Risk factors of subclinical hypothyroidism and the potential contribution to miscarriage: A review.

BACKGROUND: There is no clear cutoff value for thyroid-stimulating hormone (TSH) level that defines subclinical hypothyroidism (SCH). Moreover, TSH levels can be affected by numerous factors. Although mild SCH has been implicated in miscarriage, the relationship between TSH levels and miscarriage remains unelucidated. METHODS: We reviewed nine known risk factors affecting TSH levels and 28 studies investigating the potential association between mild SCH and miscarriage, examining whether these factors were considered. MAIN FINDINGS: Among 28 studies that examined whether mild SCH (TSH > 2.5 mIU/L) contributed to miscarriage, thyroid antibodies were measured in only 15. TSH measurement methods were described in 18 studies. Although the iodinated contrast medium used in hysterosalpingography (HSG) is stored in the body for a long time and is a risk factor for mild SCH, only one study described its potential impact on TSH levels. Nine studies, which concluded that mild SCH contributed to miscarriage, had thyroid status evaluated only after the onset of pregnancy, but not before. CONCLUSION: TSH levels can be significantly affected by patient demographics and health history, country of origin, and fertility treatment. It is important to consider these factors while evaluating mild SCH. It remains unclear how mild SCH contributes to miscarriage.

Low CSF/serum ratio of free T4 is associated with decreased quality of life in mild hypothyroidism - A pilot study.

BACKGROUND & OBJECTIVE: Patients with mild hypothyroidism often are depressed and have impaired quality of life despite serum free-T4 and T3 within reference values. Therefore, we investigated whether their symptoms were dependent on the concentrations of free -T4 and T3 in the circulation and cerebrospinal fluid (CSF). METHODS: Twenty-five newly diagnosed, untreated hypothyroid subjects and as many age- and sex-matched healthy controls were investigated. Blood and CSF sampling was performed in the morning after an overnight fast. Quality of life (QoL) was assessed by a Likert scale. In the hypothyroid subjects, the MADRS rating scale was also used to evaluate symptoms of depression. Furthermore, the results obtained by the questionnaires were related to serum and CSF levels of free- T4 and T3 as well as the ratios between them in CSF and in serum. RESULTS: Self-reported health was considerably lower in hypothyroid subjects. MADRS was considerably higher than the normal range for healthy individuals. Low CSF/serum free-T4 ratio was correlated with an increased depressed state according to MADRS (p < 0.01), and in addition, CSF/serum free-T4 ratio correlated positively with the self-reported general health Likert scale (p < 0.05). Concentrations of TSH, or free-T3 in serum or CSF, were not associated with an increased depressed state or self-reported general health. CONCLUSIONS: Low CSF/serum ratio of free-T4 was correlated with impaired general health and mood, in contrast to serum measurements not showing any correlations. These findings might partly explain why some patients with hypothyroidism suffer from mental symptoms, despite adequate serum levels of free-T4. However, the findings need to be confirmed in further and larger studies.

Implantation failure in rats with subclinical hypothyroidism is associated with LIF/STAT3 signaling.

BACKGROUND: Pregnant women with subclinical hypothyroidism are associated with an increased risk of spontaneous abortion. This study aims to investigate the mechanisms underlying the effects of maternal subclinical hypothyroidism during early pregnancy on abortion in the uterus, focusing upon the LIF/STAT3 signaling pathway. METHODS: One hundred five Wistar rats were randomly divided into three groups (35 rats in each group): control (CON) group, subclinical hypothyroidism (SCH) group and overt hypothyroidism (OH) group. We examined the weight of rat uteri, rat placenta and embryos. We also determined the number of implantation sites and the embryo absorption rates. The protein and mRNA expressions of TSHR, TR-α, TR-ß, LIFR, gp130, JAK1, p-STAT3 and STAT3 were measured by immunohistochemical staining, real-time PCR and Western blotting. RESULTS: The weights of rat uteri, rat placenta and embryos were significantly reduced in the SCH and OH groups. The number of implantation sites was significantly decreased in the SCH and OH groups, while embryo absorption rates were significantly increased. The mRNA and protein expressions of TSHR were upregulated in the SCH and OH groups, while TR-α and TR-ß showed no difference when compared between the three groups. The expression levels of LIFR, gp130, JAK1 and p-STAT3 were significantly higher in the SCH and OH groups. CONCLUSIONS: Clinical and subclinical hypothyroidism during early pregnancy might cause adverse pregnancy outcomes. Implantation failure in rats with subclinical hypothyroidism was associated with abnormal LIF/STAT3 signaling.

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.

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.

Congenital hypothyroidism: insights into pathogenesis and treatment.

Congenital hypothyroidism occurs in approximately 1 in 2000 newborns and can have devastating neurodevelopmental consequences if not detected and treated promptly. While newborn screening has virtually eradicated intellectual disability due to severe congenital hypothyroidism in the developed world, more stringent screening strategies have resulted in increased detection of mild congenital hypothyroidism. Recent studies provide conflicting evidence about the potential neurodevelopmental risks posed by mild congenital hypothyroidism, highlighting the need for additional research to further define what risks these patients face and whether they are likely to benefit from treatment. Moreover, while the apparent incidence of congenital hypothyroidism has increased in recent decades, the underlying cause remains obscure in most cases. However, ongoing research into genetic causes of congenital hypothyroidism continues to shed new light on the development and physiology of the hypothalamic-pituitary-thyroid axis. The identification of IGSF1 as a cause of central congenital hypothyroidism has uncovered potential new regulatory pathways in both pituitary thyrotropes and gonadotropes, while mounting evidence suggests that a significant proportion of primary congenital hypothyroidism may be caused by combinations of rare genetic variants in multiple genes involved in thyroid development and function. Much remains to be learned about the origins of this common disorder and about the optimal management of less severely-affected infants.

Mild hypothyroidism improves glucose tolerance in experimental type 2 diabetes.

BACKGROUND: Co-existence of type 2 diabetes and hypothyroidism is an emerging trend observed in clinical practice. Although the effects of isolated type 2 diabetes and hypothyroidism are well known, there are limited studies addressing the metabolic complications when these two conditions co-exist. The aim of the present study was to assess the interaction between type 2 diabetes and hypothyroidism with respect to glucose tolerance, dyslipidemia and redox balance in a state were these two diseases coexist. METHODS: Sixty male Wistar Albino rats were randomised into six groups. Group 1: control, Group 2: overt hypothyroidism, Group 3: mild hypothyroidism, Group 4: type 2 diabetes, Group 5: mild hypothyroidism + type 2 diabetes, Group 6: overt hypothyroidism + type 2 diabetes. Experimental hypothyroidism was created by the administration of propyl-2-thiouracil and type 2 diabetes by feeding rats with 60% fructose (w/w). The duration of the study was 6 weeks. All the parameters were estimated at the start (basal) and the end of the study. Intraperitoneal glucose tolerance test was carried out and area under curve (AUC) calculated to assess the glucose tolerance. Thyroid profile, lipid profile and oxidative stress parameters were also measured. RESULTS: Plasma TSH level was elevated 3-fold in the mild hypothyroid group and 15.2-fold in the overt hypothyroid group in comparison to the control group. Thyroid profile was found to be normal in type 2 diabetic group. There was no significant difference between hypothyroidism and hypothyroidism+diabetes groups with respect to thyroid profile. Among the six groups the degree of glucose intolerance was found to be maximum for overt hypothyroidism+diabetes group, followed by diabetes group and overt hypothyroidism group. An interesting finding was that glucose intolerance was significantly reduced in mild hypothyroidism+diabetes group (increase in AUC: 48.04%) in comparison with isolated diabetes group (increase in AUC: 71.63%). Similar results were obtained with parameters of oxidative stress. Oxidative stress was observed in overt hypothyroidism+diabetes, diabetes, overt hypothyroidism groups with severity decreasing in that order. Coexistence of mild hypothyroidism with diabetes decreased oxidative stress in comparison with isolated diabetes group. There was no statistical difference in lipid profile between mild hypothyroidism+diabetes and isolated diabetes group. CONCLUSION: Presence of mild hypothyroidism in type 2 diabetes confers a protective effect with respect to glucose tolerance and redox balance whereas presence of overt hypothyroidism in type 2 diabetes has a deleterious effect. The increased incidence of hypothyroidism in diabetes, especially subclinical hypothyroidism, could be a reflection of a physiological attempt by the body to mitigate damage wrought by diabetes.

Retrospective analysis of infants designated as positive on mass-screening for congenital hypothyroidism at kagoshima university.

Mass-screening for congenital hypothyroidism has identified cases of mild hypothyroidism, transient hypothyroidism, and transient hyperthyrotropinemia as well as typical hypothyroidism. In this paper, we examine the clinical data of the cases found positive in the screening test at our hospital. From 1989 to 1999 there were 72 patients with positive screening tests who started levothyroxine sodium (l-T4; Thyradin-S) as supplement therapy. At the age of 3 to 4 yr the patients were re-evaluated to determine whether treatment should be continued. Thyroid scintigraphies were done at the same time. We divided these cases into 4 groups. Those in group 1A started l-T4 in early infancy without a TRH test because of obvious clinical evidence of hypothyroidism, and treatment was continued after re-evaluation (n=37). Those in group 1B also started treatment in early infancy without a TRH test, but treatment was discontinued after re-evaluation (n=20). Patients in group 2A started l-T4 after evaluation by a TRH test and treatment was continued after re-evaluation (n=14), while those in group 2B started treatment after a TRH test, but after re-evaluation, treatment was discontinued (n=1). In group 2A, only a low dose of l-T4 was needed, and a slightly elevated TSH and slightly decreased free T4 (FT4) were observed after the drug washout period. However, these patients had an exaggerated response to the TRH test at re-evaluation. These findings indicate that this group, forming not a small part of whole screening-positive subjects, had mild hypothyroidism. Such patients require careful follow-up and repeated evaluation to determine whether treatment should be continued.