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1.
Erythrocytosis Following Testosterone Therapy.
Ohlander, SJ, Varghese, B, Pastuszak, AW
Sexual medicine reviews. 2018;(1):77-85
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Abstract
INTRODUCTION A rapid increase in awareness of androgen deficiency has led to substantial increases in prescribing of testosterone therapy (TTh), with benefits of improvements in mood, libido, bone density, muscle mass, body composition, energy, and cognition. However, TTh can be limited by its side effects, particularly erythrocytosis. This review examines the literature on testosterone-induced erythrocytosis and polycythemia. AIM: To review the available literature on testosterone-induced erythrocytosis, discuss possible mechanisms for pathophysiology, determine the significance of formulation, and elucidate potential thromboembolic risk. METHODS A literature review was performed using PubMed for articles addressing TTh, erythrocytosis, and polycythemia. MAIN OUTCOME MEASURES Mechanism, pharmacologic contribution, and risk of testosterone-induced erythrocytosis. RESULTS For men undergoing TTh, the risk of developing erythrocytosis compared with controls is well established, with short-acting injectable formulations having the highest associated incidence. Potential mechanisms explaining the relation between TTh and erythrocytosis include the role of hepcidin, iron sequestration and turnover, erythropoietin production, bone marrow stimulation, and genetic factors. High blood viscosity increases the risk for potential vascular complications involving the coronary, cerebrovascular, and peripheral vascular circulations, although there is limited evidence supporting a relation between TTh and vascular complications. CONCLUSION Short-acting injectable testosterone is associated with greater risk of erythrocytosis compared with other formulations. The mechanism of the pathophysiology and its role on thromboembolic events remain unclear, although some data support an increased risk of cardiovascular events resulting from testosterone-induced erythrocytosis. Ohlander SJ, Varghese B, Pastuszak AW. Erythrocytosis Following Testosterone Therapy. Sex Med Rev 2018;6:77-85.
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Effect of timing of levothyroxine administration on the treatment of hypothyroidism: a three-period crossover randomized study.
Skelin, M, Lucijanić, T, Liberati-Čizmek, AM, Klobučar, SM, Lucijanić, M, Jakupović, L, Bakula, M, Lončar, JV, Marušić, S, Matić, T, et al
Endocrine. 2018;(2):432-439
Abstract
AIM: Hypothyroidism is a common clinical problem that is successfully treated with hormone substitutes in the form of levothyroxine (LT4). LT4 is a drug with a narrow therapeutic index and is usually administered by strict rules, standardly at least half an hour before breakfast. The aim of this study was to investigate a possible effect of different timings of administration on thyroid function status and lipid profile. METHODS The study included patients with the diagnosis of primary hypothyroidism, which were using a stable dose of levothyroxine. They were randomized into three different groups regarding the timing of LT4 administration in a crossover fashion. Each timing regimen lasted for at least 8 weeks; timing regimen A-half an hour before breakfast; timing regimen B-an hour before the main meal of the day; timing regimen C-at bedtime (minimally 2 h after dinner). The hormones (TSH, fT3, fT4) and lipid profile (triglycerides, HDL-, LDL-, and total cholesterol) were measured before the study, at the beginning of every timing regimen and at the end of the study. RESULTS Altogether, 84 patients finished the study. Different timings of LT4 administration were non-inferior in comparison to the standard one and between each other. Median differences in TSH level between baseline and timing regimens were: baseline vs. A = -0.017 95% C.I. (-0.400-0.192); baseline vs. B = -0.325 95% C.I. (-0.562-0.023); baseline vs. C = -0.260 95% C.I. (-0.475-0.000). There were no statistically significant differences in either TSH, fT4, or fT3 when compared between all three timing regimens of LT4 administration and the baseline. There were no statistically significant differences in any of the lipid profile parameters (triglycerides, HDL-, LDL-, and total cholesterol) when compared between all three timing regimens of LT4 administration and the baseline. CONCLUSION The three investigated timing regimens of LT4 administration were equally efficient and offer additional options regarding the treatment individualization.
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Primary Adrenal Insufficiency: Managing Mineralocorticoid Replacement Therapy.
Esposito, D, Pasquali, D, Johannsson, G
The Journal of clinical endocrinology and metabolism. 2018;(2):376-387
Abstract
CONTEXT Mineralocorticoid (MC) replacement therapy in patients with primary adrenal insufficiency (PAI) was introduced more than 60 years ago. Still, there are limited data on how MC substitution should be optimized, because MC dosing regimens have only been systematically investigated in a few studies. We review the management of current standard MC replacement therapy in PAI and its plausible impact on outcome. DESIGN Using PubMed, we conducted a systematic review of the literature from 1939 to 2017, with the following keywords: adrenal insufficiency, MC deficiency, aldosterone, cardiovascular disease, hypertension, and heart failure. RESULTS The current standard treatment consists of fludrocortisone (FC) given once daily in the morning, aiming at normotension, normokalemia, and plasma renin activity in the upper normal range. Available data suggest that patients with PAI may be underreplaced with FC as symptoms and signs indicating chronic MC underreplacement, such as salt craving and postural dizziness persist, in many treated patients with PAI. Data acquired from large registry-based studies show that glucocorticoid doses for replacement in PAI are higher than those estimated from endogenous production. Glucocorticoid overreplacement may reduce the need of MC replacement but may also be a consequence of inadequate MC replacement. CONCLUSIONS The commonly used MC replacement in PAI may not be adequate in some patients. Insufficient MC substitution may be responsible for poor cardiometabolic outcome and the failure to restore well-being adequately in patients with PAI. Well-designed studies oriented at optimizing MC replacement therapy are urgently needed.
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Alternatives to Testosterone Therapy: A Review.
Lo, EM, Rodriguez, KM, Pastuszak, AW, Khera, M
Sexual medicine reviews. 2018;(1):106-113
Abstract
INTRODUCTION Although testosterone therapy (TTh) is an effective treatment for hypogonadism, recent concerns regarding its safety have been raised. In 2015, the US Food and Drug Administration issued a warning about potential cardiovascular risks resulting from TTh. Fertility preservation is another reason to search for viable alternative therapies to conventional TTh, and in this review we evaluate the literature examining these alternatives. AIMS To review the role and limitations of non-testosterone treatments for hypogonadism. METHODS A literature search was conducted using PubMed to identify relevant studies examining medical and non-medical alternatives to TTh. Search terms included hypogonadism, testosterone replacement therapy, testosterone therapy, testosterone replacement alternatives, diet and exercise and testosterone, varicocele repair and testosterone, stress reduction and testosterone, and sleep apnea and testosterone. MAIN OUTCOME MEASURES Review of peer-reviewed literature. RESULTS Medical therapies examined include human chorionic gonadotropins, aromatase inhibitors, and selective estrogen receptor modulators. Non-drug therapies that are reviewed include lifestyle modifications including diet and exercise, improvements in sleep, decreasing stress, and varicocele repair. The high prevalence of obesity and metabolic syndrome in the United States suggests that disease modification could represent a viable treatment approach for affected men with hypogonadism. CONCLUSIONS These alternatives to TTh can increase testosterone levels and should be considered before TTh. Lo EM, Rodriguez KM, Pastuszak AW, Khera M. Alternatives to Testosterone Therapy: A Review. Sex Med Rev 2018;6:106-113.
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Effects of Altering Levothyroxine Dose on Energy Expenditure and Body Composition in Subjects Treated With LT4.
Samuels, MH, Kolobova, I, Niederhausen, M, Purnell, JQ, Schuff, KG
The Journal of clinical endocrinology and metabolism. 2018;(11):4163-4175
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Abstract
BACKGROUND It is unclear whether variations in thyroid status within or near the reference range affect energy expenditure, body mass, or body composition. METHODS 138 subjects treated with levothyroxine (LT4) for hypothyroidism with normal TSH levels underwent measurement of total, resting, and physical activity energy expenditure; thermic effect of food; substrate oxidation; dietary intake; and body composition. They were assigned to receive an unchanged, higher, or lower LT4 dose in randomized, double-blind fashion, targeting one of three TSH ranges (0.34 to 2.50, 2.51 to 5.60, or 5.61 to 12.0 mU/L). The doses were adjusted every 6 weeks to achieve target TSH levels. Baseline measures were reassessed at 6 months. RESULTS At study end, the mean LT4 doses and TSH levels were 1.50 ± 0.07, 1.32 ± 0.07, and 0.78 ± 0.08 µg/kg (P < 0.001) and 1.85 ± 0.25, 3.93 ± 0.38, and 9.49 ± 0.80 mU/L (P < 0.001), respectively, in the three arms. No substantial metabolic differences in outcome were found among the three arms, although direct correlations were observed between decreases in thyroid status and decreases in resting energy expenditure for all subjects. The subjects could not ascertain how their LT4 dose had been adjusted but the preferred LT4 dose they perceived to be higher (P < 0.001). CONCLUSIONS Altering LT4 doses in subjects with hypothyroidism to vary TSH levels in and near the reference range did not have major effects on energy expenditure or body composition. Subjects treated with LT4 preferred the perceived higher LT4 doses despite a lack of objective effect. Our data do not support adjusting LT4 doses in patients with hypothyroidism to achieve potential improvements in weight or body composition.
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Quality of Life in Hypoparathyroidism.
Vokes, TJ
Endocrinology and metabolism clinics of North America. 2018;(4):855-864
Abstract
Patients with hypoparathyroidism have a multitude of physical, emotional, and cognitive complaints consistent with reduced quality of life (QOL). Impaired QOL in patients treated with conventional therapy with calcium and active vitamin D has been documented in epidemiologic (registry) studies, case-controlled studies, and surveys, and at baseline in clinical trials of parathyroid hormone (PTH). Treatment with PTH has been shown to improve QOL in some but not all studies.
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Potential application of testosterone replacement therapy as treatment for obesity and type 2 diabetes in men.
Fink, J, Matsumoto, M, Tamura, Y
Steroids. 2018;:161-166
Abstract
Sedentary lifestyle and over-nutrition are the main causes of obesity and type 2 diabetes (T2D). However, the same causes are major triggers of hypogonadism. Many T2D patients show low testosterone levels while hypogonadal men seem to be prone to become diabetic. Testosterone plays a major role in the regulation of muscle mass, adipose tissue, inflammation and insulin sensitivity and is therefore indirectly regulating several metabolic pathways, while T2D is commonly triggered by insulin resistance, increased adipose tissue and inflammation, showing a negative correlation between testosterone levels and T2D. Testosterone replacement therapy (TRT) is widely used in patients with symptoms of hypogonadism, however it is not commonly used as preventive intervention or treatment for T2D patients even though hypogonadal patients share many common symptoms (obesity, insulin insensitivity, increased inflammation, decrease in muscle mass and strength) with T2D patients. Even though TRT is often associated with side effects such as prostatic hypertrophy or cancer, cardiovascular risks due to increase in the number of red blood cells and infertility, several studies have shown that TRT remains a potent intervention improving metabolic functions such as glycated haemoglobin, blood sugar, total cholesterol and visceral fat. The purpose of this review is to discuss the possible benefits and risks of TRT in the prevention and treatment of obesity and T2D and assess the health risks and benefits of common T2D medications and testosterone.
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THERAPY OF ENDOCRINE DISEASE: T4 + T3 combination therapy: is there a true effect?
Wiersinga, WM
European journal of endocrinology. 2017;(6):R287-R296
Abstract
About 5%-10% of hypothyroid patients on T4 replacement therapy have persistent symptoms, despite normal TSH levels. It was hoped that T4 + T3 combination therapy might provide better outcomes, but that was not observed according to a meta-analysis of 11 randomized clinical trials comparing T4 monotherapy with T4 + T3 combination therapy. However, the issue is still subject of much research because normal thyroid function tests in serum may not necessarily indicate an euthyroid state in all peripheral tissues. This review evaluates recent developments in the field of T4 + T3 combination therapy. T4 monotherapy is associated with higher serum FT4 levels than in healthy subjects, and subnormal serum FT3 and FT3/FT4 ratios are observed in about 15% and 30% respectively. T4 + T3 combination therapy may mimic more closely thyroid function tests of healthy subjects, but it has not been demonstrated that relatively low serum FT3 or FT3/FT4 ratios are linked to persistent symptoms. One study reports polymorphism Thr92Ala in DIO2 is related to lower serum FT3 levels after thyroidectomy, and that the D2-Ala mutant reduces T4 to T3 conversion in cell cultures. Peripheral tissue function tests such as serum cholesterol reflect thyroid hormone action in target tissues. Using such biochemical markers, patients who had a normal serum TSH during postoperative T4 monotherapy, were mildly hypothyroid, whereas those with a TSH 0.03-≤0.3 mU/L were closest to euthyroidism. Peripheral tissue function tests suggest euthyroidism more often in patients randomized to T4 + T3 rather than that to T4. Preference for T4 + T3 combination over T4 monotherapy was dose-dependently related to the presence of two polymorphisms in MCT10 and DIO2 in one small study. It is not known if persistent symptoms during T4 monotherapy disappear by switching to T4 + T3 combination therapy. The number of patients on T4 + T3 therapy has multiplied in the last decade, likely induced by indiscriminate statements on the internet. Patients are sometimes not just asking but rather demanding this treatment modality. It creates tensions between patients and physicians. Only continued research will answer the question whether or not T4 + T3 combination therapy has true benefits in some patients.
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Effects of parathyroid hormone rhPTH(1-84) on phosphate homeostasis and vitamin D metabolism in hypoparathyroidism: REPLACE phase 3 study.
Clarke, BL, Vokes, TJ, Bilezikian, JP, Shoback, DM, Lagast, H, Mannstadt, M
Endocrine. 2017;(1):273-282
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Abstract
In hypoparathyroidism, inappropriately low levels of parathyroid hormone lead to unbalanced mineral homeostasis. The objective of this study was to determine the effect of recombinant human parathyroid hormone, rhPTH(1-84), on phosphate and vitamin D metabolite levels in patients with hypoparathyroidism. Following pretreatment optimization of calcium and vitamin D doses, 124 patients in a phase III, 24-week, randomized, double-blind, placebo-controlled study of adults with hypoparathyroidism received subcutaneous injections of placebo or rhPTH(1-84) (50 µg/day, titrated to 75 and then 100 µg/day, to permit reductions in oral calcium and active vitamin D doses while maintaining serum calcium within 2.0-2.2 mmol/L). Predefined endpoints related to phosphate homeostasis and vitamin D metabolism were analyzed. Serum phosphate levels decreased rapidly from the upper normal range and remained lower with rhPTH(1-84) (P < 0.001 vs. placebo). At week 24, serum calcium-phosphate product was lower with rhPTH(1-84) vs. placebo (P < 0.001). rhPTH(1-84) treatment resulted in significant reductions in oral calcium dose compared with placebo (P < 0.001) while maintaining serum calcium. After pretreatment optimization, baseline serum 25-hydroxyvitamin D (25[OH]D) and 1,25-dihydroxyvitamin D (1,25[OH]2D) levels were within the normal range in both groups. After 24 weeks, 1,25(OH)2D levels were unchanged in both treatment groups, despite significantly greater reductions in active vitamin D dose in the rhPTH(1-84) group. In hypoparathyroidism, rhPTH(1-84) reduces serum phosphate levels, improves calcium-phosphate product, and maintains 1,25(OH)2D and serum calcium in the normal range while allowing significant reductions in active vitamin D and oral calcium doses.
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GH Supplementation Effects on Cardiovascular Risk in GH Deficient Adult Patients: A Systematic Review and Meta-analysis.
Giagulli, VA, Castellana, M, Perrone, R, Guastamacchia, E, Iacoviello, M, Triggiani, V
Endocrine, metabolic & immune disorders drug targets. 2017;(4):285-296
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Abstract
BACKGROUND AND OBJECTIVE The current meta-analysis aims at evaluating whether the existing clinical evidence may ascertain the effects of growth hormone (GH) replacement therapy on cardiovascular risk, both in isolated GH deficiency (GHD) and in compensated panhypopituitarism including GH deficit. METHODS Original articles published from 1991 to 2015 were searched on Medline (Pubmed). Among an overall number of 181 potentially suitable studies, 24 fulfilled the selection criteria and were included in the analysis. Data aggregation was carried out through the calculation of the absolute risk reduction. The meta-analysis was then conducted by means of a fixed-effects model, according to the heterogeneity test (Chi-square statistic). RESULTS Fat-free mass (FFM) increase and fat mass (FM) reduction were found, together with a C-LDL reduction, a wide variation in glycaemia and a neutral effect on glycated haemoglobin (HbA1c) and blood pressure. These effects were valid both for isolated GHD patients and for those with compensated panhypopituitarism. The global outcome D showed a nonsignificant reduction of the overall cardiovascular risk (0.53; 95% C.I. -1.23, 2.85). CONCLUSION Our meta-analysis shows no signnificatly positive trend in cardiovascular risk after both short and long-term GH supplementation therapy in adult GHD patients. However, a reduction of LDL cholesterol levels has been found. No differences were found between isolated GHD participants and those affected by panhypopituitarism well compensated since at least 3 months.