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1.
Plasma Metabolomics Profile of "Insulin Sensitive" Male Hypogonadism after Testosterone Replacement Therapy.
Zolla, L, Ceci, M
International journal of molecular sciences. 2022;(3)
Abstract
Male hypogonadism is a disorder characterized by low levels of testosterone, but patients can either show normal insulin (insulin-sensitive (IS)) or over time they can become insulin-resistant (IR). Since the two groups showed different altered metabolisms, testosterone replacement therapy (TRT) could achieve different results. In this paper, we analyzed plasma from 20 IS patients with low testosterone (<8 nmol/L) and HOMAi < 2.5. The samples, pre- and post-treatment with testosterone for 60 days, were analyzed by UHPLC and mass spectrometry. Glycolysis was significantly upregulated, suggesting an improved glucose utilization. Conversely, the pentose phosphate pathway was reduced, while the Krebs cycle was not used. Branched amino acids and carnosine metabolism were positively influenced, while β-oxidation of fatty acids (FFA) was not activated. Cholesterol, HDL, and lipid metabolism did not show any improvements at 60 days but did so later in the experimental period. Finally, both malate and glycerol shuttle were reduced. As a result, both NADH and ATP were significantly lower. Interestingly, a significant production of lactate was observed, which induced the activation of the Cori cycle between the liver and muscles, which became the main source of energy for these patients without involving alanine. Thus, the treatment must be integrated with chemicals which are not restored in order to reactivate energy production.
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2.
Hormonal and Metabolic Changes of Aging and the Influence of Lifestyle Modifications.
Pataky, MW, Young, WF, Nair, KS
Mayo Clinic proceedings. 2021;(3):788-814
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Abstract
Increased life expectancy combined with the aging baby boomer generation has resulted in an unprecedented global expansion of the elderly population. The growing population of older adults and increased rate of age-related chronic illness has caused a substantial socioeconomic burden. The gradual and progressive age-related decline in hormone production and action has a detrimental impact on human health by increasing risk for chronic disease and reducing life span. This article reviews the age-related decline in hormone production, as well as age-related biochemical and body composition changes that reduce the bioavailability and actions of some hormones. The impact of hormonal changes on various chronic conditions including frailty, diabetes, cardiovascular disease, and dementia are also discussed. Hormone replacement therapy has been attempted in many clinical trials to reverse and/or prevent the hormonal decline in aging to combat the progression of age-related diseases. Unfortunately, hormone replacement therapy is not a panacea, as it often results in various adverse events that outweigh its potential health benefits. Therefore, except in some specific individual cases, hormone replacement is not recommended. Rather, positive lifestyle modifications such as regular aerobic and resistance exercise programs and/or healthy calorically restricted diet can favorably affect endocrine and metabolic functions and act as countermeasures to various age-related diseases. We provide a critical review of the available data and offer recommendations that hopefully will form the groundwork for physicians/scientists to develop and optimize new endocrine-targeted therapies and lifestyle modifications that can better address age-related decline in heath.
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The effect of exercise training on cardiometabolic health in men with prostate cancer receiving androgen deprivation therapy: a systematic review and meta-analysis.
Bigaran, A, Zopf, E, Gardner, J, La Gerche, A, Murphy, DG, Howden, EJ, Baker, MK, Cormie, P
Prostate cancer and prostatic diseases. 2021;(1):35-48
Abstract
BACKGROUND Growing evidence suggests that men exposed to androgen deprivation therapy (ADT) have an increased risk of cardiovascular disease. While exercise has shown to attenuate some adverse effects of ADT, the effects on cardiometabolic health have not been systematically evaluated. OBJECTIVE To evaluate the effect of exercise on cardiometabolic health in men with prostate cancer (PCa) receiving ADT. METHODS A systematic literature search of MEDLINE, EMBASE, CINHAL, SCOPUS, WEB OF SCIENCE and SPORTSDICUS from database inception to April 2020 was performed. A quantitative synthesis using Cohens d effect size and a meta-analysis using random-effects models were conducted. RESULTS Overall, fourteen randomised controlled trials (RCTs) and four non-randomised studies were included. Eleven RCTs (n = 939 patients) were included in the meta-analysis. Exercise training improved the 400-m-walk test (MD -10.11 s, 95% CI [-14.34, -5.88]; p < 0·00001), diastolic blood pressure (-2.22 mmHg, [-3.82, -0.61]; p = 0.007), fasting blood glucose (-0.38 mmol/L, [-0.65, -0.11]; p = 0.006), C-reactive protein (-1.16 mg/L, [-2.11, -0.20]; p = 0.02), whole-body lean mass (0.70 kg, [0.39, 1.01]; p < 0.0001), appendicular lean mass (0.59 kg, [0.43, 0.76]; p < 0.00001), whole-body fat mass (-0.67 kg, [-1.08, -0.27]; p = 0.001), whole-body fat percentage (-0.79%, [-1.16, -0.42]; p < 0.0001), and trunk fat mass (-0.49 kg, [-0.87, -0.12]; p = 0.01), compared to usual care. No significant effects on systolic blood pressure or blood lipid metabolism were detected. CONCLUSIONS In a small subset of evaluated studies, exercise may favourably improve some but not all markers of cardiometabolic health. Future exercise intervention trials with cardiometabolic outcomes as primary endpoints are needed to confirm these initial findings.
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Hepatic focal nodular hyperplasia after pediatric hematopoietic stem cell transplantation: The impact of hormonal replacement therapy and iron overload.
Cattoni, A, Rovelli, A, Prunotto, G, Bonanomi, S, Invernizzi, P, Perego, R, Mariani, AM, Balduzzi, A
Pediatric blood & cancer. 2020;(4):e28137
Abstract
BACKGROUND The advent of techniques for the assessment of iron overload (liver T2*-MRI) has led to the awareness that focal nodular hyperplasia (FNH) represents a possible incidental finding after hematopoietic stem cell transplantation (HSCT), though its pathogenesis is still unclear. METHODS We performed a retrospective analysis of the liver T2*-MRI scans performed between 2013 and 2018 in a single pediatric HSCT Unit and recorded the number of patients with FNH (group A). Patients incidentally diagnosed with FNH at imaging performed for different clinical indications were included in group B. RESULTS Nine of 105 (8.6%) patients from group A were diagnosed with FNH. Group B included three patients. Overall, 12 patients were diagnosed 4.4 ± 3.1 years after HSCT. At univariate analysis, female gender (odds ratio [OR] 3.77, P = .03), moderate-to-severe iron overload (OR 6.97, P = .01), and hormone replacement therapy (HRT) administered for at least 6 months (OR 18.20, P = .0002) exposed patients to a higher risk of developing FNH. The detrimental effect of HRT was significant also at multivariate analysis (OR 7.93, P = .024). MRI-T2* values in affected patients were statistically lower than healthy controls (P < .001). CONCLUSIONS We confirm the high incidence of FNH among transplanted pediatric patients and demonstrate the potential pathogenic role of HRT and iron overload.
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5.
Nephrocalcinosis, Renal Dysfunction, and Calculi in Patients With Primary Hypoparathyroidism on Long-Term Conventional Therapy.
Saha, S, Kandasamy, D, Sharma, R, Bal, C, Sreenivas, V, Goswami, R
The Journal of clinical endocrinology and metabolism. 2020;(4)
Abstract
CONTEXT There are concerns about the long-term safety of conventional therapy on renal health in patients with hypoparathyroidism. Careful audit of these would help comparisons with upcoming parathyroid hormone therapy. OBJECTIVE We investigated nephrocalcinosis, renal dysfunction, and calculi, their predictors and progression over long-term follow-up in patients with primary hypoparathyroidism (PH). DESIGN AND SETTING An observational study at a tertiary care center was conducted. PARTICIPANTS AND METHODS A total of 165 PH patients receiving conventional therapy were evaluated by radiographs, ultrasonography, and computed tomography. Their glomerular filtration rate (GFR) was measured by Tc-99m-diethylenetriamine penta-acetic acid clearance. Clinical characteristics, serum total calcium, phosphorus, creatinine, hypercalciuria, and fractional excretion of phosphorus (FEPh) at presentation and during follow-up were analyzed as possible predictors of renal complications. Controls were 165 apparently healthy individuals. RESULTS Nephrocalcinosis was present in 6.7% of PH patients but not in controls. Patients younger than 15 years at presentation and with higher serum calcium-phosphorus product were at higher risk. Nephrocalcinosis showed no significant association with cataract and intracranial calcification. Prevalence of renal calculi was comparable between hypoparathyroid patients and controls (5% vs 3.6%, P = .58). Fourteen percent of patients had a GFR less than 60 mL/min/1.73 m2. Increased FEPh during follow-up was the significant predictor of low GFR. Nephrocalcinosis developed in 9% of patients over 10 years of conventional therapy. CONCLUSION A total of 6.7% of PH patients had nephrocalcinosis, and 14% showed renal dysfunction. Prevalence of renal calculi was similar in patients and controls. Nine percent of patients developed nephrocalcinosis over 10 years of conventional therapy.
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6.
Leptin-Mediated Changes in the Human Metabolome.
Lawler, K, Huang-Doran, I, Sonoyama, T, Collet, TH, Keogh, JM, Henning, E, O'Rahilly, S, Bottolo, L, Farooqi, IS
The Journal of clinical endocrinology and metabolism. 2020;(8):2541-52
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Abstract
CONTEXT While severe obesity due to congenital leptin deficiency is rare, studies in patients before and after treatment with leptin can provide unique insights into the role that leptin plays in metabolic and endocrine function. OBJECTIVE The aim of this study was to characterize changes in peripheral metabolism in people with congenital leptin deficiency undergoing leptin replacement therapy, and to investigate the extent to which these changes are explained by reduced caloric intake. DESIGN Ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) was used to measure 661 metabolites in 6 severely obese people with congenital leptin deficiency before, and within 1 month after, treatment with recombinant leptin. Data were analyzed using unsupervised and hypothesis-driven computational approaches and compared with data from a study of acute caloric restriction in healthy volunteers. RESULTS Leptin replacement was associated with class-wide increased levels of fatty acids and acylcarnitines and decreased phospholipids, consistent with enhanced lipolysis and fatty acid oxidation. Primary and secondary bile acids increased after leptin treatment. Comparable changes were observed after acute caloric restriction. Branched-chain amino acids and steroid metabolites decreased after leptin, but not after acute caloric restriction. Individuals with severe obesity due to leptin deficiency and other genetic obesity syndromes shared a metabolomic signature associated with increased BMI. CONCLUSION Leptin replacement was associated with changes in lipolysis and substrate utilization that were consistent with negative energy balance. However, leptin's effects on branched-chain amino acids and steroid metabolites were independent of reduced caloric intake and require further exploration.
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7.
Glucocorticoid Replacement Affects Serum Adiponectin Levels and HDL-C in Patients With Secondary Adrenal Insufficiency.
Hayashi, R, Tamada, D, Murata, M, Kitamura, T, Mukai, K, Maeda, N, Otsuki, M, Shimomura, I
The Journal of clinical endocrinology and metabolism. 2019;(12):5814-5822
Abstract
CONTEXT Low serum adiponectin and high-density lipoprotein-cholesterol (HDL-C) levels are risk factors for cardiovascular disease. Patients with primary adrenal insufficiency are at higher risk of cardiovascular complications compared with healthy subjects. However, there is no information on the relationship between adiponectin and glucocorticoid replacement therapy in patients with secondary adrenal insufficiency (SAI). OBJECTIVE To determine the effects of intrinsic adrenal function and glucocorticoid replacement therapy on serum adiponectin levels and lipid profile in patients with SAI. DESIGN Part 1: a cross-sectional study. Part 2: a randomized, double-blind, crossover study. SETTING Osaka University Hospital, Osaka, Japan. PATIENTS Part 1: 58 patients diagnosed with nonfunctioning pituitary adenoma who underwent insulin tolerance test (ITT) for assessment of adrenal function. Part 2: 12 SAI patients randomly received hydrocortisone replacement therapy at a dose of 10, 20, or 30 mg/d for 4 weeks per term for three terms. OUTCOME MEASUREMENTS Part 1: we analyzed the relationship between serum cortisol levels during ITT and serum adiponectin levels and the lipid profile. Part 2: serum adiponectin levels and lipid profile were measured every 4 weeks. RESULTS Serum levels of adiponectin and HDL-C correlated significantly with peak cortisol levels after ITT. Serum adiponectin and HDL-C levels were significantly lower in patients with SAI than non-SAI. Serum levels of adiponectin and HDL-C increased in a hydrocortisone dose-dependent manner. CONCLUSIONS Glucocorticoid replacement therapy increased serum levels of adiponectin, an adipose-derived anti-atherogenic factor, and HDL-C in patients with SAI.
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Personalized approach to growth hormone replacement in adults.
van Bunderen, CC, Glad, C, Johannsson, G, Olsson, DS
Archives of endocrinology and metabolism. 2019;(6):592-600
Abstract
Growth hormone (GH) deficiency (GHD) in adults is well-characterized and includes abnormal body composition, reduced bone mass, an adverse cardiovascular risk profile, and impaired quality of life. In the early 1990s, it was also shown that patients with hypopituitarism without GH replacement therapy (GHRT) had excess mortality. Today, GHRT has been shown to decrease or reverse the negative effects of GHD. In addition, recent papers have shown that mortality and morbidity are approaching normal in hypopituitary patients with GHD who receive modern endocrine therapy including GHRT. Since the first dose-finding studies, it has been clear that efficacy and side effects differ substantially between patients. Many factors have been suggested as affecting responsiveness, such as sex, age, age at GHD onset, adherence, and GH receptor polymorphisms, with sex and sex steroid replacement having the greatest impact. Therefore, the individual tailoring of GH dose is of great importance to achieve sufficient efficacy without side effects. One group that stands out is women receiving oral estrogen replacement, who needs the highest dose. Serum insulin-like growth factor-1 (IGF-1) is still the most used biochemical biomarker for GH dose titration, although the best serum IGF-1 target is still debated. Patients with GHD due to acromegaly, Cushing's disease, or craniopharyngioma experience similar effects from GHRT as others. Arch Endocrinol Metab. 2019;63(6):592-600.
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Safety and efficacy of testosterone for women: a systematic review and meta-analysis of randomised controlled trial data.
Islam, RM, Bell, RJ, Green, S, Page, MJ, Davis, SR
The lancet. Diabetes & endocrinology. 2019;(10):754-766
Abstract
BACKGROUND The benefits and risks of testosterone treatment for women with diminished sexual wellbeing remain controversial. We did a systematic review and meta-analysis to assess potential benefits and risks of testosterone for women. METHODS We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science for blinded, randomised controlled trials of testosterone treatment of at least 12 weeks' duration completed between Jan 1, 1990, and Dec 10, 2018. We also searched drug registration applications to the European Medicine Agency and the US Food and Drug Administration to identify any unpublished data. Primary outcomes were the effects of testosterone on sexual function, cardiometabolic variables, cognitive measures, and musculoskeletal health. This study is registered with the International Prospective Register of Systematic Reviews (PROSPERO), number CRD42018104073. FINDINGS Our search strategy retrieved 46 reports of 36 randomised controlled trials comprising 8480 participants. Our meta-analysis showed that, compared with placebo or a comparator (eg, oestrogen, with or without progestogen), testosterone significantly increased sexual function, including satisfactory sexual event frequency (mean difference 0·85, 95% CI 0·52 to 1·18), sexual desire (standardised mean difference 0·36, 95% CI 0·22 to 0·50), pleasure (mean difference 6·86, 95% CI 5·19 to 8·52), arousal (standardised mean difference 0·28, 95% CI 0·21 to 0·35), orgasm (standardised mean difference 0·25, 95% CI 0·18 to 0·32), responsiveness (standardised mean difference 0·28, 95% CI 0·21 to 0·35), and self-image (mean difference 5·64, 95% CI 4·03 to 7·26), and reduced sexual concerns (mean difference 8·99, 95% CI 6·90 to 11·08) and distress (standardised mean difference -0·27, 95% CI -0·36 to -0·17) in postmenopausal women. A significant rise in the amount of LDL-cholesterol, and reductions in the amounts of total cholesterol, HDL-cholesterol, and triglycerides, were seen with testosterone administered orally, but not when administered non-orally (eg, by transdermal patch or cream). An overall increase in weight was recorded with testosterone treatment. No effects of testosterone were reported for body composition, musculoskeletal variables, or cognitive measures, although the number of women who contributed data for these outcomes was small. Testosterone was associated with a significantly greater likelihood of reporting acne and hair growth, but no serious adverse events were recorded. INTERPRETATION Testosterone is effective for postmenopausal women with low sexual desire causing distress, with administration via non-oral routes (eg, transdermal application) preferred because of a neutral lipid profile. The effects of testosterone on individual wellbeing and musculoskeletal and cognitive health, as well as long-term safety, warrant further investigation. FUNDING Australian National Health and Medical Research Council.
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10.
Pharmacological management of osteoporosis in postmenopausal women: The current state of the art.
Gatti, D, Fassio, A
Journal of population therapeutics and clinical pharmacology = Journal de la therapeutique des populations et de la pharmacologie clinique. 2019;(4):e1-e17
Abstract
Osteoporosis is a common disease that increases fracture risk. Fragility fractures bring heavy consequences in terms of mortality and disability, with burdensome health and social costs. In subjects with clinical bone fragility, the first goal is to identify the secondary forms of osteoporosis, especially in young subjects, in males and in patients who recently experienced a fragility fracture. In addition, before considering any sort of treatment, it is fundamental to check for adequate calcium and vitamin D intake, since their deficiency is the most common reason for drug failure.In the last decade of the 20th century, several molecules have been developed and proved to be effective in achieving the true goal of any antiosteoporotic drug: fracture prevention.In this article, we considered the most commonly prescribed antiresorptive drugs (hormonal therapy, bisphosphonates, and denosumab), the anabolic agents (teriparatide), the dual-action drugs (romosozumab), and the drugs characterized by an unclear mechanism of action (strontium ranelate) to provide physicians with useful insights for their clinical practice. We discussed the main criteria for the appropriate choice selection and management of each treatment. Finally, we addressed the current controversies related to treatment discontinuation, sequential, and combination therapy.