Retrospective study on long-term effects of hormone replacement therapy (HRT) and iron chelation therapy on glucose homeostasis and insulin secretion in female ß- thalassemia major (ß-TM) patients with acquired hypogonadotropic- hypogonadism (AHH).

BACKGROUND AND AIM: Hypogonadism and abnormalities of glucose homeostasis, resulting from iron-induced pituitary and pancreatic ß-cell dysfunction respectively, are the most frequently reported endocrine abnormalities in patients with ß-thalassemia major (ß-TM), also identified as transfusion-dependent thalassemia (TDT). STUDY DESIGN AND PATIENTS: The aim of the present retrospective study was to evaluate the long-term effects of hormone replacement therapy (HRT) on glucose metabolism and insulin secretion/sensitivity during 3-h oral glucose tolerance test (OGTT) in adolescent and young ß-TM women with acquired hypogonadototropic -hypogonadism (AHH).Twelve hypogonadal ß-TM females with AHH on HRT were followed for 8.26 ± 1.49 years. RESULTS: At baseline, 10 patients (83.3%) had normal OGTT, 1 patient presented with impaired glucose tolerance (IGT) and 1 patient had an isolated PG level of 165 mg/dL at 1-h during OGTT (H-NGT). At last evaluation, 7 patients (58.4 %) had normal OGTT, while 5 patients (41.6%) had abnormal OGTT. Reduced insulin sensitivity and impaired first-phase insulin secretion were also documented. Three of 4 ß-TM patients on treatment with estradiol hemihydrate MX 50 patches plus oral medroxyprogesterone acetate (MPA), associated with a very effective iron chelation therapy, maintained normal glucose tolerance from baseline to last evaluation. Significant adverse events due to HRT or additional endocrine complications were not documented in any cases during the follow-up. CONCLUSION: Deterioration of glycemia (dysglycemia) occurred in 45.4% (5/11) of thalassemic females on long-term HRT. Additional studies are needed to elucidate the validity of our preliminary observations.

Does Iodine Intake Modify the Effect of Maternal Dysglycemia on Birth Weight in Mild-to-Moderate Iodine-Deficient Populations? A Mother-Newborn Prospective Cohort Study.

It is unclear how maternal glycemic status and maternal iodine status influence birth weight among individuals with mild-to-moderate iodine deficiency (ID). We studied the association between birth weight and both maternal glucose levels and iodine intake among pregnant women with mild-to-moderate ID. Glucose values were assessed using a glucose challenge test (GCT) and non-fasting glucose levels that were determined before delivery; individuals' iodine statuses were assessed using an iodine food frequency questionnaire; and serum thyroglobulin (Tg) and urinary iodine concentrations (UIC) were used to assess each group's iodine status. Thyroid antibodies and free thyroxine (FT4) levels were measured. Obstetric and anthropometric data were also collected. Large-for-gestational age (LGA) status was predicted using a Cox proportional hazards model with multiple confounders. Tg > 13 g/L was independently associated with LGA (adjusted hazard ratio = 3.4, 95% CI: 1.4-10.2, p = 0.001). Estimated iodine intake correlated with FT4 among participants who reported consuming iodine-containing supplements (ICS) after adjusting for confounders (ß = 0.4, 95% CI: 0.0002-0.0008, p = 0.001). Newborn weight percentiles were inversely correlated with maternal FT4 values (ß = -0.2 95% CI:-0.08--56.49, p = 0.049). We conclude that in mild-to-moderate ID regions, insufficient maternal iodine status may increase LGA risk. Iodine status and ICS intake may modify the effect that maternal dysglycemia has on offspring weight.

The effect of season, management and endocrinopathies on vitamin D status in horses.

BACKGROUND: Vitamin D deficiency is common in humans and is increasingly linked to the pathogenesis of a multitude of diseases including obesity and metabolic syndrome. The biology of vitamin D in horses is poorly described; the relative contribution of the diet and skin synthesis to circulating concentrations is unclear and associations with the endocrine disease have not been explored. OBJECTIVES: To determine the relationship between management, season and endocrine disease and vitamin D status in horses. STUDY DESIGN: Cross-sectional cohort study. METHODS: Plasma concentrations of 25-hydroxyvitamin D2 (25(OH)D2 ) and D3 (25(OH)D3 ) were measured by liquid chromatography-tandem mass spectrometry in 34 healthy unsupplemented grazing ponies and 22 stabled Thoroughbreds receiving supplementary vitamin D3 in feed. A nested group of 18 grazing ponies were sampled on long and short days (>12 and <12 h of light/day) to determine the effect of sunlight exposure. In addition, the relationships between age, sex, adiposity, serum insulin, adrenocorticotropic hormone and vitamin D status were assessed in a mixed group of 107 horses using a linear regression model. RESULTS: All animals had a measurable level of 25(OH)D2 (median 10.7 nmol/L) whilst 25(OH)D3 was only detected in Thoroughbreds receiving D3 supplementation. Thoroughbreds had lower concentrations of 25(OH)D2 than ponies (7.4 vs. 12.6 nmol/L, p < 0.01). In grazing ponies, 25(OH)D2 concentrations were significantly higher on long days compared to short days (14.4 vs. 8.7 nmol/L, p < 0.01), whilst 25(OH)D3 was undetectable. Measures of increased adiposity, but not basal insulin, were associated with higher 25(OH)D2 concentrations, conversely to humans. Increasing ACTH was associated with lower 25(OH)D2 (p < 0.01). MAIN LIMITATIONS: Vitamin D2 concentrations were not measured in grass or forage. CONCLUSIONS: In horses 25(OH)D2 is the predominant vitamin D metabolite, and there is an apparent lack of endogenous vitamin D3 production. The relationship between vitamin D and endocrine disorders in horses does not reflect that of other species and warrants further investigation.

Current evidence on the impact of the COVID-19 pandemic on paediatric endocrine conditions.

Severe acute respiratory coronavirus 2 (SARS-CoV-2) interacts with the host cells through its spike protein by binding to the membrane enzyme angiotensin-converting enzyme 2 (ACE2) and it can have a direct effect on endocrine function as ACE2 is expressed in many glands and organs with endocrine function. Furthermore, several endocrine conditions have features that might increase the risk of SARS-CoV-2 infection and the severity and course of the infection, as obesity for the underlying chronic increased inflammatory status and metabolic derangement, and for the possible changes in thyroid function. Vitamin D has immunomodulatory effects, and its deficiency has negative effects. Adrenal insufficiency and excess glucocorticoids affect immune conditions also besides metabolism. This review aims to analyze the rationale for the fear of direct effects of SARS-Cov-2 on endocrinological disorders, to study the influence of pre-existing endocrine disorders on the course of the infection, and the actual data in childhood. Currently, data concerning endocrine function during the pandemic are scarce in childhood and for many aspects definite conclusions cannot be drawn, however, data on properly managed patients with adrenal insufficiency at present are re-assuring. Too little attention has been paid to thyroid function and further studies may be helpful. The available data support a need for adequate vitamin D supplementation, caution in obese patients, monitoring of thyroid function in hospitalized patients, and confirm the need for an awareness campaign for the increased frequency of precocious puberty, rapidly progressive puberty and precocious menarche. The changes in lifestyle, the increased incidence of overweight and the change in the timing of puberty lead also to hypothesize that there might be an increase in ovarian dysfunction, as for example polycystic ovarian disease, and metabolic derangements in the next years, and in the future we might be facing fertility problems. This prompts to be cautious and maintain further surveillance.

Hypothalamic syndrome.

Hypothalamic syndrome (HS) is a rare disorder caused by disease-related and/or treatment-related injury to the hypothalamus, most commonly associated with rare, non-cancerous parasellar masses, such as craniopharyngiomas, germ cell tumours, gliomas, cysts of Rathke's pouch and Langerhans cell histiocytosis, as well as with genetic neurodevelopmental syndromes, such as Prader-Willi syndrome and septo-optic dysplasia. HS is characterized by intractable weight gain associated with severe morbid obesity, multiple endocrine abnormalities and memory impairment, attention deficit and reduced impulse control as well as increased risk of cardiovascular and metabolic disorders. Currently, there is no cure for this condition but treatments for general obesity are often used in patients with HS, including surgery, medication and counselling. However, these are mostly ineffective and no medications that are specifically approved for the treatment of HS are available. Specific challenges in HS are because the syndrome represents an adverse effect of different diseases, and that diagnostic criteria, aetiology, pathogenesis and management of HS are not completely defined.

The prevalence of elevated biotin in patient cohorts presenting for routine endocrinology, sepsis, and infectious disease testing.

Elevated blood biotin levels may interfere with some biotin-streptavidin immunoassays, used in clinical laboratories to aid diagnosis. The objective of this study was to determine the prevalence of elevated blood biotin levels in three at risk patient cohorts, where misclassification of disease status would have a high clinical impact. This retrospective, single-center study screened residual, de-identified plasma samples (N = 700) from adult patients undergoing routine thyroid stimulating hormone (TSH) (n = 500), procalcitonin (PCT) (n = 100), or human immunodeficiency virus (HIV) (n = 100) testing using the Elecsys® BRAHMS PCT (Roche Diagnostics), Access TSH (3rd IS) (Beckman Coulter Inc), and ARCHITECT HIV Ag/Ab Combo (Abbott Laboratories) immunoassays, respectively, for elevated levels of biotin (quantified by gas chromatography-time of flight mass spectrometry). Patients taking biotin supplements were included and dosages recorded from medical records. In the overall study cohort, blood biotin levels ranged 0.1-21.3 ng/mL; 44.3% (310/700) of samples were < 1 ng/mL, 54.7% (383/700) were 1-<10 ng/mL, and 1% (7/700) were ≥ 10 ng/mL. The sub-cohorts had similar ranges of biotin levels: 0.5-21.3 ng/mL (TSH), 0.1-12.1 ng/mL (PCT), and 0.3-7.3 ng/mL (HIV). In the 44 patients (6.3% of overall study cohort) who were documented as taking biotin supplements (range of doses, 2.5-10 mg/day), blood biotin levels ranged 0.9-21.3 ng/mL; 2.3% (1/44) of samples were < 1 ng/mL, 86.4% (38/44) were 1-<10 ng/mL, and 11.4% (5/44) were ≥ 10 ng/mL. Most patients who reported taking biotin supplements had blood biotin levels ≥ 1 ng/mL and the highest blood biotin level detected was 21.3 ng/mL.

Endocrine disorders in patients with Fabry disease: insights from a reference centre prospective study.

CONTEXT: Fabry Disease (FD) is a rare X-linked storage disease characterised by a-galactosidase A deficiency and diffuse organ accumulation of glycosphingolipids. Enzyme replacement and chaperone therapies are only partially effective. It remains unclear if FD-related endocrine disorders contribute to the observed morbidity. OBJECTIVE: To investigate the function of the endocrine system in patients with FD. DESIGN: We conducted an observational prospective study from 2017 to 2020. SETTING AND PATIENTS: We included 77 patients with genetically confirmed FD (27 men, 20/27 Classic, 7/26 Late Onset phenotype, 50 women, 41/50 and 9/50 respectively), who are systematically followed by our reference centre. RESULTS: 36/77 (46.8%) patients had VitD deficiency (25(0H)VitD <20 µg/L) despite the fact that 19/36 (52.8%) were substituted with cholecalciferol. Only 21/77 (27.3%) patients had normal VitD levels without VitD substitution. 11/77 (14.3%) had significant hypophosphatemia (p < 0.80 mmol/L). Three new cases (3.9%) of subclinical, two (2.6%) of overt and six (7.8%) of known hypothyroidism were identified. Of note, men had significantly higher renin levels than women [61.4 (26.1-219.6) vs.25.4 (10.9-48.0) mU/L, p = 0.003]. There were no major abnormalities in adrenal, growth and sex-hormone axes. Patients of Classic phenotype had significantly higher High-Density Lipoprotein Cholesterol (HDL-C) levels (p = 0.002) and in men those levels were positively correlated with globotriaosylsphingosin (Lyso-Gb3) values. 10/77 (13%) of the patients were underweight. CONCLUSIONS: VitD supplementation should be considered for all patients with FD. Thyroid screening should be routinely performed. Malnutrition should be prevented or treated, particularly in Classic phenotype patients. Overall, our data suggest that FD specialists should actively seek and diagnose endocrine disorders in their patients.

Detection of endocrine disorders in young children with multi-transfused thalassemia major.

BACKGROUND: Beta thalassemia major (TM) is the most common inherited genetic disorder worldwide. Patients are at risk of iron overload, which leads to various forms of tissue damage, including endocrinopathies. The aim of this study was to evaluate the prevalence and risk factors of endocrine disorders in young patients with multi-transfused TM receiving iron chelation therapy. METHODS: The inclusion criteria included all known cases of TM according to hemoglobin electrophoresis data, aged 12 years or younger, during the study period. The patient's age, gender, parent's consanguinity, clinical examination, and types of iron chelating agents used were recorded. Serum ferritin level, complete blood count (CBC), blood glucose homeostasis, thyroid, and parathyroid functions were determined. RESULTS: One hundred twenty patients met the inclusion criteria; 70% of them had malnutrition. The presence of endocrine disorders was observed in 28/120 (23.33%) patients. The most common endocrine disorders were thyroid disorders, either subclinical or clinical hypothyroidism in 11/120 (9.17%) patients, followed by abnormalities in glucose homeostasis 9/120 (7.5%). The prevalence of impaired glucose tolerance, impaired fasting glucose, and diabetes mellitus in the present study was 5 (4.17%), 4 (3.33%), and 0 (00%), respectively, while the least frequent endocrine disorder seen in our patients was hypoparathyroidism in 8/120 (6.66%). We noted that high serum ferritin levels and poor patient compliance to therapy were significantly associated with increased endocrine disorders (OR 0.98, 95% CI 0.96-0.99, P = 0.003 and OR 0.38, 95% CI 0.16:0.93, P = 0.03, respectively). Combined chelating iron agents significantly decreased the prevalence of endocrine disorders when compared with monotherapy (OR 0.40, 95% CI 0.16:0.97, P = 0.04). CONCLUSION: Endocrine disorders could occur in TM patients early before or equal to 12 years of life in about one-fourth of the patients. A high serum ferritin level and poor patient compliance to therapy were significantly associated with increased endocrine disorders. Combined iron-chelating agents were associated with a decreased prevalence of endocrine disorders when compared with monotherapy.

A Systematic Review and Meta-Analysis of Stature Growth Complications in ß-thalassemia Major Patients.

Background: Blood transfusion is a traditional treatment for ß-thalassemia (ß-thal) that improves the patients' anemia and lifespan, but it may lead to iron overload in parenchymal tissue organs and endocrine glands that cause their dysfunctions as the iron regulatory system can't excrete excess iron from the bloodstream. Objective: To evaluate the prevalence of iron-related complications (short stature, growth retardation, and growth hormone deficiency) in ß-thalassemia major (ßTM) patients. Methods: We performed an electronic search in PubMed, Scopus, and Web of Sciences to evaluate the prevalence of growth hormone impairment in ß-thalassemia major (ßTM) patients worldwide. Qualities of eligible studies were assessed by the Joanna Briggs Institute checklist for the prevalence study. We used Comprehensive Meta-Analysis (Version 2) to calculate the event rate with 95% CIs, using a random-effects model for all analyses. Findings: Seventy-four studies were included from five continents between 1978 and 2019; 70.27% (Asia), 16.21% (Europe), 6.75% (Africa), 2.70% (America), 1.35% (Oceania), and 2.70% (Multicenter). The overall mean age of the participants was about 14 years. The pooled prevalence of short stature (ST) was 48.9% (95% CI 35.3-62.6) and in male was higher than female (61.9%, 95% CI 53.4-69.7 vs. 50.9%, CI 41.8-59.9). The pooled prevalence of growth retardation (GR) was 41.1% and in male was higher than in female (51.6%, 95% CI 17.8-84 vs. 33.1%, CI 9.4-70.2). The pooled prevalence of growth hormone deficiency (GHD) was 26.6% (95% CI 16-40.8). Conclusion: Our study revealed that near half of thalassemia patients suffer from growth impairments. However, regular evaluation of serum ferritin levels, close monitoring in a proper institute, suitable and acceptable treatment methods besides regular chelation therapy could significantly reduce the patients' complications.

Clinical characteristics of endocrinopathies in Chinese patients with hereditary haemochromatosis.

AIMS: Hereditary haemochromatosis (HH) is a genetic disorder characterised by systemic iron overload and can lead to end-organ failure. However, very few data on this disorder, especially those on endocrine gland involvement in Chinese populations, are currently available. This study aimed to analyse the clinical features of endocrinopathies in patients with HH to generate concern among endocrinologists and improve the management of this disorder. MATERIALS AND METHODS: Chinese patients with HH-related endocrine dysfunction were enrolled at Peking Union Medical College Hospital from January 2010 to December 2018. All clinical data were analysed and summarised. RESULTS: A total of six patients were enrolled in this study, comprising five men and one woman; the average age was 36.5 ± 13.3 years. Mean serum ferritin concentration was 4508.8 ± 1074.3 ng/ml, and median transferrin saturation was 97.9% (96.6%-110.0%). Endocrine gland involvement associated with HH included the pancreas (5/6 patients), the adenohypophysis (5/6 patients) and the bones (1/6 patients); secondary endocrinopathies consisted of diabetes mellitus, hypogonadism, adrenal insufficiency and osteoporosis. Based on phlebotomy and iron chelation therapy, five patients were treated with exogenous insulin preparations, and three patients were treated with exogenous sex hormone replacement therapy. The clinical symptoms of five patients improved, although one patient died of hepatic encephalopathy and multiple organ failure. CONCLUSIONS: HH can cause multiple endocrinopathies. The possibility of HH should be carefully considered in patients with endocrine gland dysfunctions and concomitant elevated serum ferritin levels. Endocrine gland function should also be assessed and followed up in patients with a clear diagnosis of HH.

Endocrine disorders in Prader-Willi syndrome: a model to understand and treat hypothalamic dysfunction.

Prader-Willi syndrome is a rare genetic neurodevelopmental disorder resulting from the loss of expression of maternally imprinted genes located in the paternal chromosomal region, 15q11-13. Impaired hypothalamic development and function is the cause of most of the phenotypes comprising the developmental trajectory of Prader-Willi syndrome: from anorexia at birth to excessive weight gain preceding hyperphagia, and early severe obesity with hormonal deficiencies, behavioural problems, and dysautonomia. Growth hormone deficiency, hypogonadism, hypothyroidism, premature adrenarche, corticotropin deficiency, precocious puberty, and glucose metabolism disorders are the main endocrine dysfunctions observed. Additionally, as a result of hypothalamic dysfunction, oxytocin and ghrelin systems are impaired in most patients. Standard pituitary and gonadal hormone replacement therapies are required. In this Review, we discuss Prader-Willi syndrome as a model of hypothalamic dysfunction, and provide a comprehensive description of the accumulated knowledge on genetics, pathophysiology, and treatment approaches of this rare disorder.

Hypothalamic Inflammation as a Potential Pathophysiologic Basis for the Heterogeneity of Clinical, Hormonal, and Metabolic Presentation in PCOS.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age. It is a heterogeneous condition characterized by reproductive, endocrine, metabolic, and psychiatric abnormalities. More than one pathogenic mechanism is involved in its development. On the other hand, the hypothalamus plays a crucial role in many important functions of the body, including weight balance, food intake, and reproduction. A high-fat diet with a large amount of long-chain saturated fatty acids can induce inflammation in the hypothalamus. Hypothalamic neurons can sense extracellular glucose concentrations and participate, with a feedback mechanism, in the regulation of whole-body glucose homeostasis. When consumed nutrients are rich in fat and sugar, and these regulatory mechanisms can trigger inflammatory pathways resulting in hypothalamic inflammation. The latter has been correlated with metabolic diseases, obesity, and depression. In this review, we explore whether the pattern and the expansion of hypothalamic inflammation, as a result of a high-fat and -sugar diet, may contribute to the heterogeneity of the clinical, hormonal, and metabolic presentation in PCOS via pathophysiologic mechanisms affecting specific areas of the hypothalamus. These mechanisms could be potential targets for the development of effective therapies for the treatment of PCOS.

Approach to Patients with Unintentional Weight Loss.

Unintentional weight loss is a common clinical problem with a broad differential diagnosis that is clinically important because of the associated risks of morbidity and mortality. Community-dwelling adults are often diagnosed with malignancy, nonmalignant gastrointestinal disorders, and psychiatric disorders as the cause of unintentional weight loss, whereas institutionalized older adults are diagnosed most often with psychiatric disorders. Up to a quarter of patients do not have a diagnosis after comprehensive workup, and close follow-up is warranted. Treatment involves management of underlying causes.

Acupuncture Medical Therapy and its Underlying Mechanisms: A Systematic Review.

As a traditional Chinese alternative health care approach, acupuncture is gaining increasing attention and reputation in China and overseas. While becoming increasingly popular globally, some consumers and professionals still know little about the therapy and underlying mechanisms of acupuncture. Due to local superiority, there are large numbers of both clinical applications and mechanistic studies performed in China compared to countries overseas. Herein, this review attempts to give a comprehensive profile of the development, application, and mechanisms of acupuncture in treating major diseases. The number of clinical publications concerning acupuncture-treated neurological diseases, endocrine and metabolic diseases, circulatory diseases, respiratory diseases, etc. is first counted, and then, the application and therapeutic mechanisms of acupuncture on the predominant diseases in each category, including obesity, facial paralysis, sciatica, depression, hypertension, asthma, etc., are specifically discussed in this paper. The evolution of acupuncture tools and the rationality of acupoints are also discussed. This review not only summarizes the mechanisms of acupuncture but also provides useful information, such as specific acupoints and acupuncture procedures, for treating common diseases. Therefore, the current study provides useful information for both investigators and acupuncturists.

Selenium in Endocrinology-Selenoprotein-Related Diseases, Population Studies, and Epidemiological Evidence.

Selenium (Se), apart from iodine, iron, and calcium, is one of the nutrient-derived key elements strongly affecting the endocrine system. However, no specific hormonal "feedback" regulation for Se status has yet been identified, in contrast to the fine-tuned hormone network regulating Ca2+ and phosphate balance or hepcidin-related iron status. Since its discovery as an essential trace element, the effects of Se excess or deficiency on the endocrine system or components of the hypothalamic-pituitary-periphery feedback circuits, the thyroid hormone axis, glucoregulatory and adrenal hormones, male and female gonads, the musculoskeletal apparatus, and skin have been identified. Analysis of the Se status in the blood or via validated biomarkers such as the hepatically derived selenoprotein P provides valuable diagnostic insight and a rational basis for decision making on required therapeutic or preventive supplementation of risk groups or patients. Endocrine-related epidemiological and interventional evidence linking Se status to beneficial or potentially adverse actions of selected selenoproteins mediating most of the (patho-) physiological effects are discussed in this mini-review. Autoimmune thyroid disease, diabetes and obesity, male fertility, as well as osteoporosis are examples for which observational or interventional studies have indicated Se effects. The currently prevailing concept relating Se and selenoproteins to "oxidative stress," reactive oxygen species, radical hypotheses, and related strategies of pharmacological approaches based on various selenium compounds will not be the focus. The crucial biological function of several selenoproteins in cellular redox-regulation and specific enzyme reactions in endocrine pathways will be addressed and put in clinical perspective.

Vitamin D effects and endocrine diseases.

A lack of vitamin D has been linked to autoimmune diseases including type 1 diabetes, autoimmune thyroiditis and to obesity. The prevalence of vitamin D deficiency is higher in diabetic or obese children and patients with thyroiditis compared to healthy controls. Moreover, low vitamin D values seem to be associated with major complications and poor glycemic control, in particular in obese children. Supplementation with vitamin D, which has immune-regulatory properties, may support our therapies and improve the outcomes in different diseases. Although some studies suggest a possible role of vitamin D in the etiology of autoimmune diseases and obesity, data on supplementation benefits are inconclusive and further studies are needed. In this paper, we focus on the current evidence regarding vitamin D function in endocrine diseases and possible benefits of its supplementation in pediatric age.