL, Maggiore Hospital, Bologna, Italy
| | - Giulia Rastrelli
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Mario Serio" Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Clotilde Sparano
- Endocrinology Unit, Mario Serio" Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Valeria Carinci
- Cardiology Unit, Azienda AUSL, Maggiore Hospital, Bologna, Italy
| | - Gianni Casella
- Cardiology Unit, Azienda AUSL, Maggiore Hospital, Bologna, Italy
| | - Linda Vignozzi
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Mario Serio" Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | | | - Mario Maggi
- Endocrinology Unit, Mario Serio" Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
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19
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Choi S, Chon J, Yoo MC, Shim GY, Kim M, Soh Y, Won CW. The Association of Free Testosterone with Sarcopenic Obesity in Community-Dwelling Older Men: A Cross-Sectional Study. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:754. [PMID: 38792937 PMCID: PMC11123342 DOI: 10.3390/medicina60050754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 04/27/2024] [Accepted: 04/30/2024] [Indexed: 05/26/2024]
Abstract
Background and Objectives: Sarcopenic obesity, a clinical condition coexisting with obesity and sarcopenia, is associated with a high risk of functional impairment, reduced quality of life, and increased mortality. A decline in age-related free testosterone (FT) levels has been reported to be associated with decreased muscle mass and muscle strength and increased fat mass. However, the association between low FT levels and risk of sarcopenic obesity has not been well studied. This study aimed to investigate the direct association between low FT levels and sarcopenic obesity. Materials and Methods: This cross-sectional study used data of 982 community-dwelling men aged 70-84 years from the Korean Frailty and Aging Cohort Study. Sarcopenia was defined according to the criteria of the Asian Group for Sarcopenia (AWGS) 2019. Obesity was defined as a body fat mass ≥28.3%. Participants who met both sarcopenia and obesity criteria were defined as having sarcopenic obesity. Low FT levels were defined as FT levels <17.35 pmol/L according to the Endocrine Society Clinical Practice Guidelines. Results: The prevalence of sarcopenia, obesity, and sarcopenic obesity was significantly higher in the low-FT group than in the normal-FT group. Low FT levels were significantly associated with a higher risk of obesity (odds ratio [OR], 2.09, 95% confidence interval [CI], 1.11-3.92), sarcopenia (2.57, 95% CI 1.08-6.10), and sarcopenic obesity (3.66, 95% CI 1.58-8.47) compared with the healthy control group. The risk of low appendicular skeletal muscle mass index (ASMI) (1.78, 95% CI 1.04-3.02) and high fat mass (1.92, 95% CI 1.12-3.31) was significantly higher in the low-FT group than in the normal-FT group. Conclusions: This study showed that low FT levels were associated with a higher risk of sarcopenic obesity. Low FT levels were mainly related to body composition parameters such as low ASMI and high fat mass.
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Affiliation(s)
- Seongmin Choi
- Department of Physical Medicine and Rehabilitation Medicine, Kyung Hee University Medical Center, Seoul 02477, Republic of Korea; (S.C.); (J.C.); (M.C.Y.); (G.Y.S.)
- Department of Physical Medicine and Rehabilitation, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jinmann Chon
- Department of Physical Medicine and Rehabilitation Medicine, Kyung Hee University Medical Center, Seoul 02477, Republic of Korea; (S.C.); (J.C.); (M.C.Y.); (G.Y.S.)
| | - Myung Chul Yoo
- Department of Physical Medicine and Rehabilitation Medicine, Kyung Hee University Medical Center, Seoul 02477, Republic of Korea; (S.C.); (J.C.); (M.C.Y.); (G.Y.S.)
| | - Ga Yang Shim
- Department of Physical Medicine and Rehabilitation Medicine, Kyung Hee University Medical Center, Seoul 02477, Republic of Korea; (S.C.); (J.C.); (M.C.Y.); (G.Y.S.)
| | - Miji Kim
- Department of Biomedical Science and Technology, College of Medicine, East-West Medical Research Institute, Kyung Hee University, Seoul 02447, Republic of Korea;
| | - Yunsoo Soh
- Department of Physical Medicine and Rehabilitation Medicine, Kyung Hee University Medical Center, Seoul 02477, Republic of Korea; (S.C.); (J.C.); (M.C.Y.); (G.Y.S.)
| | - Chang Won Won
- Department of Family Medicine, Kyung Hee University Medical Center, Seoul 02447, Republic of Korea
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20
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Bhasin S, Lincoff AM, Nissen SE, Wannemuehler K, McDonnell ME, Peters AL, Khan N, Snabes MC, Li X, Li G, Buhr K, Pencina KM, Travison TG. Effect of Testosterone on Progression From Prediabetes to Diabetes in Men With Hypogonadism: A Substudy of the TRAVERSE Randomized Clinical Trial. JAMA Intern Med 2024; 184:353-362. [PMID: 38315466 PMCID: PMC10845044 DOI: 10.1001/jamainternmed.2023.7862] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 11/29/2023] [Indexed: 02/07/2024]
Abstract
Importance The effect of testosterone replacement therapy (TRT) in men with hypogonadism on the risk of progression from prediabetes to diabetes or of inducing glycemic remission in those with diabetes is unknown. Objective To evaluate the efficacy of TRT in preventing progression from prediabetes to diabetes in men with hypogonadism who had prediabetes and in inducing glycemic remission in those with diabetes. Design, Setting, and Participants This nested substudy, an intention-to-treat analysis, within a placebo-controlled randomized clinical trial (Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy Response in Hypogonadal Men [TRAVERSE]) was conducted at 316 trial sites in the US. Participants included men aged 45 to 80 years with hypogonadism and prediabetes or diabetes who were enrolled in TRAVERSE between May 23, 2018, and February 1, 2022. Intervention Participants were randomized 1:1 to receive 1.62% testosterone gel or placebo gel until study completion. Main Outcomes and Measures The primary end point was the risk of progression from prediabetes to diabetes, analyzed using repeated-measures log-binomial regression. The secondary end point was the risk of glycemic remission (hemoglobin A1c level <6.5% [to convert to proportion of total hemoglobin, multiply by 0.01] or 2 fasting glucose measurements <126 mg/dL [to convert to mmol/L, multiply by 0.0555] without diabetes medication) in men who had diabetes. Results Of 5204 randomized participants, 1175 with prediabetes (mean [SD] age, 63.8 [8.1] years) and 3880 with diabetes (mean [SD] age, 63.2 [7.8] years) were included in this study. Mean (SD) hemoglobin A1c level in men with prediabetes was 5.8% (0.4%). Risk of progression to diabetes did not differ significantly between testosterone and placebo groups: 4 of 598 (0.7%) vs 8 of 562 (1.4%) at 6 months, 45 of 575 (7.8%) vs 57 of 533 (10.7%) at 12 months, 50 of 494 (10.1%) vs 67 of 460 (14.6%) at 24 months, 46 of 359 (12.8%) vs 52 of 330 (15.8%) at 36 months, and 22 of 164 (13.4%) vs 19 of 121 (15.7%) at 48 months (omnibus test P = .49). The proportions of participants with diabetes who experienced glycemic remission and the changes in glucose and hemoglobin A1c levels were similar in testosterone- and placebo-treated men with prediabetes or diabetes. Conclusions and Relevance In men with hypogonadism and prediabetes, the incidence of progression from prediabetes to diabetes did not differ significantly between testosterone- and placebo-treated men. Testosterone replacement therapy did not improve glycemic control in men with hypogonadism and prediabetes or diabetes. These findings suggest that TRT alone should not be used as a therapeutic intervention to prevent or treat diabetes in men with hypogonadism. Trial Registration ClinicalTrials.gov Identifier: NCT03518034.
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Affiliation(s)
- 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
| | - A. Michael Lincoff
- Cleveland Clinic Coordinating Center for Clinical Research, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
| | - Steven E. Nissen
- Cleveland Clinic Coordinating Center for Clinical Research, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
| | - Kathleen Wannemuehler
- Department of Biostatistics and Medical Informatics, Statistical Data Analysis Center, University of Wisconsin−Madison
| | - Marie E. McDonnell
- Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Anne L. Peters
- University of Southern California Clinical Diabetes Program, The Keck School of Medicine of the University of Southern California, Los Angeles
| | | | | | - Xue Li
- AbbVie Inc, North Chicago, Illinois
| | - Geng Li
- Department of Biostatistics and Medical Informatics, Statistical Data Analysis Center, University of Wisconsin−Madison
| | - Kevin Buhr
- Department of Biostatistics and Medical Informatics, Statistical Data Analysis Center, University of Wisconsin−Madison
| | - 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, Boston, Massachusetts
- Division of Gerontology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
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21
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Sood A, Hosseinpour A, Sood A, Avula S, Durrani J, Bhatia V, Gupta R. Cardiovascular Outcomes of Hypogonadal Men Receiving Testosterone Replacement Therapy: A Meta-analysis of Randomized Controlled Trials. Endocr Pract 2024; 30:2-10. [PMID: 37797887 DOI: 10.1016/j.eprac.2023.09.012] [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: 08/25/2023] [Revised: 09/25/2023] [Accepted: 09/27/2023] [Indexed: 10/07/2023]
Abstract
OBJECTIVE To investigate the impact of testosterone replacement therapy (TRT) on cardiovascular outcomes in hypogonadal men. METHODS A meta-analysis of 26 randomized controlled trials involving 10 941 participants was conducted. Various clinical outcomes, including all-cause mortality, cardiovascular-related mortality, myocardial infarction, stroke, congestive heart failure, atrial fibrillation, pulmonary embolism, and venous thrombosis, were assessed. RESULTS No statistically significant differences were observed between the TRT group and the control group in terms of these clinical outcomes. Sensitivity analysis and publication bias assessment supported the robustness of the findings. Meta-regression analysis found no significant associations between clinical outcomes and potential covariates, including age, diabetes, hypertension, dyslipidemia, and smoking. DISCUSSION Previous research on TRT and cardiovascular events, with comparisons to studies like the Testosterone Trials and the studies conducted by Vigen et al, Finkle et al, Layton et al, and Wallis et al, is provided. The significance of the systematic review and meta-analysis approach is emphasized, particularly its exclusive focus on hypogonadal patients. CONCLUSION This study offers reassurance that TRT does not increase mortality risk or worsen cardiovascular outcomes in hypogonadal men. However, further research, especially long-term studies involving diverse populations, is essential to strengthen the evidence base and broaden the applicability of these findings.
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Affiliation(s)
- Aayushi Sood
- Department of Internal Medicine, The Wright Center for Graduate Medical Education, Scranton, Pennsylvania.
| | - Alireza Hosseinpour
- Department of Cardiovascular Medicine, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Akshit Sood
- Department of Medicine, Navjivan General and Maternity Hospital, Jalandhar, Punjab, India
| | - Sreekant Avula
- Department of Diabetes, Endocrinology & Metabolism, University of Minnesota, Minneapolis, Minnesota
| | - Jawahar Durrani
- Department of Internal Medicine, The Wright Center for Graduate Medical Education, Scranton, Pennsylvania
| | - Vishal Bhatia
- Division of Endocrinology, Department of Internal Medicine, St Vincent Medical Group, Evansville, Indiana
| | - Rahul Gupta
- Department of Cardiology, Lehigh Valley Heart Institute, Lehigh Valley Health Network, Allentown, Pennsylvania
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22
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Majumdar S, Jacob JJ, Jude EB. Obesity associated hypogonadism—a growing concern in metabolic syndrome. METABOLIC SYNDROME 2024:293-307. [DOI: 10.1016/b978-0-323-85732-1.00054-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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23
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Livingston M, Heald AH. Adult Male Hypogonadism: A Laboratory Medicine Perspective on Its Diagnosis and Management. Diagnostics (Basel) 2023; 13:3650. [PMID: 38132234 PMCID: PMC10743125 DOI: 10.3390/diagnostics13243650] [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: 08/16/2023] [Revised: 11/13/2023] [Accepted: 11/16/2023] [Indexed: 12/23/2023] Open
Abstract
Testosterone (T), the principal androgen secreted by the testes, plays an essential role in male health. Male hypogonadism is diagnosed based on a combination of associated clinical signs and symptoms and laboratory confirmation of low circulating T levels. In this review, we have highlighted factors, both biological and analytical, that introduce variation into the measurement of serum T concentrations in men; these need to be considered when requesting T levels and interpreting results. There is an ongoing need for analytical standardisation of T assays and harmonisation of pre- and post-analytical laboratory practices, particularly in relation to the laboratory reference intervals provided to clinicians. Further, there is a need to share with service users the most up-to-date and evidence-based action thresholds for serum T as recommended in the literature. Estimation of free testosterone may be helpful. Causes of secondary hypogonadism should be considered. A comprehensive approach is required in the management of male hypogonadism, including lifestyle modification as well as medication where appropriate. The goal of treatment is the resolution of symptoms as well as the optimisation of metabolic, cardiovascular, and bone health. The advice of an endocrinologist should be sought when there is doubt about the cause and appropriate management of the hypogonadism.
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Affiliation(s)
- Mark Livingston
- Department of Clinical Biochemistry, Black Country Pathology Services, The Royal Wolverhampton NHS Trust, Wolverhampton WV10 0QP, UK
- School of Medicine and Clinical Practice, The University of Wolverhampton, Wolverhampton WV1 1LY, UK
| | - Adrian H. Heald
- The School of Medicine and Manchester Academic Health Sciences Centre, Manchester University, Manchester M13 9PL, UK;
- Department of Endocrinology and Diabetes, Salford Royal Hospital, Salford M6 8HD, UK
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24
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Nguyen Hoai B, Hoang L, Nguyen Cao T, Pham Minh Q, A Jannini E. Testosterone and aging male, a perspective from a developing country. Aging Male 2023; 26:2223712. [PMID: 37335039 DOI: 10.1080/13685538.2023.2223712] [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: 04/16/2023] [Revised: 05/19/2023] [Accepted: 06/06/2023] [Indexed: 06/21/2023] Open
Abstract
PURPOSE Hypogonadism is associated with a wide range of physical and psychological symptoms that can affect the overall health of men. However, in a developing country, there are several imposing challenges in the diagnosis and treatment of hypogonadism, including a lack of awareness and understanding of the condition among healthcare providers and patients, limited resources and the high cost of treatment. This review aimed to examine the potential benefits and risks of testosterone replacement therapy (TRT) and provides a perspective of a developing country on the topic. MATERIALS AND METHODS A comprehensive literature review was conducted to gather relevant information on the impact of testosterone deficiency on ageing males and the effectiveness of TRT for treating hypogonadism. Published peer-reviewed articles were analyzed to evaluate the benefits and risks of TRT. Additionally, the unique challenges faced in the diagnosis and treatment of hypogonadism in a developing country were considered. RESULTS Testosterone replacement therapy has been shown to be an effective treatment for hypogonadism, particularly in symptomatic men with low testosterone levels. It offers potential benefits such as improvements in symptoms and overall quality of life. However, there are associated risks and side effects that need to be considered. In a developing country, challenges such as limited awareness and understanding of hypogonadism, resource constraints, and high treatment costs pose additional barriers to accessing TRT and comprehensive care. CONCLUSION In conclusion, TRT holds promise as a treatment for hypogonadism, but its implementation and accessibility face significant challenges in a developing country. Addressing these challenges, including raising awareness, allocating resources, and finding cost-effective solutions, is crucial for ensuring that men with hypogonadism in such settings receive appropriate diagnosis and treatment. Further research and efforts are needed to improve the management of hypogonadism in developing countries and optimize the potential benefits of TRT for affected individuals.
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Affiliation(s)
- Bac Nguyen Hoai
- Department of Andrology and Sexual Medicine, Hanoi Medical University's Hospital, Hanoi, Vietnam
| | - Long Hoang
- Department of Urology, Hanoi Medical University's Hospital, Hanoi, Vietnam
| | - Thang Nguyen Cao
- Department of Andrology and Sexual Medicine, Hanoi Medical University's Hospital, Hanoi, Vietnam
| | - Quan Pham Minh
- Department of Andrology and Sexual Medicine, Hanoi Medical University's Hospital, Hanoi, Vietnam
| | - Emmanuele A Jannini
- Chair of Endocrinology and Sexual Medicine (ENDOSEX), University of Rome Tor Vergata, Rome, Italy
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25
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Magnussen LV, Helskov Jørgensen L, Glintborg D, Andersen MS. Hepcidin Reduction during Testosterone Therapy in Men with Type 2 Diabetes: A Randomized, Double-Blinded, Placebo-Controlled Study. Biomedicines 2023; 11:3184. [PMID: 38137405 PMCID: PMC10740671 DOI: 10.3390/biomedicines11123184] [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: 10/09/2023] [Revised: 11/28/2023] [Accepted: 11/28/2023] [Indexed: 12/24/2023] Open
Abstract
High hepcidin is linked to low-grade inflammation and lower iron levels. The consequences of testosterone replacement therapy (TRT) on inflammation and the risk of cardiovascular disease (CVD) are undetermined. We investigate the effect of TRT on the inflammatory cardiovascular risk markers hepcidin-iron, fibroblast growth factor 23 (FGF23)-phosphate-klotho, and calprotectin pathways. METHODS A randomized, placebo-controlled, double-blinded study at an academic tertiary-care medical center. Interventions were testosterone gel (TRT, n = 20) or placebo gel (n = 19) for 24 weeks. We included 39 men (50-70 years) with type 2 diabetes (T2D) on metformin monotherapy with bioavailable testosterone levels <7.3 nmol/L. Body composition was assessed with DXA- and MRI-scans; the main study outcomes were serum hepcidin-iron, FGF23, phosphate, klotho, and calprotectin. RESULTS Hepcidin levels decreased during TRT (β = -9.5 ng/mL, p < 0.001), lean body mass (β = 1.9 kg, p = 0.001) increased, and total fat mass (β = -1.3 kg, p = 0.009) decreased compared to placebo. Delta hepcidin was not associated with changes in lean body mass or fat mass. Iron and the pathways of FGF23-phosphate-klotho and calprotectin were unchanged during TRT. CONCLUSIONS During TRT, the reduction in hepcidin was not associated with circulating iron levels, lean body mass, or fat mass; these findings suggested a direct anti-inflammatory effect of TRT and no indirect effect mediated through these factors.
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Affiliation(s)
- Line Velling Magnussen
- Department of Endocrinology and Metabolism, Odense University Hospital, 5000 Odense, Denmark; (D.G.); (M.S.A.)
| | - Louise Helskov Jørgensen
- Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, 5000 Odense, Denmark;
| | - Dorte Glintborg
- Department of Endocrinology and Metabolism, Odense University Hospital, 5000 Odense, Denmark; (D.G.); (M.S.A.)
| | - Marianne Skovsager Andersen
- Department of Endocrinology and Metabolism, Odense University Hospital, 5000 Odense, Denmark; (D.G.); (M.S.A.)
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26
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Di Costanzo A, Indolfi C, Franzone A, Esposito G, Spaccarotella CAM. Lp(a) in the Pathogenesis of Aortic Stenosis and Approach to Therapy with Antisense Oligonucleotides or Short Interfering RNA. Int J Mol Sci 2023; 24:14939. [PMID: 37834387 PMCID: PMC10573862 DOI: 10.3390/ijms241914939] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 09/28/2023] [Accepted: 10/02/2023] [Indexed: 10/15/2023] Open
Abstract
To date, no medical therapy can slow the progression of aortic stenosis. Fibrocalcific stenosis is the most frequent form in the general population and affects about 6% of the elderly population. Over the years, diagnosis has evolved thanks to echocardiography and computed tomography assessments. The application of artificial intelligence to electrocardiography could further implement early diagnosis. Patients with severe aortic stenosis, especially symptomatic patients, have valve repair as their only therapeutic option by surgical or percutaneous technique (TAVI). The discovery that the pathogenetic mechanism of aortic stenosis is similar to the atherosclerosis process has made it possible to evaluate the hypothesis of medical therapy for aortic stenosis. Several drugs have been tested to reduce low-density lipoprotein (LDL) and lipoprotein(a) (Lp(a)) levels, inflammation, and calcification. The Proprotein Convertase Subtilisin/Kexin type 9 inhibitors (PCSK9-i) could decrease the progression of aortic stenosis and the requirement for valve implantation. Great interest is related to circulating Lp(a) levels as causally linked to degenerative aortic stenosis. New therapies with ASO (antisense oligonucleotides) and siRNA (small interfering RNA) are currently being tested. Olpasiran and pelacarsen reduce circulating Lp(a) levels by 85-90%. Phase 3 studies are underway to evaluate the effect of these drugs on cardiovascular events (cardiovascular death, non-fatal myocardial injury, and non-fatal stroke) in patients with elevated Lp(a) and CVD (cardiovascular diseases). For instance, if a reduction in Lp(a) levels is associated with aortic stenosis prevention or progression, further prospective clinical trials are warranted to confirm this observation in this high-risk population.
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Affiliation(s)
- Assunta Di Costanzo
- Division of Cardiology, Cardiovascular Research Center, University Magna Graecia Catanzaro, 88100 Catanzaro, Italy;
| | - Ciro Indolfi
- Division of Cardiology, Cardiovascular Research Center, University Magna Graecia Catanzaro, 88100 Catanzaro, Italy;
| | - Anna Franzone
- Division of Cardiology, Department of Advanced Biomedical Sciences, University of Naples Federico II, 80131 Naples, Italy; (A.F.); (G.E.); (C.A.M.S.)
| | - Giovanni Esposito
- Division of Cardiology, Department of Advanced Biomedical Sciences, University of Naples Federico II, 80131 Naples, Italy; (A.F.); (G.E.); (C.A.M.S.)
| | - Carmen Anna Maria Spaccarotella
- Division of Cardiology, Department of Advanced Biomedical Sciences, University of Naples Federico II, 80131 Naples, Italy; (A.F.); (G.E.); (C.A.M.S.)
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27
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Grande G, Graziani A, De Toni L, Garolla A, Milardi D, Ferlin A. Acquired Male Hypogonadism in the Post-Genomic Era-A Narrative Review. Life (Basel) 2023; 13:1854. [PMID: 37763258 PMCID: PMC10532903 DOI: 10.3390/life13091854] [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: 07/22/2023] [Revised: 08/21/2023] [Accepted: 08/25/2023] [Indexed: 09/29/2023] Open
Abstract
Although precision medicine took its first steps from genomic medicine, it has gone far beyond genomics, considering the full complexity of cellular physiology. Therefore, the present time can be considered as the "post-genomic era". In detail, proteomics captures the overall protein profile of an analyzed sample, whilst metabolomics has the purpose of studying the molecular aspects of a known medical condition through the measurement of metabolites with low molecular weight in biological specimens. In this review, the role of post-genomic platforms, namely proteomics and metabolomics, is evaluated with a specific interest in their application for the identification of novel biomarkers in male hypogonadism and in the identification of new perspectives of knowledge on the pathophysiological function of testosterone. Post-genomic platforms, including MS-based proteomics and metabolomics based on ultra-high-performance liquid chromatography-HRMS, have been applied to find solutions to clinical questions related to the diagnosis and treatment of male hypogonadism. In detail, seminal proteomics helped us in identifying novel non-invasive markers of androgen activity to be translated into clinical practice, sperm proteomics revealed the role of testosterone in spermatogenesis, while serum metabolomics helped identify the different metabolic pathways associated with testosterone deficiency and replacement treatment, both in patients with insulin sensitivity and patients with insulin resistance.
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Affiliation(s)
- Giuseppe Grande
- Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, 35128 Padova, Italy; (A.G.); (L.D.T.); (A.G.); (A.F.)
| | - Andrea Graziani
- Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, 35128 Padova, Italy; (A.G.); (L.D.T.); (A.G.); (A.F.)
| | - Luca De Toni
- Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, 35128 Padova, Italy; (A.G.); (L.D.T.); (A.G.); (A.F.)
| | - Andrea Garolla
- Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, 35128 Padova, Italy; (A.G.); (L.D.T.); (A.G.); (A.F.)
| | - Domenico Milardi
- Division of Endocrinology, Fondazione Policlinico Universitario “Agostino Gemelli” Scientific Hospitalization and Treatment Institute (IRCCS), 00168 Rome, Italy;
| | - Alberto Ferlin
- Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, 35128 Padova, Italy; (A.G.); (L.D.T.); (A.G.); (A.F.)
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28
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Green DJ, Chasland LC, Naylor LH, Yeap BB. New Horizons: Testosterone or Exercise for Cardiometabolic Health in Older Men. J Clin Endocrinol Metab 2023; 108:2141-2153. [PMID: 36964918 PMCID: PMC10438896 DOI: 10.1210/clinem/dgad175] [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: 02/01/2023] [Revised: 03/14/2023] [Accepted: 03/22/2023] [Indexed: 03/27/2023]
Abstract
Middle-aged and older men have typically accumulated comorbidities, are increasingly sedentary, and have lower testosterone concentrations (T) compared to younger men. Reduced physical activity (PA) and lower T both are associated with, and may predispose to, metabolically adverse changes in body composition, which contribute to higher risks of cardiometabolic disease. Exercise improves cardiometabolic health, but sustained participation is problematic. By contrast, rates of T prescription have increased, particularly in middle-aged and older men without organic diseases of the hypothalamus, pituitary, or testes, reflecting the unproven concept of a restorative hormone that preserves health. Two recent large randomized trials of T, and meta-analyses of randomized trials, did not show a signal for adverse cardiovascular (CV) events, and T treatment on a background of lifestyle intervention reduced type 2 diabetes by 40% in men at high risk. Men with both higher endogenous T and higher PA levels have lower CV risk, but causality remains unproven. Exercise training interventions improve blood pressure and endothelial function in middle-aged and older men, without comparable benefits or additive effects of T treatment. Therefore, exercise training improves cardiometabolic health in middle-aged and older men when effectively applied as a supervised regimen incorporating aerobic and resistance modalities. Treatment with T may have indirect cardiometabolic benefits, mediated via favorable changes in body composition. Further evaluation of T as a pharmacological intervention to improve cardiometabolic health in aging men could consider longer treatment durations and combination with targeted exercise programs.
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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, 6150, 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, 6150, Australia
| | - Bu B Yeap
- Medical School, The University of Western Australia, Perth, WA, 6009, Australia
- Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, WA, 6150, Australia
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29
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Hackett G, Kirby M, Rees RW, Jones TH, Muneer A, Livingston M, Ossei-Gerning N, David J, Foster J, Kalra PA, Ramachandran S. The British Society for Sexual Medicine Guidelines on Male Adult Testosterone Deficiency, with Statements for Practice. World J Mens Health 2023; 41:508-537. [PMID: 36876744 PMCID: PMC10307648 DOI: 10.5534/wjmh.221027] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 11/07/2022] [Accepted: 11/23/2022] [Indexed: 03/02/2023] Open
Abstract
Testosterone deficiency (TD) is an increasingly common problem with significant health implications, but its diagnosis and management can be challenging. A multi-disciplinary panel from BSSM reviewed the available literature on TD and provide evidence-based statements for clinical practice. Evidence was derived from Medline, EMBASE and Cochrane searches on hypogonadism, testosterone therapy (T Therapy) and cardiovascular safety from May 2017 to September 2022. This revealed 1,714 articles, including 52 clinical trials and 32 placebo-controlled randomised controlled trials. A total of twenty-five statements are provided, relating to five key areas: screening, diagnosis, initiating T Therapy, benefits and risks of T Therapy, and follow-up. Seven statements are supported by level 1 evidence, eight by level 2, five by level 3, and five by level 4. Recent studies have demonstrated that low levels of testosterone in men are associated with increased risk of incident type 2 diabetes mellitus, worse outcomes in chronic kidney disease and COVID 19 infection with increased all-cause mortality, along with significant quality of life implications. These guidelines should help practitioners to effectively diagnose and manage primary and age-related TD.
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Affiliation(s)
- Geoffrey Hackett
- Department of Urology, Spire Hospital, Little Aston, Birmingham, UK
- Department of Urology, Aston University, Birmingham, UK.
| | - Michael Kirby
- Trends in Urology and Men's Health, Letchworth, UK
- Faculty of Health & Human Sciences, University of Hertfordshire & The Prostate Centre, London, UK
| | - Rowland W Rees
- Department of Urology, University Hospital Southampton and UCLH, London, UK
| | - T Hugh Jones
- Department of Endocrinology, Barnsley Hospital, Barnsley, UK
- Department of Biochemistry, Royal Hallamshire Hospital, University of Sheffield Medical School, Sheffield, UK
| | - Asif Muneer
- Division of Surgery and Interventional Science, NIHR Biomedical Research Centre UCLH, London, UK
| | - Mark Livingston
- Department of Biochemistry, Black Country Pathology Services, Walsall Manor Hospital, Walsall, UK
| | - Nick Ossei-Gerning
- Cardiff and Vale NHS Trust, Cardiff, UK
- University of South Wales TDS, Bridgend, UK
- Department of Cardiology, University of Cape Coast, Cape Coast, Ghana
| | | | | | - Philip A Kalra
- Department of Nephrology, NCA, Salford Royal Hospital, Salford, UK
| | - Sudarshan Ramachandran
- Department of Clinical Biochemistry, University Hospitals Birmingham NHS Foundation Trust, Sutton Coldfield, West Midlands, UK
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30
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Al-Sofiani ME, Asiri A, Alajmi S, Alkeridy W. Perspectives on Prediabetes and Aging. Endocrinol Metab Clin North Am 2023; 52:377-388. [PMID: 36948785 DOI: 10.1016/j.ecl.2022.10.011] [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] [Indexed: 02/18/2023]
Abstract
Diabetes prevention programs (DPPs) have been shown to effectively delay, and sometimes prevent, the progression from prediabetes to diabetes; however, labeling someone with prediabetes comes with potential negative psychological, financial, and self-perception consequences. Many older adults with prediabetes nowadays have a relatively "low-risk" form of prediabetes that rarely progresses to diabetes and may regress to normoglycemia. In this article, we review the impact of aging on glucose metabolism and provide a holistic approach to cases of prediabetes in older adults that maximizes the benefit-risk balance of interventions aimed at addressing prediabetes.
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Affiliation(s)
- Mohammed E Al-Sofiani
- Division of Endocrinology, Department of Internal Medicine, College of Medicine, King Saud University, Riyadh, Central Region, 12372, Saudi Arabia; Division of Endocrinology, Diabetes & Metabolism, The Johns Hopkins University, 1830 East Monument Street, Baltimore, MD 21287, USA.
| | - Alanood Asiri
- Division of Endocrinology, Department of Internal Medicine, College of Medicine, King Saud University, Riyadh, Central Region, 12372, Saudi Arabia
| | - Sarah Alajmi
- Division of Endocrinology, Department of Internal Medicine, College of Medicine, King Saud University, Riyadh, Central Region, 12372, Saudi Arabia
| | - Walid Alkeridy
- Department of Medicine, King Saud University, College of Medicine, Riyadh, Central Region, 12372, Saudi Arabia
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Grande G, De Toni L, Garolla A, Milardi D, Ferlin A. Plasma metabolomics in male primary and functional hypogonadism. Front Endocrinol (Lausanne) 2023; 14:1165741. [PMID: 37334300 PMCID: PMC10273261 DOI: 10.3389/fendo.2023.1165741] [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: 02/14/2023] [Accepted: 05/01/2023] [Indexed: 06/20/2023] Open
Abstract
Metabolomics proposes to unveil the molecular machinery involved in each specific disease by the comprehensive analysis of low-molecular-weight metabolites in a biological sample. This narrative mini-review analyzes previous studies applying ultra-high-performance liquid chromatography-high-resolution mass spectrometry (HRMS)-based metabolomics to highlight different metabolic pathways involved in male hypogonadism and testosterone replacement therapy, both in the case of insulin-sensitive patients with primary hypogonadism and in the case of insulin-resistant patients with functional hypogonadism. In functional hypogonadism, metabolomics revealed that different biochemical pathways are affected. In detail, glycolysis is the most important biochemical process involved in these patients. Glucose metabolism is fueled by amino acid degradation, and gluconeogenesis is widely stimulated. Some important pathways, including glycerol, are compromised. Furthermore, mitochondrial electron transport is influenced, namely, by a decrease in ATP production. On the contrary, beta-oxidation of short- and medium-chain fatty acids does not represent an energy source in hypogonadal patients. Both lactate and acetyl-CoA are converted into ketone bodies, which increased immensely. However, carnosine and β-alanine are greatly reduced. These metabolic changes are associated with increased fatigue and mental confusion. After testosterone replacement therapy, a complete restoration is achieved for only a part of the metabolites. It is of note that only in patients with functional hypogonadism treated with testosterone are ketone bodies produced at high levels, so the symptoms sometimes reported by these patients after the beginning of the therapy (difficulty in concentrating, depressed mood, brain fog, and memory impairment) might represent a specific "keto flu-like" syndrome, related to the metabolic ketonic state.
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Affiliation(s)
- Giuseppe Grande
- Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, Padova, Italy
| | - Luca De Toni
- Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, Padova, Italy
| | - Andrea Garolla
- Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, Padova, Italy
| | - Domenico Milardi
- Division of Endocrinology, Fondazione Policlinico Universitario “Agostino Gemelli” Scientific Hospitalization and Treatment Institute (IRCCS), Rome, Italy
| | - Alberto Ferlin
- Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, Padova, Italy
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Zolla L. Biomarkers to Be Used for Decision of Treatment of Hypogonadal Men with or without Insulin Resistance. Metabolites 2023; 13:681. [PMID: 37367840 DOI: 10.3390/metabo13060681] [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: 03/31/2023] [Revised: 05/10/2023] [Accepted: 05/15/2023] [Indexed: 06/28/2023] Open
Abstract
Male hypogonadism is a result of low testosterone levels, but patients could be insulin-sensitive (IS) or insulin-resistant (IR), showing different impaired metabolic pathways. Thus, testosterone coadministration, which is commonly used to reestablish testosterone levels in hypogonadism, must take into account whether or not insulin is still active. By comparing metabolic cycles recorded in IS and IR plasma before and after testosterone therapy (TRT), it is possible to know what metabolic pathways can be reactivated in the two different groups upon testosterone recovery, and it is possible to understand if antagonism or synergy exists between these two hormones. IS hypogonadism uses glycolysis, while IR hypogonadism activates gluconeogenesis through the degradation of branched-chain amino acids (BCAAs). Upon administration of testosterone, acceptable improvements are observed in IS patients, wherein many metabolic pathways are restored, while in IR patients, a reprogramming of metabolic cycles is observed. However, in both subgroups, lactate and acetyl-CoA increases significantly. In IS patients, lactate is used through the glucose-lactate cycle to produce energy, while in IR patients, both lactate and acetyl-CoA are metabolized into ketone bodies, which are used to produce energy. Thus, in IR patients, an ancestral molecular mechanism is activated to produce energy, mimicking insulin effects. Regarding lipids, in both groups, the utilization of fatty acids for energy (β-oxidation) is blocked, even after TRT; free fatty acids (FFAs) increase in the blood in IS patients, while they are incorporated into triglycerides in those with IR. In both subgroups of hypogonadism, supplementation of useful chemicals is recommended during and after TRT when metabolites are not restored; they are listed in this review.
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Affiliation(s)
- Lello Zolla
- Dipartimento Scienze Agrarie e Forestali, University of Tuscia, 01100 Viterbo, Italy
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Yassin A, Alwani M, Al-Zoubi RM, Aboumarzouk OM, Talib R, Nettleship J, Kelly D, Albaba B. Voiding function improves under long-term testosterone treatment (TTh) in hypogonadal men, independent of prostate size. Int Urol Nephrol 2023:10.1007/s11255-023-03602-4. [PMID: 37148486 DOI: 10.1007/s11255-023-03602-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 04/12/2023] [Indexed: 05/08/2023]
Abstract
BACKGROUND Functional hypogonadism is a condition in which some, but not all, older men have low testosterone levels. Rather than chronological age per se, the causality of hypogonadism includes obesity and impaired general health (e.g., metabolic syndrome). An association between testosterone deficiency and lower urinary tract symptoms (LUTS) has been reported, yet due to prostate safety concerns, men with severe LUTS (IPSS score > 19) have invariably been excluded from entering testosterone trials. Irrespective, exogenous testosterone has not been demonstrated to cause de novo or worsen mild to moderate LUTS. OBJECTIVE This study investigated whether long-term testosterone therapy (TTh) could have a protective effect on improving the symptoms of LUTS in hypogonadal men. However, the exact mechanism by which testosterone exerts is beneficial effect remains uncertain. PATIENTS AND METHODS In this study 321 hypogonadal patients with an average age of 58.9 ± 9.52 years received testosterone undecanoate in 12-week intervals for 12 years. One hundred and forty-seven of these males had the testosterone treatment interrupted for a mean of 16.9 months before it was resumed. Total testosterone, International Prostate Symptom Scale (IPSS), post-voiding residual bladder volume and aging male symptoms (AMS) were measured over the study period. RESULTS Prior to TTh interruption, it was observed that testosterone stimulation improved the men's IPSS, AMS and post-voiding residual bladder volume, while their prostate volume significantly increased. During the TTh interruption, there was a significant worsening in these parameters, although the increase in prostate volume continued. When TTh was resumed, these effects were reversed, implying that hypogonadism may require lifelong treatment.
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Affiliation(s)
- Aksam Yassin
- Surgical Research Section, Department of Surgery, Hamad Medical Corporation and Men's Health, Doha, Qatar
- Center of Medicine and Health Sciences, Dresden International University, Dresden, Germany
- Weill Cornell School of Medicine, Urology, Doha, Qatar
| | - Mustafa Alwani
- Surgical Research Section, Department of Surgery, Hamad Medical Corporation and Men's Health, Doha, Qatar
| | - Raed M Al-Zoubi
- Surgical Research Section, Department of Surgery, Hamad Medical Corporation and Men's Health, Doha, Qatar.
- Department of Biomedical Sciences, QU-Health, College of Health Sciences, Qatar University, 2713, Doha, Qatar.
- Department of Chemistry, Jordan University of Science and Technology, PO Box 3030, Irbid, 22110, Jordan.
| | - Omar M Aboumarzouk
- Surgical Research Section, Department of Surgery, Hamad Medical Corporation and Men's Health, Doha, Qatar
- College of Medicine, Qatar University, Doha, Qatar
- School of Medicine, Dentistry and Nursing, The University of Glasgow, Glasgow, UK
| | - Raidh Talib
- Surgical Research Section, Department of Surgery, Hamad Medical Corporation and Men's Health, Doha, Qatar
| | - Joanne Nettleship
- Biomolecular Research Centre, Sheffield Hallam University, Sheffield, UK
| | - Daniel Kelly
- Biomolecular Research Centre, Sheffield Hallam University, Sheffield, UK
- Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, UK
| | - Bassam Albaba
- Center of Medicine and Health Sciences, Dresden International University, Dresden, Germany
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Perry C, Budweg JB, Stein AP, Harder J, Gupta S, Nusbickel AJ, Smoot M, Patel K, Winchester DE. Assessment of Cardiovascular Risk for Noncardiac and Nonsurgical Activities. Am J Med 2023; 136:350-354. [PMID: 36566899 DOI: 10.1016/j.amjmed.2022.12.003] [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: 11/30/2022] [Revised: 12/07/2022] [Accepted: 12/08/2022] [Indexed: 12/24/2022]
Abstract
Cardiovascular risk stratification is a frequent evaluation performed by health professionals. Not uncommonly, requests for risk stratification involve activities or procedures that fall outside of the scope of current evidence-based guidelines. Estimating risk and providing guidance for these requests can be challenging due to limited available evidence. This review focuses on some of these unique requests, each of which are real examples encountered in our practice. We offer guidance by synthesizing the available medical literature and formulating recommendations on topics such as the initiation of testosterone and erectile dysfunction therapy, SCUBA and skydiving, polygraphy, and electroconvulsive therapy.
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Affiliation(s)
| | | | | | | | - Shishir Gupta
- University of Florida College of Medicine, Gainesville
| | | | | | - Keval Patel
- University of Florida College of Medicine, Gainesville
| | - David E Winchester
- University of Florida College of Medicine, Gainesville; Cardiology Section, Malcom Randall Veterans Affairs Medical Center, Gainesville, Fla.
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Kumari K, Kumar R, Memon A, Kumari B, Tehrim M, Kumari P, Shehryar M, Islam H, Islam R, Khatri M, Kumar S, Kumar A. Treatment with Testosterone Therapy in Type 2 Diabetic Hypogonadal Adult Males: A Systematic Review and Meta-Analysis. Clin Pract 2023; 13:454-469. [PMID: 36961066 PMCID: PMC10037582 DOI: 10.3390/clinpract13020041] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 03/14/2023] [Accepted: 03/16/2023] [Indexed: 03/25/2023] Open
Abstract
Testosterone replacement therapy (TRT) has been used to treat hypogonadal males with type 2 diabetes mellitus (T2DM) for a long time, despite variable results. This meta-analysis examines TRT's role in hypogonadal males with T2DM. The databases PubMed, Embase, and Google Scholar were searched for relevant RCTs and observational studies. Estimated pooled mean differences (MDs) and relative risks with 95% confidence intervals were used to measure the effects of TRT (CIs). When compared to the placebo, TRT improves glycemic management by significantly reducing glycated hemoglobin (HBA1c) levels (WMD = -0.29 [-0.57, -0.02] p = 0.04; I2 = 89.8%). Additionally, it reduces the homeostatic model assessment levels of insulin resistance (WMD = -1.47 [-3.14, 0.19]; p = 0.08; I2 = 56.3%), fasting glucose (WMD = -0.30 [-0.75, 0.15]; p = 0.19; I2 = 84.4%), and fasting insulin (WMD = -2.95 [-8.64, 2.74]; however, these results are non-significant. On the other hand, HBA1c levels are significantly reduced with TRT; in addition, total testosterone levels significantly increase with testosterone replacement therapy (WMD = 4.51 [2.40, 6.61] p = 0.0001; I2 = 96.3%). Based on our results, we hypothesize that TRT can improve glycemic control and hormone levels, as well as lower total cholesterol, triglyceride, and LDL cholesterol levels while raising HDL cholesterol in hypogonadal type 2 diabetes patients. To this end, we recommend TRT for these patients in addition to standard diabetes care.
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Affiliation(s)
- Kajol Kumari
- Medicine Department, Ghulam Muhammad Mahar Medical College, Sukkur 65200, Pakistan
| | - Rohan Kumar
- Medicine Department, Jinnah Sindh Medical University, Karachi 75510, Pakistan
| | - Areeba Memon
- Medicine Department, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Beena Kumari
- Medicine Department, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Moniba Tehrim
- Medicine Department, Karachi Medical and Dental College, Karachi 74700, Pakistan
| | - Pooja Kumari
- Medicine Department, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Muhammad Shehryar
- Medicine Department, King Edward Medical University, Lahore 54000, Pakistan
| | - Hamza Islam
- Medicine Department, Punjab Medical College, Faisalabad 38000, Pakistan
| | - Rabia Islam
- Medicine Department, Punjab Medical College, Faisalabad 38000, Pakistan
| | - Mahima Khatri
- Medicine Department, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Satesh Kumar
- Shaheed Mohtarma Benazir Bhutto Medical College, Lyari General Hospital, Karachi 74200, Pakistan
| | - Ajay Kumar
- Medicine Department, MedStar Union Memorial Hospital, Baltimore, MD 21218, USA
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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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Isidori AM, Aversa A, Calogero A, Ferlin A, Francavilla S, Lanfranco F, Pivonello R, Rochira V, Corona G, Maggi M. Adult- and late-onset male hypogonadism: the clinical practice guidelines of the Italian Society of Andrology and Sexual Medicine (SIAMS) and the Italian Society of Endocrinology (SIE). J Endocrinol Invest 2022; 45:2385-2403. [PMID: 36018454 PMCID: PMC9415259 DOI: 10.1007/s40618-022-01859-7] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 06/29/2022] [Indexed: 12/24/2022]
Abstract
PURPOSE To provide the evidence-based recommendations on the role of testosterone (T) on age-related symptoms and signs remains. METHODS The Italian Society of Andrology and Sexual Medicine (SIAMS) and the and the Italian Society of Endocrinology (SIE) commissioned an expert task force to provide an updated guideline on adult-onset male hypogonadism. Derived recommendations were based on Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. RESULTS Clinical diagnosis of adult-onset hypogonadism should be based on a combination of clinical and biochemical parameters. Testosterone replacement therapy (TRT) should be offered to all symptomatic subjects with hypogonadism after the exclusion of possible contraindications. T gels and the long-acting injectable T are currently available preparations showing the best efficacy/safety profile. TRT can improve all aspects of sexual function, although its effect is limited in more complicated patients. Body composition (reducing fat mass and increasing lean mass) is improved after TRT, either in subjects with or without metabolic syndrome or type 2 diabetes. Conversely, the role of TRT in improving glycometabolic control is more conflicting. TRT can result in increasing bone mineral density, particularly at lumbar site, but no information on fracture risk is available. Limited data support the use of TRT for improving other outcomes, including mood frailty and mobility. CONCLUSIONS TRT can improve sexual function and body composition particularly in less complicated adult and in aging subjects with hypogonadism. When hypogonadism is adequately diagnosed, T appropriately prescribed and subjects correctly followed up, no short-term increased risk of adverse events is observed. Longer and larger studies are advisable to better clarify TRT long-term efficacy/safety profile.
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Affiliation(s)
- A M Isidori
- Department of Experimental Medicine, Sapienza University of Rome - Policlinico Umberto I Hospital, Rome, Italy
| | - A Aversa
- Department of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - A Calogero
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - A Ferlin
- Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, Padua, Italy
| | - S Francavilla
- Andrology Unit, Department of Clinical Medicine, Public Health, Life and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - F Lanfranco
- Division of Endocrinology, Andrology and Metabolism, Humanitas Gradenigo, Department of Medical Sciences, University of Turin, Turin, Italy
| | - R Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Unità di Andrologia e Medicina della Riproduzione e della Sessualità Maschile e Femminile, Università Federico II di Napoli, Naples, Italy
- Staff of UNESCO Chair for Health Education and Sustainable Development, Federico II University, Naples, Italy
| | - V Rochira
- Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - G Corona
- Endocrinology Unit, Medical Department, Azienda Usl Bologna Maggiore-Bellaria Hospital, Largo Nigrisoli, 2, 40133, Bologna, Italy.
| | - M Maggi
- Endocrinology Unit, Department of Experimental, Clinical and Biomedical Sciences, University of Florence, Florence, Italy
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Abstract
Sleep serves important biological functions, and influences health and longevity through endocrine and metabolic related systems. Sleep debt, circadian misalignment and sleep disruption from obstructive sleep apnea is widespread in modern society and accumulates with life because recovery sleep is not completely restorative. Accumulated disordered sleep throughout life impacts the ageing process and the development of age-related diseases. When epidemiological and interventional studies are considered collectively, sleep loss and lower sleep duration are associated with lower morning, afternoon and 24-h testosterone; as well as higher afternoon, but not morning or 24-h cortisol. These reciprocal changes imbalances anabolic-catabolic signaling because testosterone and cortisol are respectively the main anabolic and catabolic signals in man. Fixing testosterone-cortisol balance by means of a novel dual-hormone clamp mitigates the induction of insulin resistance by sleep restriction and provided the first proof-of-concept that the metabolic harm from sleep loss can be ameliorated by approaches that do not require sleeping more. Obstructive sleep apnea is associated with lower testosterone, even after controlling for age and obesity whereas the conclusion that continuous positive airway pressure therapy has no effect on testosterone is premature because available studies are underpowered and better-quality studies suggest otherwise. High dose testosterone therapy induces OSA, but more physiological dosing may not; and this effect may be transient or may dissipate with longer term therapy. Studies investigating the origin of the diurnal testosterone rhythm, the effect of circadian misalignment on testosterone-cortisol balance, and methods to mitigate metabolic harm, are required.
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Affiliation(s)
- Peter Y Liu
- Division of Endocrinology, Metabolism and Nutrition, Department of Medicine, Harbor UCLA Medical Center and The Lundquist Institute, 1124 W Carson St., Box 446, Torrance, CA, 90502, USA.
- David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
| | - Radha T Reddy
- Division of Endocrinology, Metabolism and Nutrition, Department of Medicine, Harbor UCLA Medical Center and The Lundquist Institute, 1124 W Carson St., Box 446, Torrance, CA, 90502, USA
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Gandhi R, Kumar PR, Pattanaik SR, Sahoo D. Effect of Testosterone Undecanoate on Sexual Functions, Glycaemic Parameters, and Cardiovascular Risk Factors in Hpogonadal Men with Type 2 Diabetes Mellitus. Indian J Endocrinol Metab 2022; 26:565-574. [PMID: 39005512 PMCID: PMC11245296 DOI: 10.4103/ijem.ijem_39_22] [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: 01/19/2022] [Revised: 06/22/2022] [Accepted: 08/26/2022] [Indexed: 02/05/2023] Open
Abstract
Aims To study the effect of testosterone undecanoate on sexual functions, glycaemic parameters, and cardiovascular (CV) risk factors in hypogonadal men with type 2 diabetes mellitus (T2DM). Methods It was an open label, single-arm interventional study where testosterone undecanoate (TU) was used in 105 T2DM males aged 30-60 years with hypogonadism. The effect of TU on sexual functions was assessed using the Aging Male Symptoms (AMS) Scale and the International Index of Erectile Function-5 (IIEF-5) Questionnaire. The effect on glycaemic parameters, cardiovascular risk factors (lipids, high-sensitivity C-reactive protein [hsCRP] and carotid intima media thickness [CIMT]) were assessed over a period of 54 weeks of TU therapy. Results Prevalence of hypogonadism in T2DM patients was 19.1%, of which 74.1% had functional hypogonadism. AMS and IIEF-5 scores showed negative and positive correlation, respectively, with baseline serum testosterone levels. The AMS score showed a significant reduction of 5.8% and IIEF-5 score improved by 31.5% at 54 weeks of TU therapy. Glycosylated hemoglobin (HbA1c), homeostatic model assessment for insulin resistance (HOMA-IR), and lipids such as total cholesterol (TC), low-density lipoprotein (LDL), and triglycerides (TG) were significantly reduced by 0.6%, 10.9%, 6.28%, 9.04%, and 6.77%, respectively, at 54 weeks. CIMT was significantly reduced by 2.57% at 54 weeks, whereas no significant change observed with hsCRP. Conclusions TU is an effective treatment modality for hypogonadal men with T2DM, and it has beneficial effects on sexual functions, glycaemic parameters, and CV risk factors.
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Affiliation(s)
- Ronak Gandhi
- Department of Endocrinology, MKCG Medical College and Hospital, Odisha, India
| | - Padala Ravi Kumar
- Department of Endocrinology, MKCG Medical College and Hospital, Odisha, India
| | - Sudhi R Pattanaik
- Department of Endocrinology, MKCG Medical College and Hospital, Odisha, India
| | - Devadarshini Sahoo
- Department of Endocrinology, MKCG Medical College and Hospital, Odisha, India
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40
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Testosterone replacement therapy and cardiovascular disease. Int J Impot Res 2022; 34:685-690. [PMID: 34999717 DOI: 10.1038/s41443-021-00516-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 11/29/2021] [Accepted: 12/01/2021] [Indexed: 01/23/2023]
Abstract
The use of testosterone therapy has a complex history of apprehension and questions regarding its safety. Despite an eventual consensus that testosterone therapy was safe and effective, several studies relating to cardiovascular risks emerged in the last decade, rekindling skepticism regarding the safety of testosterone therapy. Given the utility of testosterone therapy in treating the symptoms of hypogonadism, it remains crucial to closely examine the safety of testosterone therapy. The present article synthesizes the current evidence regarding cardiovascular risks that may be associated with testosterone therapy, the potential mechanisms regarding testosterone's efficacy, and future directions in evaluating the safety of its use.
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41
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Testosterone deficiency in male organ transplant recipients. Int J Impot Res 2022; 34:679-684. [PMID: 35013565 DOI: 10.1038/s41443-021-00513-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 11/13/2021] [Accepted: 11/26/2021] [Indexed: 11/09/2022]
Abstract
Testosterone deficiency is known to affect men with increasing incidence throughout their lifespan. The clinical manifestations of testosterone deficiency, in turn, negatively impact men's quality of life and perception of overall health. The interaction of chronic systemic disease and androgen deficiency represent an area for potential intervention. Here, we explore the topic of testosterone deficiency amongst men with end-stage organ failure requiring transplantation in order to elucidate the underlying pathophysiology of androgen deficiency of chronic disease and discuss whether intervention, including testosterone replacement and organ transplantation, improve patients' outcomes and quality of life.
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Zolla L. On the Need to Distinguish between Insulin-Normal and Insulin-Resistant Patients in Testosterone Therapy. Int J Mol Sci 2022; 23:ijms232112730. [PMID: 36361519 PMCID: PMC9657366 DOI: 10.3390/ijms232112730] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/12/2022] [Accepted: 10/20/2022] [Indexed: 11/07/2022] Open
Abstract
Male hypogonadism is a disorder characterized by low levels of the hormone testosterone and patients may also have insulin sensitivity (IS) or insulin resistance (IR), such that they show different clinical complications and different metabolic pathways. In this review, we compare metabonomic differences observed between these two groups before and after testosterone therapy (TRT) in order to obtain information on whether the two hormones testosterone and insulin are synergistic or antagonistic. IS hypogonadism uses glucose as the main biofuel, while IR activates gluconeogenesis by the degradation of branched-chain amino acids. The Krebs (TCA) cycle is active in IS but connected with glutaminolysis, while in IR the TCA cycle stops at citrate, which is used for lipogenesis. In both cases, the utilization of fatty acids for energy (β-oxidation) is hampered by lower amounts of acetylcarnitine, although it is favored by the absence of insulin in IR. Increased free fatty acids (FFAs) are free in the blood in IS, while they are partially incorporated in triglycerides in IR. Thus, upon TRT, the utilization of glucose is increased more in IS than in IR, revealing that in IR there is a switch from preferential glucose oxidation to lipid oxidation. However, in both cases, a high production of lactate and acetyl-CoA is the final result, with these levels being much higher in IR. Lactate is used in IS in the glucose–lactate cycle between the liver and muscle to produce energy, while in IR lactate and acetyl-CoA are biotransformed into ketone bodies, resulting in ketonuria. In conclusion, the restoration of testosterone values in hypogonadism gives better results in IS than in IR patients: in IS, TRT restores most of the metabolic pathways, while in IR TRT impairs insulin, and when insulin is inactive TRT activates an ancestral molecular mechanism to produce energy. This evidence supports the hypothesis that, over time, hypogonadism switches from IS to IR, and in the latter case most of the insulin-related metabolisms are not reactivated, at least within 60 days of TRT. However, testosterone therapy in both IS and IR might be of benefit given supplementation with metabolites that are not completely restored upon TRT, in order to help restore physiological metabolisms. This review underlines the importance of using a systems biology approach to shed light on the molecular mechanisms of related biochemical pathways involving insulin and testosterone.
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Intake of Sugar Substitute Gummy Candies Benefits the Glycemic Response in Healthy Adults: A Prospective Crossover Clinical Trial. Gels 2022; 8:gels8100642. [PMID: 36286143 PMCID: PMC9601933 DOI: 10.3390/gels8100642] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/27/2022] [Accepted: 09/28/2022] [Indexed: 11/26/2022] Open
Abstract
Sugar reduction in food has attracted great health concerns worldwide. Gummies have been one of the most popular and highly favored candies due to their chewable properties, simplicity to swallow, and delicious taste. The general perception is that gummies raise blood sugar levels, but the truth is that gummies with the right formula can control glycemic response. The purpose of this study is to investigate the effects of the gummy dosage form and sugar types on the glycemic response control. Maltitol and erythritol as sweetener alternatives were applied in gummy candies (total and partial sugar substitutes gummy, T-SG and P-SG), with sucrose-based gummies used as comparisons (CG). A prospective crossover study was then conducted on 17 healthy adults. The effects of different types of gummies on glycemic response in healthy adults were evaluated on the basis of the participants’ glycemic index (GI) and glycemic load (GL) values. Every three-day interval, participants took CG, P-SG, T-SG, and glucose solution, respectively, and the theoretical glucose conversion content was kept the same in all groups for each trial. Each participant performed four tests with each sample and recorded the changes in blood glucose after food consumption. It was found that all three types of gummies slowed down subjects’ glycemic response when not taken in excess, and the improvement effect was in the trend of T-SG > P-SG > CG. Both P-SG and T-SG were low-GI candies (54.1 and 49.9). CG that was not consumed in excess of 17.2 g had a high GI (81.9) but a low GL (<10). Texture analysis and in vitro digestion were used to explore the effect of gummy matrix on glucose release. T-SG and P-SG retained a higher hardness and were less hydrolyzed to release glucose during digestion compared with CG. Additionally, experiments have revealed that gummies can reverse the poor glucose tolerance in women. In conclusion, gummies are a good carrier for dietary supplements due to their sustained-release characteristic of available carbohydrates and provide healthier options for people in control of glucose homeostasis.
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Alemany M. The Roles of Androgens in Humans: Biology, Metabolic Regulation and Health. Int J Mol Sci 2022; 23:11952. [PMID: 36233256 PMCID: PMC9569951 DOI: 10.3390/ijms231911952] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 09/26/2022] [Accepted: 09/27/2022] [Indexed: 11/17/2022] Open
Abstract
Androgens are an important and diverse group of steroid hormone molecular species. They play varied functional roles, such as the control of metabolic energy fate and partition, the maintenance of skeletal and body protein and integrity and the development of brain capabilities and behavioral setup (including those factors defining maleness). In addition, androgens are the precursors of estrogens, with which they share an extensive control of the reproductive mechanisms (in both sexes). In this review, the types of androgens, their functions and signaling are tabulated and described, including some less-known functions. The close interrelationship between corticosteroids and androgens is also analyzed, centered in the adrenal cortex, together with the main feedback control systems of the hypothalamic-hypophysis-gonads axis, and its modulation by the metabolic environment, sex, age and health. Testosterone (T) is singled out because of its high synthesis rate and turnover, but also because age-related hypogonadism is a key signal for the biologically planned early obsolescence of men, and the delayed onset of a faster rate of functional losses in women after menopause. The close collaboration of T with estradiol (E2) active in the maintenance of body metabolic systems is also presented Their parallel insufficiency has been directly related to the ravages of senescence and the metabolic syndrome constellation of disorders. The clinical use of T to correct hypoandrogenism helps maintain the functionality of core metabolism, limiting excess fat deposition, sarcopenia and cognoscitive frailty (part of these effects are due to the E2 generated from T). The effectiveness of using lipophilic T esters for T replacement treatments is analyzed in depth, and the main problems derived from their application are discussed.
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Affiliation(s)
- Marià Alemany
- Facultat de Biologia, Universitat de Barcelona, Av. Diagonal, 635, 08028 Barcelona, Catalonia, Spain;
- Institut de Biomedicina, Universitat de Barcelona, 08028 Barcelona, Catalonia, Spain
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Deischinger C, Slukova D, Just I, Kaufmann U, Harreiter J, van Trotsenburg M, Trattnig S, Krššák M, Kautzky-Willer A, Klepochova R, Kosi-Trebotic L. Effects of gender-affirming hormone therapy on cardiovascular risk factors focusing on glucose metabolism in an Austrian transgender cohort. INTERNATIONAL JOURNAL OF TRANSGENDER HEALTH 2022; 24:499-509. [PMID: 37901063 PMCID: PMC10601523 DOI: 10.1080/26895269.2022.2123425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/31/2023]
Abstract
Objective We aimed to investigate the effect of gender-affirming hormone therapy (GAHT) on cardiovascular disease risk factors focusing on glucose tolerance. Patients and Methods This primarily translational study enrolled 16 transgender persons assigned female at birth (AFAB), 22 assigned male at birth (AMAB), and 33 age- and BMI-matched cisgender controls at the Medical University of Vienna from 2013 to 2020. A 3-Tesla MRI scan to measure intramyocardial, pancreatic, hepatic fat content and subcutaneous-to-visceral adipose tissue ratio (SAT/VAT-ratio), an oral glucose tolerance test (oGTT), bloodwork including brain natriuretic peptide (pro-BNP), sex hormones and two glucose-metabolism related biomarkers (adiponectin, betatrophin) were performed. Results Estrogen intake was associated with higher fasting insulin (p = 0.034) and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (p = 0.037), however, lower HbA1c levels (p = 0.031) in AMAB than cisgender males. Adiponectin (p = 0.001) and betatrophin (p = 0.034) levels were higher in AMAB than cisgender males, but similar to cisgender females. Compared to cisgender females, AFAB displayed no differences in glucose metabolism or SAT/VAT-ratio. AFAB had lower pro-BNP levels (p = 0.014), higher liver enzymes (AST: p = 0.011; ALT: p = 0.012) and lower HDL levels (p = 0.017) than cisgender females, but comparable levels to cisgender males. AMAB showed an increased heart rate (p < 0.001) and pro-BNP (p = 0.002) levels, but a more favorable SAT/VAT-ratio (p = 0.013) and lower creatine kinase (CK) (p = 0.001) than cisgender males. There were no relevant differences in organ fat content between transgender persons and their respective cisgender controls. Conclusion In AMAB, most investigated parameters adapted to levels seen in cisgender females except for parameters related to fasted insulin resistance. AMAB should be monitored with respect to the development of insulin resistance.
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Affiliation(s)
- Carola Deischinger
- Department of Internal Medicine III, Clinical Division of Endocrinology and Metabolism, Gender Medicine Unit, Medical University of Vienna, General Hospital Vienna, Vienna, Austria
| | - Dorota Slukova
- Department of Internal Medicine III, Clinical Division of Endocrinology and Metabolism, Gender Medicine Unit, Medical University of Vienna, General Hospital Vienna, Vienna, Austria
| | - Ivica Just
- Department of Internal Medicine III, Clinical Division of Endocrinology and Metabolism, Gender Medicine Unit, Medical University of Vienna, General Hospital Vienna, Vienna, Austria
- High field MR Centre of Excellence, Department of Biomedical Imaging and Image guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Ulrike Kaufmann
- Department of Obstetrics and Gynaecology, Clinical Division of Gynaecologic Endocrinology and Reproductive Medicine, General Hospital Vienna, Vienna, Austria
| | - Juergen Harreiter
- Department of Internal Medicine III, Clinical Division of Endocrinology and Metabolism, Gender Medicine Unit, Medical University of Vienna, General Hospital Vienna, Vienna, Austria
| | - Mick van Trotsenburg
- Department of Obstetrics and Gynecology, University of st Pölten Lilienfeld, Vienna, Austria
| | - Siegfried Trattnig
- High field MR Centre of Excellence, Department of Biomedical Imaging and Image guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Martin Krššák
- High field MR Centre of Excellence, Department of Biomedical Imaging and Image guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Alexandra Kautzky-Willer
- Department of Internal Medicine III, Clinical Division of Endocrinology and Metabolism, Gender Medicine Unit, Medical University of Vienna, General Hospital Vienna, Vienna, Austria
| | - Radka Klepochova
- Department of Internal Medicine III, Clinical Division of Endocrinology and Metabolism, Gender Medicine Unit, Medical University of Vienna, General Hospital Vienna, Vienna, Austria
- High field MR Centre of Excellence, Department of Biomedical Imaging and Image guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Lana Kosi-Trebotic
- Department of Internal Medicine III, Clinical Division of Endocrinology and Metabolism, Gender Medicine Unit, Medical University of Vienna, General Hospital Vienna, Vienna, Austria
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Defeudis G, Maddaloni E, Rossini G, Di Tommaso AM, Mazzilli R, Di Palma P, Pozzilli P, Napoli N. Glycemic Variability in Subjects with Diabetes and Hypogonadism during Testosterone Replacement Treatment: A Pilot Study. J Clin Med 2022; 11:jcm11185333. [PMID: 36142982 PMCID: PMC9505941 DOI: 10.3390/jcm11185333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/02/2022] [Accepted: 09/06/2022] [Indexed: 11/16/2022] Open
Abstract
Background: This is a proof of concept, as a pilot study, with the aim to evaluate continuous glucose monitoring metrics (CGM) in subjects with type 2 diabetes (T2DM), treated with nutritional therapy and metformin, before and after testosterone replacement therapy (TRT). Methods: In this longitudinal observational study, subjects affected by T2DM and starting TRT for documented ED and hypogonadism were enrolled. All subjects mounted a CGM system during the v0 visit, one week before the beginning of the TRT (week−1), during v2, four weeks after the start of TRT (week 4), and v4 (week 12). CGM was worn for about 144 h after each visit. Results: A total of seven patients, referring to our clinic for erectile dysfunction (ED), were studied (aged 63.3 ± 2.3 years). Mean (± standard deviation) total testosterone level was 2.3 ± 0.6 ng/mL at baseline. After TRT, total testosterone level was 4.6 ± 3.04 ng/mL at week 4 and 3.93 ± 4.67 ng/mL at week 12. No significant differences were observed in TIR, TAR, TBR, estimated HbA1c, AUC below, and AUC above limit during the intervention period. Conclusions: This is the first study evaluating the effects of TRT on daily glucose excursions in subjects with T2DM and hypogonadism. Though we did not find any significant difference in key CGM metrics during the 12 weeks of TRT, this study confirms the glycometabolic safety of the TRT even on the most novel standardized glycemic targets.
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Affiliation(s)
- Giuseppe Defeudis
- Unit of Endocrinology and Diabetes, Department of Medicine, University Campus Bio-Medico di Roma, 00128 Rome, Italy
- Correspondence: or
| | - Ernesto Maddaloni
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Giovanni Rossini
- Unit of Endocrinology and Diabetes, Department of Medicine, University Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Alfonso Maria Di Tommaso
- Unit of Endocrinology and Diabetes, Department of Medicine, University Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Rossella Mazzilli
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Sant’Andrea Hospital, 00189 Rome, Italy
| | - Paolo Di Palma
- Unit of Urology, Hospital of Frosinone, ASL Frosinone, 03100 Frosinone, Italy
| | - Paolo Pozzilli
- Unit of Endocrinology and Diabetes, Department of Medicine, University Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Nicola Napoli
- Unit of Endocrinology and Diabetes, Department of Medicine, University Campus Bio-Medico di Roma, 00128 Rome, Italy
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Abstract
Type 2 diabetes (T2D) and obesity are common and associated with increased morbidity and mortality. Cross-sectional and longitudinal studies have demonstrated a clear association between T2D, obesity and reduced total testosterone concentration. This relationship becomes less significant or absent with correction for changes in body composition, supporting the notion that changes in body composition are mediating these effects. Moreover, this mediating effect of body composition changes is bi-directional, as evidenced by interventional studies of weight loss and testosterone treatment. On the one hand, in obese men, serum testosterone increases markedly with weight loss. On the other hand, testosterone improves body composition. This relationship is driven by multiple complex interaction between obesity and insulin resistance and the hypothalamic-pituitary-testicular axis, at all levels. Data from randomised control trials have demonstrated that intervention with testosterone therapy increases muscle mass and reduces adiposity. Most recently it has been shown that treatment with testosterone prevents progression of impaired glucose tolerance to T2D, or reverses newly diagnosed T2D beyond lifestyle intervention alone. At present there are insufficient safety data to support the use of testosterone for prevention of type 2 diabetes.
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Affiliation(s)
- Mahesh Umapathysivam
- Endocrine and Metabolic Health Unit, Royal Adelaide Hospital, South Australia; School of Medicine, University of Adelaide, South Australia
| | - Mathis Grossmann
- Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, Victoria, Australia; Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia
| | - Gary A Wittert
- Endocrine and Metabolic Health Unit, Royal Adelaide Hospital, South Australia; School of Medicine, University of Adelaide, South Australia; Freemasons Centre for Male Health and Wellbeing, South Australian Health and Medical Research Institute.
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Kumar S, Khatri M, Memon RA, Velastegui JL, Podaneva KZ, Gutierrez DB, Nadeem B, Anumolu AR, Azhar M, Zain A. Effects of testosterone therapy in adult males with hypogonadism and T2DM: A meta-analysis and systematic review. Diabetes Metab Syndr 2022; 16:102588. [PMID: 35952509 DOI: 10.1016/j.dsx.2022.102588] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 07/21/2022] [Accepted: 07/23/2022] [Indexed: 11/15/2022]
Abstract
BACKGROUND AND AIMS Testosterone supplementation therapy (TST) is a longstanding treatment for hypogonadal men with type 2 diabetes mellitus (T2DM), even though the benefits of TST are variable among trials. This meta-analysis was done to determine the specific role of TST in hypogonadal men with T2DM. METHODS PubMed, Embase, and Google Scholar were queried to discover eligible randomized controlled trials (RCTs) and observational studies. To quantify the specific effects of TST, we estimated pooled mean differences (MDs) and relative risks with 95% confidence intervals (CIs). RESULTS Our meta-analysis included 1596 hypogonadal T2DM subjects from 12 randomized controlled trials and one observational study. TST can significantly enhance glycemic control compared to placebo by decreasing homeostatic model assessment of insulin resistance (WMD = -1.55 [-2.65, -0.45]; p = 0.26; I2 = 20.2%), fasting glucose (WMD = -0.35 [-0.79, 0.10]; p = 0.07; I2 = 69.7%), fasting insulin (WMD = -2.88 [-6.12, 0.36]; p = In addition, TST can decrease cholesterol (WMD = -0.28 [-0.47, -0.09] p = 0.0008; I2 = 91%) and triglyceride (WMD = -0.23 [-0.43, -0.03] p = 0.03; I2 = 79.2%). Furthermore, Testosterone therapy is related to a significant rise in total testosterone levels (WMD = 5.08 [2.90, 7.26] p = 0.0002; I2 = 92.9%). Pooling of free testosterone levels indicated a larger increase in the patients who got TST than placebo (WMD = 81.21 [23.87, 138.54] p = 0.07; I2 = 70%). CONCLUSION Our findings suggested that TST can enhance glycemic control and hormone levels and reduce total cholesterol, triglyceride, LDL cholesterol whereas increase HDL cholesterol in hypogonadal T2DM patients. Therefore, in these patients, we propose TST alongside anti-diabetic treatment.
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Affiliation(s)
- Satesh Kumar
- Medicine, Shaheed Mohtarma Benazir Bhutto Medical College, Lyari, Parsa Citi Block E Flat 501 Near Police Headquarter, Garden East, Karachi, Pakistan.
| | - Mahima Khatri
- Medicine, Dow University of Health Sciences, Karachi, Karachi, Pakistan.
| | - Rahat Ahmed Memon
- Cardiology, Abington Jefferson Hospital, Pennsylvania, Pennsylvania, United States.
| | | | | | | | - Bilawal Nadeem
- Medicine, Kind Edward Medical University, Lahore, Lahore, Pakistan.
| | - Akhil Raj Anumolu
- Medicine, Andhra Medical College, Visakhapatnam, Andhra Pradesh, India.
| | - Masood Azhar
- Medicine, King Edward Medical University, Lahore, Lahore, Pakistan.
| | - Ahmad Zain
- Medicine, Services Institute of Medical Sciences, Lahore, Lahore, Pakistan.
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Deepika FNU, Ballato E, Colleluori G, Aguirre L, Chen R, Qualls C, Villareal DT, Armamento-Villareal R. Baseline Testosterone Predicts Body Composition and Metabolic Response to Testosterone Therapy. Front Endocrinol (Lausanne) 2022; 13:915309. [PMID: 35898448 PMCID: PMC9309506 DOI: 10.3389/fendo.2022.915309] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 06/06/2022] [Indexed: 11/20/2022] Open
Abstract
Context Male hypogonadism adversely affects body composition, bone mineral density (BMD), and metabolic health. A previous report showed that pre-treatment testosterone (T) levels of <200 ng/dl is associated with greater improvement in spine BMD with T therapy. However, to date, there is no study that investigates whether baseline T levels also influence body composition and metabolic response to T therapy. Objective The aim of this study is to determine if there are differences in the changes in body composition, metabolic profile, and bone turnover markers, in addition to BMD, in response to T therapy in men with a baseline T level of <264 ng/dl compared to those with levels ≥264 ng/dl. Methods This is a secondary analysis of a single-arm, open-label clinical trial (NCT01378299) on pharmacogenetics of response to T therapy conducted between 2011 and 2016 involving 105 men (40-74 years old), with average morning T < 300 ng/dl, given intramuscular T cypionate 200 mg every 2 weeks for 18 months. Subjects were divided into those with baseline T levels of <264 ng/dl (N = 43) and those with ≥264 ng/dl (N = 57). T and estradiol (E2) were measured by liquid chromatography/mass spectrometry; serum bone turnover markers (C-telopeptide [CTX], osteocalcin, and sclerostin), adiponectin, and leptin were measured by enzyme-linked immunosorbent assay; glycated hemoglobin (HbA1c) was measured by high-performance liquid chromatography; and areal BMD and body composition was measured by dual-energy x-ray absorptiometry (DXA). Results Men with T < 264 ng/dl showed greater increases in total fat-free mass (FFM) at 18 months compared to those with T ≥ 264 ng/dl (4.2 ± 4.1 vs. 2.7 ± 3.8%; p = 0.047) and unadjusted appendicular FFM at 6 and 18 months (8.7 ± 11.5 vs. 4.4 ± 4.3%, 7.3 ± 11.6 vs. 2.4 ± 6.8%; p = 0.033 and p = 0.043, respectively). Men with T ≥ 264 ng/dl showed significant decreases in HbA1c at 12 months (-3.1 ± 9.2 vs. 3.2 ± 13.9%; p = 0.005), fasting glucose at 18 months (-4.2 ± 31.9 vs. 13.0 ± 57.3%; p = 0.040), LDL at 6 months (-6.4 ± 27.5 vs. 12.8 ± 44.1%; p = 0.034), and leptin at 18 months (-40.2 ± 35.1 vs. -27.6 ± 31.0%; p = 0.034) compared to those with T < 264 ng/dl. No significant differences in BMD and bone turnover markers were observed. Conclusion T therapy results in improvement in body composition irrespective of baseline T levels but T < 264 ng/dl is associated with greater improvement in FFM, whereas a T level of ≥264 ng/dl favors improvement in metabolic profile.
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Affiliation(s)
- FNU Deepika
- Division of Endocrinology Diabetes and Metabolism at Baylor College of Medicine, Houston, TX, United States
- Department of Medicine, Michael E. DeBakey Veterans Affairs (VA) Medical Center, Houston, TX, United States
| | - Elliot Ballato
- Division of Endocrinology Diabetes and Metabolism at Baylor College of Medicine, Houston, TX, United States
| | - Georgia Colleluori
- Division of Endocrinology Diabetes and Metabolism at Baylor College of Medicine, Houston, TX, United States
| | - Lina Aguirre
- Division of Endocrinology, University of New Mexico School of Medicine, Albuquerque, NM, United States
- Department of Medicine, New Mexico Veterans Affairs (VA) Health Care System, Albuquerque, NM, United States
| | - Rui Chen
- Division of Endocrinology Diabetes and Metabolism at Baylor College of Medicine, Houston, TX, United States
- Department of Medicine, Michael E. DeBakey Veterans Affairs (VA) Medical Center, Houston, TX, United States
| | - Clifford Qualls
- Division of Endocrinology, University of New Mexico School of Medicine, Albuquerque, NM, United States
- Department of Medicine, New Mexico Veterans Affairs (VA) Health Care System, Albuquerque, NM, United States
- Biomedical Research Institute of New Mexico, Albuquerque, NM, United States
| | - Dennis T. Villareal
- Division of Endocrinology Diabetes and Metabolism at Baylor College of Medicine, Houston, TX, United States
- Department of Medicine, Michael E. DeBakey Veterans Affairs (VA) Medical Center, Houston, TX, United States
| | - Reina Armamento-Villareal
- Division of Endocrinology Diabetes and Metabolism at Baylor College of Medicine, Houston, TX, United States
- Department of Medicine, Michael E. DeBakey Veterans Affairs (VA) Medical Center, Houston, TX, United States
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Abstract
Sexual symptoms are the most specific determinants of low testosterone (T) observed during adulthood. In this narrative review, we summarize the most important evidence supporting the positive relationships between endogenous T levels and sexual activity in the adult male, by using preclinical and clinical observations. In addition, we also report an update of our previous meta-analysis evaluating the effects of T treatment (TRT) on sexual functioning in subjects with T deficiency. Available data indicate that TRT of symptomatic hypogonadal men can improve several aspects of sexual life, including erection. However, the effect is rather modest and lower in subjects with associated metabolic conditions. The specific observed effects are similar to those derived from lifestyle intervention. Since TRT might result in body composition improvement, it is reasonable to suppose that an initial treatment with T can improve the willingness of hypogonadal subjects to perform physical exercise and to adhere to a healthier behavior. Similar data were derived from animal models. However, it should be important to recognize that lifestyle modifications should be the first step to promote weigh reduction. TRT can be combined with lifestyle interventions only in symptomatic hypogonadal subjects especially in the presence of comorbid metabolic conditions.
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Affiliation(s)
- Giovanni Corona
- Endocrinology Unit, Medical Department, Azienda Usl, Maggiore-Bellaria Hospital, Bologna, Italy
| | - Giulia Rastrelli
- Andrology, Women's Endocrinology and Gender Incongruence Unit, "Mario Serio" Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Linda Vignozzi
- Andrology, Women's Endocrinology and Gender Incongruence Unit, "Mario Serio" Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Mario Maggi
- Endocrinology Unit, "Mario Serio" Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
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