The impact of thyroid diseases starting from birth on reproductive function.

The aim of this review is to provide relevant information regarding the impact of thyroid disease, starting from birth and mainly concerning hyperthyroidism and hypothyroidism, on reproduction. Hyperthyroidism occurs much less commonly in children than hypothyroidism, with Graves' disease (GD) being the most common cause of thyrotoxicosis in children. Children born with neonatal GD have no defects in the reproductive system that could be related to hyperthyroidism. Current treatment options include antithyroid drugs (ATD), surgery, and radioactive iodine (RAI). In males, normal thyroid function seems important, at least in some parameters, for maintenance of semen quality via genomic or non-genomic mechanisms, either by locally acting on Sertoli cells, Leydig cells, or germ cells, or by affecting crosstalk between the HPT axis and the HPG axis. Sexual behavior may also be affected in thyroxic men, although many of these patients may have normal free testosterone levels. In women, menstrual irregularities are the most common reproduction-related symptoms in thyrotoxicosis, while this disorder is also associated with reduced fertility, although most women remain ovulatory. An increase in sex hormone-binding globulin (SHBG) and androgens, thyroid autoimmunity, and an impact on uterine oxidative stress are the main pathophysiological mechanisms which may influence female fertility. Thyroid hormones are responsible for normal growth and development during pre- and postnatal life, congenital hypothyroidism (CH) being the most common cause of neonatal thyroid disorders, affecting about one newborn infant in 3500. The reproductive tract appears to develop normally in cretins. Today, CH-screening programs allow for early identification and treatment, and, as a result, affected children now achieve normal or near-normal development. Hypothyroidism in males is associated with decreased libido or impotence. Although little is currently known about the effects of hypothyroidism on spermatogenesis and fertility, it has been established that sperm morphology and motility are mainly affected. In women of reproductive age, hypothyroidism results in changes in cycle length and amount of bleeding. Moreover, a negative effect on fertility and higher miscarriage rates has also been described.

Association of two synonymous splicing-associated CpG single nucleotide polymorphisms in calpain 10 and solute carrier family 2 member 2 with type 2 diabetes.

Coding synonymous single nucleotide polymorphisms (SNPs) have attracted little attention until recently. However, such SNPs located in epigenetic, CpG sites modifying exonic splicing enhancers (ESEs) can be informative with regards to the recently verified association of intragenic methylation and splicing. The present study describes the association of type 2 diabetes (T2D) with the exonic, synonymous, epigenetic SNPs, rs3749166 in calpain 10 (CAPN10) glucose transporter (GLUT4) translocator and rs5404 in solute carrier family 2, member 2 (SLC2A2), also termed GLUT2, which, according to prior bioinformatic analysis, strongly modify the splicing potential of glucose transport-associated genes. Previous association studies reveal that only rs5404 exhibits a strong negative T2D association, while data on the CAPN10 polymorphism are contradictory. In the present study DNA from blood samples of 99 Greek non-diabetic control subjects and 71 T2D patients was analyzed. In addition, relevant publicly available cases (40) resulting from examination of 110 Personal Genome Project data files were analyzed. The frequency of the rs3749166 A allele, was similar in the patients and non-diabetic control subjects. However, AG heterozygotes were more frequent among patients (73.24% for Greek patients and 54.55% for corresponding non-diabetic control subjects; P=0.0262; total cases, 52.99 and 75.00%, respectively; P=0.0039). The rs5404 T allele was only observed in CT heterozygotes (Greek non-diabetic control subjects, 39.39% and Greek patients, 22.54%; P=0.0205; total cases, 34.69 and 21.28%, respectively; P=0.0258). Notably, only one genotype, heterozygous AG/CC, was T2D-associated (Greek non-diabetic control subjects, 29.29% and Greek patients, 56.33%; P=0.004; total cases, 32.84 and 56.58%, respectively; P=0.0008). Furthermore, AG/CC was strongly associated with very high (≥8.5%) glycosylated plasma hemoglobin levels among patients (P=0.0002 for all cases). These results reveal the complex heterozygotic SNP association with T2D, and indicate possible synergies of these epigenetic, splicing-regulatory, synonymous SNPs, which modify the splicing potential of two alternative glucose transport-associated genes.

Vandetanib for the treatment of thyroid cancer: an update.

INTRODUCTION: Medullary thyroid carcinoma (MTC) is a rare endocrine malignancy accounting for a significant percentage of thyroid cancer-related fatal events. Traditional treatment modalities used in the other types of thyroid carcinomas have been proved largely ineffective in advanced MTC. Better understanding of the molecular pathways implicated in the pathogenesis of MTC has led to the development of new drugs, which are implicated in the disruption of these molecular cascades. AREAS COVERED: This review provides the latest information regarding vandetanib , a new tyrosine kinase inhibitor mainly in the treatment of MTC. A collection of available data was conducted using the PubMed database as well as the ClinicalTrials.gov website, searching for vandetanib and thyroid cancer. EXPERT OPINION: Vandetanib targets multiple cell-signaling pathways involved in the molecular pathogenesis of thyroid cancer, namely vascular endothelial growth factor receptor-2, epidermal growth factor receptor and rearranged during transfection receptor. It is an effective approach in treating advanced MTC. However, treatment toxicity issues, as well as individual patient parameters, including disease burden and progression, should be taken into consideration before initiating vandetanib treatment.

Selenium status in patients with autoimmune and non-autoimmune thyroid diseases from four European countries.

CONTEXT: Selenium supplementation has been suggested for Hashimoto thyroiditis and Graves' ophthalmopathy. Objective, Design: Our aim is to measure selenium status (p-Se, p-SePP), urine iodine (UI) levels and urine iodine/creatinine ratio (UI/C) in different thyroid diseases (n = 416) from four European countries and to compare the results between patients with and without thyroid autoimmunity. RESULTS: p-Se and p-SePP showed positive correlation and did not correlate with UI/C. Also, these measurements were higher in patients from Italy in comparison with the other countries. Austria had the lowest UI/C ratios. Selenium deficiency exists in these four European countries. Selenium status was lower in patients with Hashimoto thyroiditis and Graves' disease in comparison with non-autoimmune thyroid disease patients and did not differ between autoimmune patients with or without thyroid peroxidase antibodies. The latter correlated positively with age. CONCLUSIONS: Our findings suggest that Se supplementation might have a beneficial effect in autoimmune thyroid patients.

Pharmacokinetic evaluation of cabozantinib for the treatment of thyroid cancer.

INTRODUCTION: Conventional treatment modalities for thyroid cancer lead to complete remission in only one-third of patients with distant metastases. On the other hand, medullary thyroid cancer (MTC) and anaplastic thyroid cancer (ATC), although rare, are responsible for a significant percentage of thyroid cancer-related deaths. New treatments are needed to treat such patients. AREAS COVERED: The aim of this review is to provide the latest information on cabozantinib (CBZ), a new tyrosine kinase inhibitor (TKI) that is currently used mainly as a treatment of MTC. The authors collated data that were retrieved from a PubMed literature search. EXPERT OPINION: CBZ targets multiple cell-signaling pathways involved in the molecular pathogenesis of thyroid cancer. These are namely VEGF receptor-2, hepatocyte growth factor receptor and rearranged during transfection receptor. Furthermore, it is a drug which may be used in cases where conventional therapies (mainly for MTC) are proved ineffective or have shown poor results with a good outcome. CBZ may also be administered alone or in combination with other drugs of the same family.

Pathogenesis of propylthiouracil-related hepatotoxicity in children: present concepts.

Propylthiouracil (PTU), carbimazole (CMZ) and methimazole (MMI) are the most common drugs used today in cases of adolescent thyrotoxicosis. Skepticism has been growing regarding the use of PTU in childhood and its association with severe liver failure. The aim of this review is to present all the recent data regarding pathogenesis of PTU hepatotoxicity in children and adolescents. Specifically, reactive drug metabolites and increased oxidative stress can directly activate inflammatory and immunological pathways. Drugs are not only immunogenic because of their chemical reactivity but also because they may bind through electrostatic forces to available T-cell receptors. Redox modulation is also a key regulatory strategy in the adaptive immune system. Subtle changes in the extracellular redox status may cause profound functional changes in redox-sensitive proteins. Genetic factors that affect drug biotransformation could also be implicated in this mechanistic model of PTU-related hepatotoxicity. Further studies are needed to fully understand the pathophysiology of PTU-induced liver damage.

Propylthiouracil hepatitis: report of a case and extensive review of the literature.

Antithyroid drugs (ATDs) have been widely and effectively used for the treatment of pediatric and adult thyrotoxicosis for more than a half century. Since the very beginning of ATD use, reports of hepatic dysfunction related to propylthiouracil (PTU) therapy have been published. We describe a case of a 12-year-old girl, who, after 4 weeks of therapy for Graves disease (GD) with PTU (300 mg/day at 100 mg given three times a day), developed fatigue, fever, diarrhea, nausea, and vomiting. The initial diagnosis was "viral gastrointestinal infection". Few days after the initiation of her symptoms, the patient developed jaundice, hepatic tenderness, and dark urine. She was admitted to the hospital where, after an extensive investigation, it was found that serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) were elevated (2312 and 1435 IU/L, respectively), alkaline phosphatase (ALP) was 171 IU/L and total bilirubin was 12.7 mg/dL, whereas direct bilirubin was 7.6 mg/dL and prothrombin time was 23.2 s (normal ratio, < 14.5 s). Serology for hepatitis A and B was negative. The diagnosis of PTU-induced hepatitis was established. PTU was discontinued, and a treatment with prednisone (50 mg/day) and vitamin K was initiated. Four weeks after admission, her hepatic tests returned to normal. We searched the English literature and we present details of all cases with PTU-related hepatic toxicity in children and adolescents published so far. Also, we provide information regarding the mechanisms and treatment of this appalling clinical entity. Finally, after recent recommendations from American Thyroid Association (ATA) and European Thyroid Association (ETA), PTU should be administered only in the first trimester of pregnancy and in cases of drug allergy to methimazole.

Breastfeeding and antithyroid drugs: a view from within.

The aim of this communication is to provide information regarding the use of antithyroid drugs (ATD) during lactation. Three ATD are used today: propylthiouracil (PTU), methimazole (MMI) and carbimazole (CMZ). The latter is a prodrug which is bioactivated to MMI. PTU is transferred in small amounts (0.025%) into milk. These amounts were considered nonsignificant for inducing adverse effects for the suckling infant. The amount of MMI excreted in milk is equal to MMI levels in serum. Due to its lower concentrations in milk, PTU was used for decades as the treatment of choice during breastfeeding. Recent studies have demonstrated that physical development, intelligence scores and thyroid status of children whose mothers had received MMI while breastfeeding were similar to those of healthy children. These new data offered clinicians an alternative drug approach. Several hepatic dysfunction studies have been published so far. Clinical manifestations varied from mild to severe hepatic failure, liver transplantation or death. Most PTU cases were more severe, idiosyncratic and not dose related. We recommend that PTU should not be prescribed for thyrotoxicosis during lactation. MMI should be used instead, in doses up to 30 mg/day, while PTU should be used in special cases for a restricted time period.

Selenium and the course of mild Graves' orbitopathy.

BACKGROUND: Oxygen free radicals and cytokines play a pathogenic role in Graves' orbitopathy. METHODS: We carried out a randomized, double-blind, placebo-controlled trial to determine the effect of selenium (an antioxidant agent) or pentoxifylline (an antiinflammatory agent) in 159 patients with mild Graves' orbitopathy. The patients were given selenium (100 µg twice daily), pentoxifylline (600 mg twice daily), or placebo (twice daily) orally for 6 months and were then followed for 6 months after treatment was withdrawn. Primary outcomes at 6 months were evaluated by means of an overall ophthalmic assessment, conducted by an ophthalmologist who was unaware of the treatment assignments, and a Graves' orbitopathy-specific quality-of-life questionnaire, completed by the patient. Secondary outcomes were evaluated with the use of a Clinical Activity Score and a diplopia score. RESULTS: At the 6-month evaluation, treatment with selenium, but not with pentoxifylline, was associated with an improved quality of life (P<0.001) and less eye involvement (P=0.01) and slowed the progression of Graves' orbitopathy (P=0.01), as compared with placebo. The Clinical Activity Score decreased in all groups, but the change was significantly greater in the selenium-treated patients. Exploratory evaluations at 12 months confirmed the results seen at 6 months. Two patients assigned to placebo and one assigned to pentoxifylline required immunosuppressive therapy for deterioration in their condition. No adverse events were evident with selenium, whereas pentoxifylline was associated with frequent gastrointestinal problems. CONCLUSIONS: Selenium administration significantly improved quality of life, reduced ocular involvement, and slowed progression of the disease in patients with mild Graves' orbitopathy. (Funded by the University of Pisa and the Italian Ministry for Education, University and Research; EUGOGO Netherlands Trial Register number, NTR524.).

Toxicological considerations for antithyroid drugs in children.

INTRODUCTION: Propylthiouracil (PTU), methimazole (MMI) and carbimazole are indicated for the treatment of hyperthyroidism in adult and pediatric patients. The aim of this review is to present all the relevant information regarding the use of antithyroid drugs (ATD) in pediatric thyrotoxic cases, the pediatric toxicology of ATD and the warning which has recently been issued for PTU by the FDA. AREAS COVERED: Epidemiology, diagnosis and treatment of pediatric thyrotoxicosis are all presented in this article. The authors also extensively discuss the details regarding the pharmacology, bioactivation, biodisposition, bioavailability and pharmacokinetic properties of the two main ATD (MMI and PTU). EXPERT OPINION: The FDA recently reported that use of PTU is associated with a higher risk for clinically serious or fatal liver injury compared to MMI in both adult and pediatric patients. They also found that congenital malformations were reported approximately three times more often with prenatal exposure to MMI compared with PTU and especially with the use of MMI during the first trimester of pregnancy. The authors believe that PTU should not be used in pediatric patients unless the patient is allergic to or intolerant of MMI, and there are no other treatment options available. That being said, PTU may be the treatment of choice during, and just before, the first trimester of pregnancy.

Pharmacological treatment of hyperthyroidism during lactation: review of the literature and novel data.

Antithyroid drugs (ATD) are used as a first line treatment in thyrotoxicosis. Propylthiouracil (PTU), carbimazole (CMZ) and methimazole (MMI) are available. During absorption CMZ is bioactivated to MMI. Initially, mothers were not allowed to breastfeed during treatment with ATD. Newer studies minimized the risk for mother and infant. PTU should be preferred over MMI due to its lower milk concentration. Recent studies have shown severe hepatic dysfunction for both ATD, but especially for PTU, in hyperthyroid patients. Most of those cases were idiosyncratic, not-dose related and presented a latent period of occurrence. No biomarkers could predict hepatic damage. The American Thyroid Association (ATA) has recommended that PTU should not be prescribed as the first line agent in children and adolescents. Its use might be accepted in the first trimester of pregnancy for severe thyrotoxicosis or for patients with previous MMI adverse reactions. Considering the potential harmful effects of PTU, MMI should be used instead during lactation.

Rising serum 25-hydroxy-vitamin D levels after weight loss in obese women correlate with improvement in insulin resistance.

OBJECTIVE: The objective of the study was to examine changes of 25-hydroxy-vitamin D (25OHD) and PTH blood levels 4 and 20 wk after low-calorie diet-induced weight loss. METHODS: Forty-four obese women [aged 40.6 +/- 11.4 yr, body mass index (BMI) 36.7 +/- 4.9 kg/m(2)] and 25 controls (BMI 22.9 +/- 1.5 kg/m(2)) were examined. Anthropometric and cardiometabolic parameters and 25OHD and PTH levels were determined at baseline and 4 and 20 wk after a low-calorie diet. RESULTS: At baseline, 25OHD levels were lower in obese compared with control subjects (17 +/- 6.0 vs. 23.8 +/- 8.7 ng/ml, P < 0.001), whereas no differences were found in PTH levels. In all women, a negative correlation was found between 25OHD levels and body weight (BW) (r -0.32, P < 0.001), BMI (r -0.37, P < 0.001), waist circumference (r -0.26, P < 0.05), and percent fat mass (r -0.38, P = 0.001) as determined by bioelectrical impedance analysis. The 4-wk low-calorie diet (n = 37) reduced BW and led to significant improvements in the homeostasis model assessment (HOMA) index and lipid levels. The 20-wk low-calorie diet (n = 26) resulted in reduction of BW and BMI by 10%, HOMA index (4.7 +/- 3.8 vs. 3.10 +/- 1.7, P < 0.01), and lipids levels (except high density lipoprotein cholesterol) and increase in 25OHD (15.4 +/- 6.0 vs. 18.3 +/- 5.1 ng/ml, P < 0.05), compared with baseline. PTH levels were unchanged. The increase of 25OHD levels was associated with the reduction of insulin levels and HOMA index (r -0.43, P < 0.05). CONCLUSIONS: Blood 25OHD levels were low in obese women and correlated inversely with severity measures of obesity. Weight loss of 10% after low-calorie diet increased 25OHD levels, and this increase was mainly associated with improvement of insulin resistance.

Corticosteroids in the medical treatment of thyroid ophthalmopathy: when and how? Somatostatin analogues: where we stand today.

Glucocorticoids (GCs) are used for Graves' ophthalmopathy (GO) in two different clinical settings: 1) moderately severe to severe eye disease; and 2) mild eye disease, for which radioiodine therapy is given to treat concomitant hyperthyroidism. Intravenous pulse corticosteroids have a small but statistically significant advantage in terms of response rate compared with oral corticosteroids and cause significantly fewer adverse events. Steroids should be used for as short a period of time as possible. The need for large doses of steroid over a long period of time is a hint that other treatment modalities need to be explored. Combination treatment with oral steroids and ciclosporin, another immunosuppressant, are more efficacious than use of either agent alone. The same applies to combination treatment with oral steroids and orbital radiotherapy. Somatostatin analogues (SM-as) have marginal clinical efficacy and are expensive. More potent analogues, like SOM230, could prove to be the treatment of choice in moderately severe cases of GO. The latter, in contrast to the thus far used analogues, has a rather high affinity for all SM receptors except SM receptor 4.

Orbital fat decompression for Graves' orbitopathy: a literature review.

Thyroid eye disease manifests as orbital inflammation resulting in extraocular muscle enlargement and orbital fat proliferation. This causes exophthalmos, ocular motility impairment and eyelid retraction. Numerous surgical procedures have been introduced for correction of exophthalmos by removal of bony walls. The limited success and high complication rate of the early methods lead to the evolution of an alternative procedure for reduction of retrobulbar volume by removal of intraorbital fat. The indications for this procedure extended from orbital decompression to compressive optic neuropathy with satisfactory results. The moderate complication rate and the fact that orbits with predominant muscle enlargement respond purely to this technique leads to the evolution of a combined procedure with orbital fat removal and bony wall decompression. The scattered published evidence comprising retrospective case series highlights the need for prospective controlled clinical trials in order to improve patient care and clinical practice.

Pediatric aspects in Graves' orbitopathy.

Although pediatric Graves' disease is an uncommon condition, children have about the same (or slightly increased) risk as adults to develop Graves' ophthalmopathy (GO) once they have contracted Graves' hyperthyroidism. GO occurs in the same proportion between sexes but with a milder clinical presentation compared with adults. Lid lag, soft tissue involvement and proptosis are the commonest manifestations, whereas restricted eye muscle motility, severe strabismus and optic neuropathy are practically absent. Genetic, immunologic and environmental factors may be associated with the different appearance of GO in children and adolescents. Interestingly, manifestation of GO begins to resemble the adult findings more closely when adolescence approaches. This could be explained by increasing smoking prevalence with age as long as smoking is a proven to be a risk factor for GO, and the odds increase significantly with increasing severity of GO. Management of hyperthyroidism is essential for the control of complications and seems to offer improvement of eye changes upon restoration of euthyroidism. Antithyroid drugs are the first choice treatment. Lasting remission rates though are achieved in less than 30% of cases. Long periods of therapy are needed and risk for side effects (often serious) increases. In resistant or severe cases early radical treatment with surgery or radioiodine is needed. Both can be equally effective and safe in selected cases. Identification of subjects prone to relapses is critical for optimal management. Regarding treatment of thyroid eye disease in childhood, most physicians who are dealing with such cases prefer a 'wait-and-see' policy. Pharmacological intervention, predominantly with steroids, is considered appropriate in case of deterioration or no improvement of eye changes when the patient has become euthyroid. It has been shown that somatostatin analogs (SM-as) might be of therapeutic value in the treatment of active eye disease in adults. Newer generations of SM-as that target a wider range of somatostatin receptors may show markedly superior results in the treatment of ophthalmopathy. Surgical orbital decompression is hardly ever necessary due to the mild nature of the disease, while retrobulbar irradiation, which has been proved beneficial in adults, has no place in the treatment of juvenile GO, in view of the theoretical risk of tumor induction.

Epidemiology and predisposing factors of obesity in Greece: from the Second World War until today.

Over the last 30 years overweight and obesity among adults and children have been on the rise, and since 1997 WHO has designated obesity as a major public health problem. In Greece both adult and childhood obesity is now recognized as an epidemic problem, probably more important than in other European countries. The issue is more serious in male adolescents and adults. There is also a tendency for weight increase along the last 30 years. Metabolic syndrome and type 2 diabetes mellitus are also rising rapidly in the Greek population. The reasons for this epidemic in Greece are not clear. Possible explanations could emerge from the delayed but sharp economic evolution of the country, as well as the abandonment of the traditional Mediterranean diet. Other predisposing factors in Greek children are parental obesity, frequent television viewing, low rates of breastfeeding and, in adolescent girls, smoking and alcohol consumption. Emerging measures are needed to confront this epidemic.

The use of sibutramine in the management of obesity and related disorders: an update.

AIMS: To review the major trials that evaluated the efficacy and safety of the use of sibutramine for weight loss and the impact of this agent on obesity-related disorders. METHODS AND RESULTS: The most important articles on sibutramine up to January 2009 were located by a PubMed and Medline search. Sibutramine reduces food intake and body weight more than placebo and has positive effects on the lipid profile (mainly triglycerides and high density lipoprotein cholesterol), glycemic control and inflammatory markers in studies for up to one year. Preliminary studies showed that sibutramine may also improve other obesity-associated disorders such as polycystic ovary syndrome, left ventricular hypertrophy, binge eating disorder and adolescent obesity. The high discontinuation rates and some safety issues mainly due to the increase in blood pressure and pulse rate have to be considered. Additionally, it has not yet been established that treatment with sibutramine will reduce cardiovascular events and total mortality. CONCLUSIONS: Sibutramine, in conjunction with lifestyle measures, is a useful drug for reducing body weight and improving associated cardiometabolic risk factors and obesity-related disorders. Studies of longer duration are required to determine the precise indications of the drug, to evaluate safety issues and to assess its efficacy on cardiovascular mortality.

Graves orbitopathy: a perspective.

Advances in the past few years have helped clinicians understand some of the pathogenetic mechanisms of Graves orbitopathy (GO), particularly the role of receptors for TSH and insulin-like growth factor I in the orbit. Optimal treatment strategies have been formulated and published by the European Group on Graves' Orbitopathy, which are hoped to improve the management of patients with this condition. The administration of intravenous pulses of steroids has been established as a superior treatment approach compared with other steroid regimens. In addition, orbital radiotherapy was effective in a subgroup of patients with GO who had eye dysmotility. The use of immunotherapies for the treatment of GO is currently being explored; of these, rituximab has emerged as a promising new agent.