Mild Hypothyroidism Research Articles

Thyroid hormone therapy of hypothyroidism in pregnancy.

Hypothyroidism is the most frequent pregnancy-related thyroid dysfunction, including overt and subclinical hypothyroidism. Studies show that even mild hypothyroidism may eventuate in adverse gestational outcomes and intellectual impairment of offspring. Women with overt hypothyroidism (OH) must be treated by levothyroxine (LT4) pre- and during pregnancy, however, it is controversial that when and how to initiate LT4 therapy and further optimize dosing so that pregnant women and their offspring may truly benefit. In the review we will analyze the changes in thyroid hormone requirements in pregnant women, the timing of LT4 treatment and adjustment of LT4 dose according to etiology in patients with hypothyroidism during pregnancy, and adjustment of LT4 after delivery.

Management of Subclinical and Overt Hypothyroidism Following Hemithyroidectomy in Children and Adolescents: A Pilot Study.

Background: To reduce surgical complications and avoid lifelong thyroid hormone replacement, hemithyroidectomy is preferred in children and adolescents with benign nodular thyroid disease. However, hypothyroidism following hemithyroidectomy may occur, and postoperative thyroid hormone replacement for hypothyroidism following hemithyroidectomy is usually administered without a full understanding of the clinical characteristics of hypothyroidism.Methods: To investigate the incidence and risk factors of hypothyroidism after hemithyroidectomy in children and adolescents, and to identify whether postoperative thyroid hormone replacement is necessary, a retrospective review of 43 patients under 18 years of age who underwent hemithyroidectomy from January 2009 to October 2016 was conducted. All hypothyroid patients were retrospectively analyzed to determine the incidence and predisposing factor(s) of postoperative hypothyroidism. All patients were measured regarding age, sex, serum thyrotropin (TSH), anti-thyroid antibody, and histological evidence of lymphocytic infiltration. Hypothyroid patients were measured for symptoms, timing of diagnosis, and thyroid hormone replacement.Results: The mean age at the time of surgery was 13.65 ± 3.04 years. Of the cohort, 34 patients were female (79.07%), and the mean follow-up time was 28 ± 9 months. Hypothyroidism was diagnosed in 11 of the 43 patients. The mean postoperative TSH level was 7.17 ± 2.13 μIU/ml. The mean preoperative TSH level was 3.11 ± 0.59 μIU/ml in hypothyroid patients compared with 1.92 ± 0.72 μIU/ml in euthyroid patients (P < 0.05). A preoperative TSH level >2.2 μIU/l and lymphocytic infiltration graded 3 or 4 were found to be independent risk factors for the development of hypothyroidism. There were no significant differences between groups in terms of patient age or sex.Conclusions: In the pediatric and adolescent population, patients with elevated preoperative TSH levels or the presence of lymphocytic infiltration may increase the risk of risk of hypothyroidism. In our study, postoperative levothyroxine (L-T4) treatment was necessary in 16.28% of cases after hemithyroidectomy. Patients with mild postoperative hypothyroidism should be followed up, without the need for immediate L-T4 replacement, so as to expect patients to recover spontaneously.

Challenges in Interpreting Thyroid Stimulating Hormone Results in the Diagnosis of Thyroid Dysfunction.

The pituitary hormone, thyrotropin (TSH), is regarded as the primary biomarker for evaluating thyroid function and is useful in guiding treatment with levothyroxine for patients with hypothyroidism. The amplified response of TSH to slight changes in thyroid hormone levels provides a large and easily measured signal in the routine care setting. Laboratories provide reference ranges with upper and lower cutoffs for TSH to define normal thyroid function. The upper limit of the range, used to diagnose subclinical (mild) hypothyroidism, is itself a matter for debate, with authoritative guidelines recommending treatment to within the lower half of the range. Concomitant diseases, medications, supplements, age, gender, ethnicity, iodine status, time of day, time of year, autoantibodies, heterophilic antibodies, smoking, and other factors influence the level of TSH, or the performance of current TSH assays. The long-term prognostic implications of small deviations of TSH from the reference range are unclear. Correction of TSH to within the reference range does not always bring thyroid and other biomarkers into range and will not always resolve the patient's symptoms. Overt hypothyroidism requires intervention with levothyroxine. It remains important that physicians managing a patient with symptoms suggestive of thyroid disease consider all of the patient's relevant disease, lifestyle, and other factors before intervening on the basis of a marginally raised TSH level alone. Finally, these limitations of TSH testing mitigate against screening the population for the undoubtedly substantial prevalence of undiagnosed thyroid disease, until appropriately designed randomised trials have quantified the benefits and harms from this approach.

Association of Thyroid Function with Handgrip Strength: Data from the Study of Health in Pomerania and the Berlin Aging Study II.

Background: Untreated overt hypo- and hyperthyroidism can lead to detrimental effects on muscle tissue and physical performance, but it is still unclear whether subclinical hypo- or hyperthyroidism has clinically relevant effects on muscle function and physical performance. The objective of this study was to determine associations of thyrotropin (TSH) with grip strength and physical performance. Methods: A sample of 6196 participants from the Study of Health in Pomerania and the Berlin Aging Study II was included in this cross-sectional analysis. Handgrip strength was measured with a hand-held dynamometer and physical performance was assessed with the timed up and go (TUG) test. Results: Serum TSH levels were significantly inversely associated with handgrip strength (β -0.11; [95% confidence interval, CI, -0.18 to -0.03]; p < 0.05) in multivariable linear regression. Individuals with high (β -1.06; [95% CI -1.86 to -0.26]; p < 0.05) or low (β -0.99; [95% CI -1.70 to -0.28]; p < 0.05) serum TSH levels had a significantly lower handgrip strength than individuals with serum TSH levels within the reference range. There was no association between TSH and the TUG time. Age showed a significant influence on the association of TSH with grip strength and TUG time. Conclusions: Even mild disturbances of thyroid function might lead to a relevant decline in grip strength, particularly in young and middle-aged subjects. Mild subclinical hypothyroidism might not be that unfavorable with regard to physical function in terms of handgrip strength at older age. Further studies are needed to clarify causal relationships.

Wide Spectrum of DUOX2 Deficiency: From Life-Threatening Compressive Goiter in Infancy to Lifelong Euthyroidism.

Six patients are described with bi-allelic DUOX2 variants and widely variable phenotypes. Patient 1 is an infant with a compressive hypothyroid goiter causing respiratory distress, which was promptly alleviated by levothyroxine (LT4). He was a compound heterozygote for DUOX2 variants, including a novel deletion of 540 base pairs. Patients 2 and 3 are siblings with the same compound heterozygous mutations of DUOX2, yet one had overt hypothyroidism at 14 months and the other lifelong euthyroidism. Patient 4 is a compound heterozygote individual and has mild persistent congenital hypothyroidism; his sister (patient 5) only had a borderline thyrotropin elevation at newborn screening, consistent with homozygous DUOX2 variants with a mild impact on enzyme activity. Their euthyroid mother (patient 6) is a compound heterozygote for the same DUOX2 mutations as her son. Targeted exome sequencing did not reveal any relevant modifiers. It is concluded that (i) prompt LT4 replacement in infants with respiratory distress due to a hypothyroid goiter makes surgery unnecessary; and (ii) the clinical expression of DUOX2 deficiency varies widely between individuals and over time, justifying periodic reevaluation of the need for LT4 replacement.

SUN-546 Coexistent Resistance to Thyroid Hormone Beta and Viral Thyroiditis

Background Resistance to thyroid hormone beta (RTHbeta) is a rare genetic disorder caused by a defective beta form of the thyroid hormone receptor and is characterized by elevated T3 and T4, non-suppressed TSH and variable tissue resistance to thyroid hormone (TH). In most cases a heterozygous mutation in THRB gene is identified. Clinical case A 32 year old adopted Caucasian woman presented with chest pain in the primary care setting in December 2016. Associated symptoms included palpitations, insomnia, poor concentration, restlessness, tremor, mood swings, headaches, irritability, increased appetite, dry scalp, cold extremities, weight gain and diarrhoea. She had no goitre. Based on thyroid function test (TFT) results, she was suspected to have hyperthyroidism and was commenced on antithyroid drugs for 13 months, but treatment was later stopped due to mouth ulcers. At this stage, further tests in our hospital showed elevated fT3 (8.4 pmol/L, RR 3.5-6.5 pmol/L) and fT4 (33.5 pmol/L, RR 10.0-19.8 pmol/L) and non-suppressed TSH (1.35 mU/L, RR 0.35-5.50 mU/L), without evidence of assay interference. SHBG and MRI pituitary were normal. THRB sequencing identified a heterozygous pathogenic mutation (R438H). She further reported that she struggled in school which prevented her from completing university education and remembered that her biological mother had learning disability. She was further assessed in our clinical research facility. Surprisingly, TFT results were very different: fT3 23.6 pmol/L, fT4 97.3 pmol/L and fully suppressed TSH (<0.03mU/L). Resting energy expenditure (REE) measured by indirect calorimetry was markedly raised [0.214 MJ/kg of lean body mass (LBM)]; compared to that seen in healthy controls (mean (SD): 0.148 (0.013) MJ/kg LBM). Given a recent coryzal illness and negative TRAB, thyrotoxicosis was deemed to be in keeping with thyroiditis. The TFT pattern evolved, without treatment, to mild hypothyroidism (fT3 6.8 pmol/L, fT4 16.2 pmol/L and TSH 21.54 mU/L), then returned to the pattern at presentation: elevated fT3 and fT4 and non-suppressed TSH (fT3 10.6 pmol/L, fT4 31.6 pmol/L, TSH 2.09 mU/L). Given ongoing thyrotoxic symptoms, identical to those present at time of referral, Tri-iodothyroacetic Acid (TRIAC) was commenced. Conclusion Coincident thyroid dysfunction can further complicate interpretation of TFTs in patients with RTHbeta. Notably, individuals with RTHbeta and coexistent thyrotoxicosis can exhibit a suppressed TSH, with underlying pituitary resistance to TH action only becoming evident once TH levels fall. Although thyroiditis rarely complicates RTHbeta, it has been reported that autoimmune thyroid disease occurs more commonly, so interpretation of such unusual TFT patterns may be required during the course of management of these individuals.

SAT-563 Nonshivering Thermogenesis as a Compensatory Mechanism for Reduced Metabolism in Severely Hypothyroid Mice

ABSTRACT The rate of obesity is steadily increasing in the United States and around the world. This is a major health concern, as obesity is associated with multiple leading causes of death, including heart disease, stroke, type 2 diabetes, and a subset of cancers [1]. Reduced thermogenesis causes fat and weight gain, whereas increased thermogenesis promotes weight and fat loss [2-5]. Therefore, stimulating adaptive thermogenesis is a promising approach to treating the obesity epidemic. However, current avenues of research have yet to identify a thermogenic target that could be used to efficaciously promote weight loss. The sodium/iodide symporter (NIS) is the key plasma membrane protein that mediates the sodium-dependent active transport of iodide into the thyroid follicular cells, the first step in the biosynthesis of the thyroid hormones (THs) [6]. Using a drug-free model of severe hypothyroidism (mice that are knockouts for NIS placed on a low-iodide diet), we found that these mice do not gain weight and exhibit a trend towards higher energy expenditure than is exhibited by a model of mild hypothyroidism (wild-type mice on a low-iodide diet). Severely hypothyroid mice exhibit significantly increased expression of markers of adipose tissue and skeletal muscle adaptive thermogenesis at room temperature (22°C). These mice may upregulate thermogenic mechanisms to compensate for reduced basal metabolism. This hypothesis is supported by the fact that severely hypothyroid mice are cold intolerant when transferred from thermoneutrality to a 4°C cold challenge, despite increased levels of thermogenic markers. Our results are consistent with the hypothesis that severely hypothyroid mice upregulate thermogenic mechanisms to maintain homeostasis, which ultimately protects them from weight gain.

Four Potentially Practice-Changing Articles From 2018

Four key articles published in 2018 have been selected to represent clinical situations where recent evidence may prompt changes in practice relevant to the nursing home population. There is no evidence of benefit for levothyroxine replacement in mild subclinical hypothyroidism. Duloxetine may be considered as an option for the treatment of pain and stiffness in osteoarthritis of the knees. Supplemental oxygen in the absence of hypoxemia is unnecessary and potentially harmful. Methylphenidate has modest benefit in treating apathy in dementia. For each subject, a brief review of the pertinent article is followed by a “bottom line” recommendation.

Investigating the Effect of Experimental Hypothyroidism on Insulin/Thyroid Hormones and Hepatic Steatosis

Background: The close physiological and biochemical relationships between insulin/thyroid hormones and intermediary metabolism, as well as hepatic homeostasis, are well documented. Apart from significant changes in thyroid hormones levels and altered insulin secretion or resistance, there is no consistency regarding the presence of hepatic storage diseases and fatty liver in hypothyroid patients. Objectives: The main objective of the current study was to evaluate the effect of experimental hypothyroidism on insulin level and histological alterations in the liver such as changes in lipid and glycogen reservoirs. Methods: In this study, 20 adult male Wistar rats were assigned to two similar groups including control and hypothyroid. Experimental hypothyroidism was induced by 0.02% propylthiouracil (PTU) administered to rats via drinking water for two months. The rates were then killed and blood samples were assayed for TSH, T4, T3, insulin hormones, and lipid profile. The left lobes of rats’ livers were also used for the histological study. Results: Our results indicated that the two-month administration of 0.02% PTU induced mild hypothyroidism associated with about a 50% reduction in the insulin level. The examination of liver samples showed that there were no significant changes in the overall architecture of liver tissue as compared to normal controls; that is, hepatocytes morphology, appearance, and position of the core, as well as glycogen content, were the same. The main finding of the current work was that in the hypothyroid group, the mild steatosis was accompanied by dyslipidemia. Conclusions: Based on our findings, a two-month administration of 0.02% PTU induces mild hypothyroidism in rates associated with a 50% decrease in the insulin level and mild steatosis in liver hepatocytes. This condition in long period may predispose hypothyroid individuals to develop diabetes mellitus and fatty liver simultaneously.

Efficacy of Ayurvedic Interventions in Hypothyroidism

Thyroid disorders have been one among the most challenging and most common endocrine disorders that we confront worldwide. Major thyroid disorders include hypothyroidism, hyperthyroidism, goiter/iodine deficiency, Hashimoto's thyroiditis, and thyroid cancer. Among these, hypothyroidism is arguably the most challenging as its multifarious clinical presentation often goes unnoticed. Hypothyroidism can be attributed to the deficiency of thyroid hormones, triiodothyronine (T3) and thyroxine (T4), in the body. Mild or subclinical hypothyroidism refers to the condition where peripheral thyroid hormone levels are within normal range, but serum thyroid-stimulating hormone (TSH) levels are mildly elevated. Data to date are scarce that include direct experimental, pharmacological, or preclinical types of evidence of treating hypothyroidism with Ayurvedic and herbal drugs. The scope of this manuscript covers the utility of conventional Ayurveda or herbal drugs in ameliorating the pathophysiological symptoms of hypothyroidism. Treatment strategies have been evolving since the early and mid-twentieth century, starting from using the whole thyroid extract to the modern-day thyroxine monotherapy by L-thyroxine. Despite these advances, there remains a considerably large population who endure the symptoms of hypothyroidism. Various assortments of formulations are available for such conditions in Ayurveda system of medicine since the very early days of civilization. In Ayurveda, though there are not any direct reference of thyroid, Galaganda and Gandamala, which possess symptomatic similarities with thyroid disorders, have been mentioned frequently in the texts. With the present data available, it is concluded that natural resources around can be utilized for the prevention and amelioration of hypothyroidism in mammals.

DUOX Defects and Their Roles in Congenital Hypothyroidism.

Extracellular hydrogen peroxide is required for thyroperoxidase-mediated thyroid hormone synthesis in the follicular lumen of the thyroid gland. Among the NADPH oxidases, dual oxidases, DUOX1 and DUOX2, constitute a distinct subfamily initially identified as thyroid oxidases, based on their level of expression in the thyroid. Despite their high sequence similarity, the two isoforms present distinct regulations, tissue expression, and catalytic functions. Inactivating mutations in many of the genes involved in thyroid hormone synthesis cause thyroid dyshormonogenesis associated with iodide organification defect. This chapter provides an overview of the genetic alterations in DUOX2 and its maturation factor, DUOXA2, causing inherited severe hypothyroidism that clearly demonstrate the physiological implication of this oxidase in thyroid hormonogenesis. Mutations in the DUOX2 gene have been described in permanent but also in transient forms of congenital hypothyroidism. Moreover, accumulating evidence demonstrates that the high phenotypic variability associated with altered DUOX2 function is not directly related to the number of inactivated DUOX2 alleles, suggesting the existence of other pathophysiological factors. The presence of two DUOX isoforms and their corresponding maturation factors in the same organ could certainly constitute an efficient redundant mechanism to maintain sufficient H2O2 supply for iodide organification. Many of the reported DUOX2 missense variants have not been functionally characterized, their clinical impact in the observed phenotype remaining unresolved, especially in mild transient congenital hypothyroidism. DUOX2 function should be carefully evaluated using an in vitro assay wherein (1) DUOXA2 is co-expressed, (2) H2O2 production is activated, (3) and DUOX2 membrane expression is precisely analyzed.

Experimentally induced subclinical hypothyroidism causes decreased functional connectivity of the cuneus: A resting state fMRI study

ObjectiveThe aim of this study was to experimentally evaluate the effects of subclinical mild hypothyroidism on brain network connectivity as determined by resting state fMRI (rsfMRI) which serves as a proxy for global changes in brain function. MethodsFifteen otherwise healthy patients with complete hypothyroidism under stable, long term levothyroxine substitution volunteered for the study. They reduced their pretest levothyroxine dosage by 30% for 52–56 days. Basally and after partial levothyroxine withdrawal, rsfMRI along with a neuropsychological analysis was performed. RsfMRI was subjected to graph-theory-based analysis to investigate whole-brain intrinsic functional connectivity. ResultsThe desired subclinical hypothyroidism was achieved in all subjects. This was associated with a significant decrease in resting-state functional connectivity specifically in the cuneus (0.05 FWE corrected at cluster level) which was mainly caused by a weaker functional connectivity to the cerebellum and regions of the default mode network, i.e. the medial prefrontal cortex, the precuneus and the bilateral angular gyri. The decrease in cuneus connectivity was correlated to the increase in TSH serum levels. A working memory task showed a slightly longer reaction time and less accuracy after partial levothyroxine withdrawal. ConclusionEven short-term partial levothyroxine partial withdrawal leads to deficits in working memory tasks and to a weaker integration of the cuneus within the default mode network.

Effects of Shuganjianpihuatanxingqi decoction on mild subclinical hypothyroidism: A SPIRIT compliant randomized controlled trial study protocol.

Introduction:Mild subclinical hypothyroidism (SCH) can cause depression, fatigue, cognitive dysfunction, or other hypothyroid symptoms, and even progress to hypothyroidism. The treatment of mild SCH is controversial. Shuganjianpihuatanxingqi decoction (SD) is a frequently prescribed Chinese herbal medicine in patients with mild SCH. However, scientific evidence is needed to confirm the therapeutic effect of SD.Methods and analysis:This study is a randomized, double-blind, and controlled clinical trial. A total of 228 participants with the diagnosis of mild SCH will be randomly assigned to the SD or placebo group in a ratio of 1:1. Participants will receive treatment for 12 weeks and undergo 12-month follow-up. The primary outcome measure is the thyroid-stimulating hormone level, and secondary outcomes will be the differences in the results of Thyroid-related Quality of Life Questionnaire, blood lipids, and Traditional Chinese Medicine Symptom Score Scale between baseline and at 12 weeks after intervention.Ethics and dissemination:The study has been approved by Guang’anmen Hospital of China Academy of Chinese Medical Sciences (no.2018-005-ky-01). The trial results will be published via peer-reviewed journals and the Clinical Research Information Service.Trial registration number:ChiCTR1800015781 (approval date: 20 April 2018).

Mild Hypothyroidism in Childhood: Who, When, and How Should Be Treated?

Mild hypothyroidism, also known as subclinical hypothyroidism (SH), is biochemically defined as serum TSH levels above the upper limit of the reference range, in the presence of normal serum concentrations of total T4 and free T4 (FT4). In the neonatal period, mild hypothyroidism can be defined by the presence of a TSH value between 6 and 20 mIU/L and normal FT4 levels. After the neonatal period, SH can be defined mild if TSH ranges between 4.5 and 10 mIU/L. The management of mild hypothyroidism in childhood is challenging. The major concern is to establish whether this condition should always be considered an expression of mild thyroid dysfunction. Indeed, the effects of untreated mild hypothyroidism are still not completely defined. In the neonatal period, concern exists about neurocognitive outcome; in children, although there is no clear evidence of alterations in growth or neurocognitive development, subtle cardiovascular abnormalities have been documented. Therefore, there is still uncertainty about the need of treatment across all ages, and the management should be based on the age of the child, the etiology, and the degree of TSH elevation, as well as on other patient factors. This review updates current evidences on diagnosis and management of mild hypothyroidism in childhood.

Thyroid Function Changes in the Elderly and Their Relationship to Cardiovascular Health: A Mini-Review

Background: Thyroid hormones have significant effects on the cardiovascular systems. In general, hyperthyroidism is associated with an increased risk of dysrhythmias, while hypothyroidism may cause atherosclerosis. Recent large studies have sought to identify aging-associated changes in thyroid function and their relevance to cardiovascular morbidity and mortality in the elderly. Conflicting results have often been published, likely due to the heterogeneity of the studied populations. Objective: This review seeks to briefly summarize the most recent large population studies analyzing thyroid changes with aging and interpreting their effects on cardiovascular health in the elderly. Methods: Selective review of recent literature. Results: The emerging pattern suggests a slight decrease in thyroid function in the elderly leading to slightly higher thyroid stimulating hormone (TSH) levels. However, the incidence of mild hyperthyroidism also increases, especially in populations with historical or current iodine deficiency. Large observational studies suggest that the potential harm from mild hypothyroidism seen in younger population tends to diminish in older subjects, while the harm from mild hyperthyroidism becomes more significant. A markedly increased risk of atrial fibrillation is a well-established consequence of subclinical hyperthyroidism in patients in the sixth decade of life and beyond. Conclusions: The absence of large prospective interventional data does not allow the formulation of strict clinical recommendations, but a higher TSH threshold for treating both subclinical hypothyroidism and subclinical hyperthyroidism in the elderly seems reasonable.

Antidepressant-Resistant Depression in Patients With Comorbid Subclinical Hypothyroidism or High-Normal TSH Levels.

Antidepressant-Resistant Depression in Patients With Comorbid Subclinical Hypothyroidism or High-Normal TSH Levels.

Mild subclinical hypothyroidism is associated with paediatric dyslipidaemia.

There is a lack of consensus on the cardiometabolic consequences of mild subclinical hypothyroidism (SCH) among children. The objective of the current study was to compare lipid profiles in children with mild SCH with those of euthyroid children. Retrospective medical record review. Children (ages 2-18years) who had undergone simultaneous measurement of TSH, free thyroxine (T4) and lipids. Lipids in children with mild SCH (TSH 5-<10 mIU/L and normal free T4, n=228) were compared with those in euthyroid children (n=1215). TSH level was positively associated with total cholesterol and nonhigh density lipoprotein (non-HDL) cholesterol [β 0.05(0.03-0.08), P<.0001 and β 0.05(0.03-0.08), P<.0001, respectively]. Total cholesterol was significantly higher in children and adolescents with mild SCH compared with euthyroid children (4.43±1.14mmol/L vs 4.2±0.85mmol/L, P=.0005). Similarly, non-HDL cholesterol level was also higher in children with mild SCH relative to euthyroid children (3.08±1.14mmol/L vs 2.91±0.8mmol/L, P=.001). The adjusted odds ratio of having elevated total cholesterol and elevated non-HDL cholesterol was greater in children with mild SCH compared with euthyroid children (OR 1.88, 95% CI; 1.28-2.73; P=.001 and 1.72, 95% CI 1.2-2.5; P=.003, respectively). The presence of thyroid autoimmunity was not associated with higher rates of dyslipidaemia. Mild SCH in children and adolescents was associated with higher rates of elevated total cholesterol and elevated non-HDL cholesterol. Randomized placebo controlled studies are warranted to determine if treatment of mild SCH in children leads to improvement in lipid profile.

In Utero and Postnatal Propylthiouracil-Induced Mild Hypothyroidism Impairs Maternal Behavior in Mice.

Thyroid hormones (THs) play crucial roles in general and brain development. Even if the hypothyroidism is mild, it may alter brain function, resulting in irreversible behavioral alterations. Although various behavioral analyses have been conducted, the effects of propylthiouracil (PTU) treatment during in utero and postnatal periods on maternal behavior have not yet been studied. The present study examined in mice whether THs insufficiency during development induce behavioral changes. Pregnant C57BL/6j mice were divided into three groups, and each group was administered different dosages of PTU (0, 5, or 50 ppm) in drinking water during in utero and postnatal periods (from gestational day 14 to postnatal day 21). First, locomotor activity and cognitive function were assessed in the offspring at 10 weeks. Next, female offspring were mated with normal mice and they and their offspring were used to assess several aspects of maternal behavior (identifying first pup, returning all pups to nest, time spent nursing, and licking pups). As expected, locomotor and cognitive functions in these mice were disrupted in a PTU dose-dependent manner. On postpartum day 2, dams who had been exposed 50 ppm PTU during in utero and postnatal periods displayed a significantly longer time identifying the first pup and returning all three pups back to the nest, less time nursing, and decreased licking behavior. The decrease in maternal behavior was significantly correlated with a decrease in cognition. These results indicate that insufficiency of THs during in utero and postnatal periods impairs maternal behavior, which may be partly induced by impaired cognitive function.

Over- and Under-Treatment of Hypothyroidism Is Associated with Excess Mortality: A Register-Based Cohort Study.

This study investigated the association between hypothyroidism and mortality in both treated and untreated hypothyroid patients, and the consequences of over- and under-treatment with respect to mortality. This was a register-based cohort study of 235,168 individuals who had at least one serum thyrotropin (TSH) during 1995-2011 (median follow-up 7.2 years). Hypothyroidism was defined as at least two measurements of TSH >4.0 mIU/L within a half year spaced by at least 14 days, or one measurement of TSH >4.0 mIU/L and two filled prescriptions of levothyroxine the following year. All-cause mortality rates were calculated using multivariable Cox regression analysis adjusted for age, sex, and comorbidities using the Charlson Comorbidity Index. Mortality was increased in untreated hypothyroid individuals (n = 673; hazard ratio [HR] = 1.46 [confidence interval (CI) 1.26-1.69]; p < 0.001) compared to euthyroid controls. Results remained significant even when subdividing according to mild (TSH >4.0 mIU/L and ≤10 mIU/L; p < 0.001) and marked hypothyroidism (TSH >10 mIU/L; p = 0.002). Mortality was increased in both treated and untreated hypothyroid individuals for each six months a patient had increased TSH (HR = 1.05 [CI 1.02-1.07], p < 0.0001, and HR = 1.05 [CI 1.02-1.07], p = 0.0009, respectively). In patients who received levothyroxine, the HR for mortality increased by a factor 1.18 ([CI 1.15-1.21]; p < 0.0001) for each six months a patient exhibited decreased TSH. This finding was essentially unchanged after stratification by disease severity (mild or marked hypothyroidism) and age (older and younger than 65 years). Mortality was increased in untreated but not in treated hypothyroid individuals, independently of age and severity of hypothyroidism. Duration of decreased TSH in treated individuals had a greater impact on mortality than did duration of elevated TSH. These results stress the need for close monitoring of treatment in individuals receiving thyroid hormone replacement therapy.

Subclinical Hypothyroidism in Children and Adolescents: a single-center retrospective study

Introduction: The ideal management of subclinical hypothyroidism, particularly the mild form, remains unclear. Our objectives were to describe the clinical management of subclinical hypothyroidism in children and adolescents and the natural course of the disease with conservative management. Material and Methods: We retrospectively analyzed clinical records of patients, under the age of 18 years, referred to our pediatric endocrinology department due to subclinical hypothyroidism between 2009 and 2014, with ≥1 year of followup. Patients under one month of age and with TSH (thyroidstimulating hormone) levels 5 uUI/mL with a normal serum free thyroxine. Mild and severe subclinical hypothyroidism were defined when TSH was <10 uUI/mL and ≥10 uUI/mL, respectively. Results: We included 69 patients (62.3% girls) with a median age at diagnosis of 8.0 [(25th percentile-75th percentile (P25-P75): 4.75-11.0)] years. Most of the patients (80.6%) were symptomatic and Hashimoto thyroiditis was the most frequent identified cause. A mild form of subclinical hypothyroidism was diagnosed in 79.7% of the patients. All patients with severe subclinical hypothyroidism initiated therapy with levothyroxine in contrast with 43.6% in the mild subclinical hypothyroidism group. Among patients not treated, 73.3% had TSH normalized after one year of follow-up and none progressed to overt hypothyroidism. Conclusion: The mild form of subclinical hypothyroidism was the most common typepf disease and, among patients managed conservatively, the majority presented normal thyroid function after one year of follow-up and none progressed to overt hypothyroidism. Our results reinforce the idea that, in most patients, subclinical hypothyroidism is a benign condition with a low risk of progression to overt thyroid dysfunction. However, further studies are needed to evaluate the potential long-term effects of the condition in untreated patients and to clarify the best clinical approach and follow-up strategy.