[Menopausal hormone therapy: internal-endocrine point of view]. / Die menopausale Hormontherapie aus internistisch endokrinologischer Sicht.

The history of menopausal hormone therapy (MHT) started in 1942 in the US and became very popular in the 1960s worldwide because of the beneficial effects on vasomotor-vegetative and vulvovaginal symptoms. These symptoms may begin already in the premenopausal period, and can last for more than 10 years with reduced quality of life. Many women with vasomotor-vegetative symptoms do not visit a gynaecologist first but primarily a general physician or cardiologist because of instable blood pressure and palpitations, leading to the focus on the heart. To avoid unnecessary examinations and treatment with ß-blockers or antidepressants, an interdisciplinary look is necessary. In most cases, appropriate and low dose hormone replacement will relieve the symptoms and restore quality of life. In addition, it is worthwhile to know about the long-term effect of hormone deficiency as well as replacement on the different organ systems and the possible influences of hormone replacement therapy including contra indications. This is especially necessary after the uncertainties raised after the first deleterious announcements of the currently corrected results of the WHI (women's health initiative) study.

Recent data on iodine intake in Germany and Europe.

Iodine is essential for the synthesis of thyroid hormones. These regulate metabolism, promote growth, development and maturation of all organs, especially the brain. Most iodine is found in oceans and most continental soil and ground water is deficient in iodine. Therefore, around 2 billion individuals are estimated to have insufficient iodine intake and are at risk of iodine deficiency disorders. The best carrier for save iodine supplementation is salt, as the daily intake of salt is mainly constant. Due to the collaboration between international and national organisations and the salt industry, many developing and developed countries introduced universal salt iodization (USI) or have mandatory or voluntary fortification programs. In Germany as in most European countries the use of iodized salt is voluntary not only in household but also in the food industry. Two recent epidemiological surveys in Germany revealed that 33% of children and 32% of adults are still suffering from mild to moderate iodine deficiency. The best surrogate parameter for iodine deficiency is goitre. The goitre prevalence is around 30% in children as well as in adults which is in accordance with the documented iodine deficiency. From other European countries epidemiological derived data on iodine intake are only available from Denmark and Poland. Further efforts are under way to reveal the iodine status with proper methods in all European countries. On this background it might be possible to establish adequate iodine fortification programs in all European countries.

Comparison of color-Doppler and qualitative and quantitative strain-elastography for differentiation of thyroid nodules in daily practice.

OBJECTIVE: Strain-elastography provides a new ultrasound-based method that can offer information about the stiffness of thyroid nodules as an indicator of malignancy. The aim of our study was to compare the utility of color-Doppler and strain-elastography in differentiating between benign and malignant nodules. DESIGN AND METHODS: 77 thyroid nodules (70 benign and 7 malignant) from 70 unselected patients (48 female/22 male, mean age 49.7±14.3 years) were evaluated with color-Doppler and elastography based on a five-scale elastogram score for qualitative elastography and strain ratio for quantitative elastography. As reference tissue we chose normal thyroid tissue [strain ratio a (SR a)] and cervical muscles [strain ratio b (SR b)]. The cytological or histological results were used as a reference standard. Diagnostic performances of qualitative and quantitative elastography were compared using ROC curves. RESULTS: Vascularization score 3 or 4 was associated with malignancy (p=0.024) as well as elastogram score 4 or 5 (p=0.070, n.s.s.). SR a was indicatively higher and SR b lower in the group of malignant nodules (p=0.065 and p=0.246, n.s.s.). The best cut-off points predicting malignancy were 3.32 for SR a (66.7% sensitivity, 83.3% specificity) and 0.10 for SR b (71.4% sensitivity, 67.1% specificity). CONCLUSION: In our study, the accuracy of elastography did not surpass other sonographic parameters in differentiating thyroid nodules. The technique can play a role as a supplementary parameter in assessment of malignancy to improve diagnostic efficacy. The best parameter is SR a, but SR b can serve as an alternative if SR a is not assessable.

Multi-scale simulation of plant stem reinforcement by brachysclereids: A case study in apple fruit peduncles.

Sclereid formation in addition to or in gaps of fragmented fibre rings is common in dicotyledonous plant stems. Whether this sclereid formation is force-triggered remains open so far. In fruit peduncles of several Malus species as modified plant stems, for example, the persistent fibre ring is displaced to the centre by formation of cortex parenchyma during growth. Parenchyma cells subsequently differentiate into an additional layer of brachysclereids, previously interpreted as an adaptation to continuously rising fruit loads. The present study pursues a multi-scale numerical modelling approach, to verify the important effect for different cellular architectures in both sclerenchyma categories on the stiffness of these tissues and the entire peduncle. First, different material properties are simulated analogue to plant tissues on the basis of three cell types. A regular three-dimensional and a random Voronoi microstructure combined with various mechanical cell wall parameters are applied. Using homogenisation simulations based on HILL's principle, numerical calculations predict a lower effective homogenised tissue stiffness of isodiametric brachysclereids compared to those of fibres, confirming experimentally obtained data from Malus fruit peduncles. Furthermore, a curved peduncle model with a complex arrangement of different material layers is generated. Diverse material sets are tested under three representative loadings, using an adaptive diffuse domain approach (AMDiS). The model explains the function of sclereids as considerable contributors to the stiffness against bending and tensile deformations, as well as torsion, especially in consequence of superimposed load conditions in the case of a curved plant stem.

Interrelations between thyrotropin levels and iodine status in thyroid-healthy children.

BACKGROUND: Worldwide, iodine prophylaxis measures have improved iodine status in populations. Several studies have reported an increase in thyrotropin (TSH) levels coinciding with this prophylaxis. Whether this implies an increased risk for hypothyroidism or simply reflects a physiologic TSH adaptation mechanism is not clear. METHODS: Data on iodine and thyroid status of 6-17 year old children and adolescents (n=9175), collected between 2003 and 2006 in the German-wide Health Interview and Examination Survey for Children and Adolescents (KiGGS) Study, provided the basis for the analyses of mutual relationships of urinary iodine status (assessed by iodine/creatinine ratio in spot urines), serum TSH levels, and thyroid volume (determined by ultrasound). For data analyses (multivariable linear regression analysis), only those children were included for whom none of the available parameters (including free triiodothyronine [fT3], free thyroxine [fT4], and thyroperoxidase antibody [TPO-Ab] measurements) indicated a potential pathophysiologic thyroid status (n=6101). RESULTS: In this population-based sample of thyroid-healthy children, higher urinary iodine excretion was associated with higher TSH levels (p<0.05), adjusted for sex, age, body surface area, body mass index, fT3/fT4 ratio, and time of blood sampling. Higher TSH levels were not associated with a higher prevalence of TPO-Ab but with lower thyroid volume (p<0.001, fully adjusted). For the present study sample, one-time spot measurements of urinary iodine excretion were not related to thyroid volume, the long-term marker of iodine status. CONCLUSION: Our findings show for the first time in thyroid-healthy children that smaller thyroid volume is associated with higher normal TSH levels. A decreased thyroid cell mass and cell amount, as induced by an improved iodine status, does presumably require a higher TSH signal to maintain a constant thyroid hormone production, suggesting an underlying physiologic adaptation. Correspondingly, an increased TSH level should not be used as the single criterion to evaluate the prevalence of hypothyroidism, and the repeatedly observed parallel increases of iodine supply and TSH levels should not readily be interpreted as evidence for an increased hypothyroidism risk. These insights, contradicting conventional interpretations, may contribute to dispel uncertainties about the safety of iodine prophylaxis measures.

A NOMPC-dependent membrane-microtubule connector is a candidate for the gating spring in fly mechanoreceptors.

BACKGROUND: Mechanoreceptors contain compliant elements, termed "gating springs," that transfer macroscopic stimuli impinging on the cells into microscopic stimuli that open the mechanosensitive channels. Evidence for gating springs comes from mechanical experiments; they have not been identified molecularly or ultrastructurally. RESULTS: We show that the filamentous structures that connect the plasma membrane to the microtubules are compliant structural elements in the mechanoreceptive organelle of fly campaniform receptors. These filaments colocalize with the ankyrin-repeat domain of the transient receptor potential (TRP) channel NOMPC. In addition, they resemble the purified ankyrin-repeat domain in size and shape. Most importantly, these filaments are nearly absent in nompC mutants and can be rescued by the nompC gene. Finally, mechanical modeling suggests that the filaments provide most of the compliance in the distal tip of the cell, thought to be the site of mechanotransduction. CONCLUSIONS: Our results provide strong evidence that the ankyrin-repeat domains of NOMPC structurally contribute to the membrane-microtubule connecting filaments. These filaments, as the most compliant element in the distal tip, are therefore good candidates for the gating springs.

Thyroid (dys-)function in normal and disturbed pregnancy.

INTRODUCTION: During pregnancy, physiologic changes in maternal thyroid function take place especially due to hormonal as well as metabolic processes. Human chorionic gonadotropin activates the maternal thyroid gland leading to increased thyroid hormone production. A sufficient availability of maternal thyroid hormones is essential for fetal development, especially during the first trimester of pregnancy, when the fetal thyroid gland is not yet functional. MATERIALS AND METHODS: Current knowledge of thyroid dysfunction including thyroid autoimmunity, hypothyroidism or hyperthyroidism is summarized with special focus on miscarriage and pregnancy disorders. Therefore, a Medline research as well as an analysis of current guidelines on thyroid function and pregnancy was performed. RESULTS: A study focusing on TSH levels in normal and disturbed pregnancies, the risk of miscarriage in association with thyroid autoantibodies, and (subclinical) hypothyroidism in infertile and fertile women were included. CONCLUSION: Maternal thyroid dysfunction negatively affects pregnancy outcome. Besides a routine iodine supplementation in pregnant women and treatment of hypo as well as hyperthyroidism, TSH levels should routinely be measured in women during childbearing years and adjusted to concentrations <2.5 mIU/l in order to optimize maternal health and fetal development.

High (but not low) urinary iodine excretion is predicted by iodine excretion levels from five years ago.

BACKGROUND: It has not been investigated whether there are associations between urinary iodine (UI) excretion measurements some years apart, nor whether such an association remains after adjustment for nutritional habits. The aim of the present study was to investigate the relation between iodine-creatinine ratio (ICR) at two measuring points 5 years apart. METHODS: Data from 2,659 individuals from the Study of Health in Pomerania were analyzed. Analysis of covariance and Poisson regressions were used to associate baseline with follow-up ICR. RESULTS: Baseline ICR was associated with follow-up ICR. Particularly, baseline ICR >300 µg/g was related to an ICR >300 µg/g at follow-up (relative risk, RR: 2.20; p < 0.001). The association was stronger in males (RR: 2.64; p < 0.001) than in females (RR: 1.64; p = 0.007). In contrast, baseline ICR <100 µg/g was only associated with an ICR <100 µg/g at follow-up in males when considering unadjusted ICR. CONCLUSIONS: We detected only a weak correlation with respect to low ICR. Studies assessing iodine status in a population should take into account that an individual with a low UI excretion in one measurement is not necessarily permanently iodine deficient. On the other hand, current high ICR could have been predicted by high ICR 5 years ago.

The role of iodine and delta-iodolactone in growth and apoptosis of malignant thyroid epithelial cells and breast cancer cells.

OBJECTIVE: As we previously demonstrated, the inhibitory effect of iodine on thyroid cell growth is mediated by iodolactones, especially 6-iodo-5-hydroxy-eicosatrienoic acid (delta-iodolactone). In this communication we compare the effect of iodide, molecular iodine and delta-iodolactone on growth inhibition and apoptosis on three human thyroid carcinoma cell lines (B-CPAP cells, FTC-133 cells and 8505C cells) as well as on human breast cancer cells (MCF 7). METHODS: Thyroid carcinoma cells were cultured in Dulbecco's modified Eagle's medium (DMEM) and MCF 7 cells in Rowswell Park Memorial Institute (RPMI) culture medium, both containing 10% (v/v) Fetal Calf Serum (FCS), until they were confluent. Around 2000 cells were then distributed in 12-well plates and grown for 48 h in either DMEM (thyroid cancer cells) or in RPMI medium (MCF 7 cells) both containing 5% FCS. Thereafter, different concentrations of iodide, iodine or delta-iodolactone were added for 24 h. Growth rate was estimated by cell counting in a Coulter Counter adapted for epithelial cells. Apoptosis was determined by a mitochondrial potential assay. RESULTS: The growth rate of B-CPAP cells was unaffected by iodide, but was reduced by high concentreations of molecular iodine (100 and 500 microM). However, delta-iodolactone significantly reduced cell proliferation already with low concentrations (5 microM and 10 microM) and further in a dose-dependent manner up to 82%. FTC-133 and 8505C cells were unaffected by iodide, iodine or delta-iodolactone. In contrast, in MCF 7 cells, molecular iodine (100 microM) inhibited growth from 100% to 83% but delta-iodolactone (1, 5 and 10 microM) dose-dependently decreased growth rate from 100% to 82% and 62%, respectively. The inhibition of growth was through apoptosis, and not necrosis, as the amount of apoptotic cells corresponded to the growth inhibition. CONCLUSION: delta-Iotaodolactone seems to be the main iodocompound which can inhibit growth and induce apoptosis in B-CPAP cells as well as in MCF 7 breast cancer cells.

[Epidemiology, pathophysiology, guideline-adjusted diagnostics, and treatment of thyroid nodules]. / Epidemiologie, Pathophysiologie, leitliniengerechte Diagnostik und Therapie des Schilddrüsenknotens.

BACKGROUND: Clinically relevant thyroid carcinomas can be found in 5-6% of nodular goiters which undergo surgery. Moreover, multinodular goiters fre- quently contain hot areas. Therefore, efficient and rational methods for the differential diagnosis and decision are required to identify those nodules with an increased cancer risk or those which are hot among the many thyroid nodules. METHODS: Description of a newly revised and further guidelines and consensus statements as well as selected literature search. RESULTS: Already history, ultrasound and TSH (thyroid-stimulating hormone) determination do allow a first risk assessment for the further diagnostic work-up. Fine-needle biopsy (FNB) offers the best sensitivity and specificity for the distinction between benign and malignant thyroid nodules. The combination of several clinical and ultrasound criteria and laboratory determinations (calcitonin) can help with the selection of thyroid nodules with scintigraphically normal or decreased uptake > 1 cm for FNB. However, the efficiency of FNB requires sufficient training and experience of both the cytopathologist and the person performing FNB. CONCLUSION: Whereas solitary thyroid nodules with a suspicion for malignancy should be referred to the surgeon, euthyroid thyroid nodules without clinical ultrasound or cytological indicators of malignancy may be followed up - possibly under medication -, if surgery is not indicated by local complaints, tracheal or mediastinal involvement.

Selenium and thyroid.

Inadequate supply of the essential trace element selenium (Se) has been associated with predisposition for, or manifestation of, various human diseases such as Keshan and Kashin-Beck disease, cancer, impaired immune function, neurodegenerative and age-related disorders and disturbances of the thyroid hormone axis. Se deficiency in combination with inadequate iodine contributes to the pathogenesis of myxedematous cretinism. The recent identification of various distinct selenocysteine-containing proteins, encoded by 25 human genes, provides information on the molecular and biochemical basis of beneficial and possible adverse effects of this trace element. The thyroid gland is among the human tissues with the highest Se content per mass unit similar to other endocrine organs and the brain. Selenoproteins involved in cellular antioxidative defence systems and redox control, such as the glutathione peroxidase (GPx) and the thioredoxin reductase (TxnRd) family, are involved in protection of the thyroid gland from excess hydrogen peroxide and reactive oxygen species produced by the follicles for biosynthesis of thyroid hormones. In addition, the three key enzymes involved in activation and inactivation of thyroid hormones, the iodothyronine deiodinases (DIO1,2,3), are selenoproteins with development, cell- and pathology-related expression patterns. While nutritional Se supply is normally sufficient for adequate expression of functional Dio enzymes with exception of long-term parenteral nutrition and certain diseases impairing gastrointestinal absorption of Se compounds, the nutritional Se supply for the protection of the thyroid gland and synthesis of some more abundant selenoproteins of the GPx and the TrxR family might be limiting their proper expression under (patho-)physiological conditions.

Thyroid diseases in pregnancy.

PURPOSE OF REVIEW: Thyroid disorders are common in pregnancy and affect maternal and fetal outcome. RECENT FINDINGS: The reference values for normal thyroid function during first and second trimester had been re-evaluated recently. Hypothyroxinemia affects the neuropsychological development of the child. Maternal thyroid dysfunction or only the presence of thyroid-specific antibodies is associated with increased risk for early abortion, preterm delivery and neonatal morbidity. Pregnant women under levothyroxine treatment are often undertreated or overtreated. Screening for thyroid dysfunction of pregnant women is recommended and cost-effective. SUMMARY: Recently, the recommended dose for iodine intake during pregnancy had been increased from 200 to 250 microg/day, because recent studies revealed that even mild-to-moderate iodine intake might affect the neuropsychological development of the child. About 5-18% of all pregnant women exhibit elevated thyroid-specific antibodies, but only 0.3% develop overt hypothyroidism and 0.1-0.4% overt hyperthyroidism. However, those pregnant women with autoimmune thyroiditis and normal thyroid function may have a restricted thyroid reserve, followed by hypothyroxinemia and/or thyroid-stimulating hormone increase during pregnancy. The incidence of miscarriage, preterm delivery and small for date offspring might be increased and probably a delayed neuropsychological development. Routine thyroid function testing at least as early as possible in all pregnant women is emphasized.

Selenium and thyroid hormone axis in critical ill states: an overview of conflicting view points.

In critical ill states the plasma selenium levels are low and inversely correlated with the severity and outcome of the disease. The plasma selenium levels indicate the amount of circulating selenoproteins and selenoenzymes. These are important for the maintenance of the redox system, modulating the immune system and also for thyroid hormone metabolism. Not only all three deiodinases (D1-3) are selenoenzymes, but within the thyroid gland there are several other selenoenzymes, which are important for the maintenance of normal thyroid function. In critical ill states also triodothyronine (T3) is low and reverse T3 elevated, and also TSH and thyroxin (T4) are low, correlating like low plasma selenium with the severity of the disease. Subsequently, several intervention trials had been performed to evaluate whether an adjuvant selenium supplementation might attenuate the course of the disease and improve outcome. The selenium supplementation improved outcome and even reduced mortality in some but not all prospective randomized trials. A few prospective randomized intervention trials with selenium supplementation had also been performed to evaluate the hypothesis, whether low selenium is the cause of low-T3-syndrome, however, with conflicting results and no clear evidence that low D1 activity is due to the selenium deficiency in critical illness. Because D1 catalyses the conversion of T4 to T3 and also the clearance of reverse T3, low D1 activity would sufficiently explain low plasma T3 and elevated reverse T3. It had been, however, clearly shown that cytokines are responsible for the inhibition of D1 activity, but D2 and D3 are even higher during acute inflammation in critically ill patients. One of the most important effects of selenium on the immune system seems to be the reduction of cytokine release and therefore an indirect connection between low selenium and low D1 activity has to be postulated and not a lower D1 activity due to lower availability of selenium for the D1 expression.