[Thyroid disorders during pregnancy]. / Schilddrüsenerkrankungen in der Schwangerschaft.

Thyroid disorders may not only be the cause infertility but also increases the incidence of miscarriages and the morbidity of the pregnancies. During pregnancy the demand of thyroid hormones increases to about 30 - 50 % and the thyroid has to cope with this increase. In Germany the iodine intake has improved significantly during the last 20 years, but still is borderline low with an mean intake of about 120 microg iodide per day. Therefore it is still recommended that pregnant women are supplemented with about 100 - 150 microg of iodide during pregnancy and the time of breast-feeding, to avoid hypothyroidism of the foetus with concomitant delay of the brain development. Not only women with subclinical hypothyroidism, but only elevated TPO antibodies have a significant increase in early miscarriage and preterm delivery. An early supplementation with Levothyroxin despite euthyroidism might reduce these risks. Those women also more frequently develop postpartum thyroiditis. This risk can be reduced by a supplementation with selenium during and after pregnancy. Graves' disease is a rare disorder and only about 0,1 - 0,4 pregnancies are affected. The course of the disease is biphasic, with an exacerbation within the first trimester and an improvement thereafter, but a recurrence after delivery. Overt thyrotoxicosis has to be treated with propylthiouracil, to maintain euthyroidism during pregnancy. The TSH receptor antibodies are transferred to the foetus with the risk of thyrotoxicosis. Special care of the foetus is therefore necessary. Transient mild hyperthyroidism may occur in women with very high HCG levels during the first three months of pregnancy. This often is associated with hyperemesis gravidarum. Subclinical hypothyroidism of the mother will disturb the normal development of the foetus and therefore has to be treated even when TSH is within the upper normal level. Special care is necessary in women with elevated TPO antibodies, because these more often develop postpartum thyroiditis.

Tailor treatment to the patient in thyrotoxicosis.

All the management options for thyrotoxicosis have advantages and disadvantages. It is important to have a full discussion with the patient to ensure that a treatment option is selected that is tailored to the individual.

CD7 and CD28 are required for murine CD4+CD25+ regulatory T cell homeostasis and prevention of thyroiditis.

CD7 and CD28 are T cell Ig superfamily molecules that share common signaling mechanisms. To determine roles CD7 and CD28 might play in peripheral lymphocyte development and function, we have generated CD7/CD28-double-deficient mice. CD7- and CD28-single-deficient and CD7/CD28-double-deficient mice had normal levels of CD4 and CD8-single-positive T cells in thymus and spleen. However, CD28-deficient mice had decreased CD4+CD25+ T cells in spleen compared with wild-type mice, and CD7/CD28-double-deficient mice had decreased numbers of CD4+CD25+ T cells in both thymus and spleen compared with both wild-type and CD28-deficient mice. Functional studies demonstrated that CD4+CD25+ T cells from CD28-deficient and CD7/CD28-double-deficient mice could mediate suppression of CD3 mAb activation of CD4+CD25- wild-type T cells, but were less potent than wild-type CD4+CD25+ T regulatory cells. Thyroiditis developed in aged CD7/CD28-double-deficient mice (>1 year) that was not seen in age-matched control mice or single CD7- or CD28-deficient mice, thus suggesting in vivo loss of T regulatory cells allowed for the development of spontaneous thyroiditis. Taken together, these data demonstrated collaborative roles for both CD7 and CD28 in determination of number and function of CD4+CD25+ T regulatory cells in the thymus and peripheral immune sites and in the development of spontaneous thyroiditis.

IL-4 prevents insulitis and insulin-dependent diabetes mellitus in nonobese diabetic mice by potentiation of regulatory T helper-2 cell function.

Beginning at the time of insulitis, nonobese diabetic (NOD) mice demonstrate a thymocyte and peripheral T cell proliferative hyporesponsiveness induced by TCR cross-linking, which is associated with reduced IL-2 and IL-4 secretion. We previously reported that NOD CD4+ T cell hyporesponsiveness is reversed completely in vitro by exogenous IL-4, and that administration of IL-4 to NOD mice prevents the onset of insulin-dependent diabetes mellitus (IDDM). This result suggested that T cell-mediated destruction of pancreatic islet beta cells may result from a hyporesponsiveness in regulatory Th2 cells favoring a Th1 cell-mediated environment in the pancreas. In the present study, we tested this possibility by analysis of the mechanisms of protection from IDDM afforded by IL-4 treatment in NOD mice. We show that IL-4 protects NOD mice from insulitis and IDDM when administered i.p. three times a week for 10 wk beginning at 2 wk of age. This occurs by the modulation of the homing of autoreactive cells to inflammatory sites and the stabilization of a protective Th2-mediated environment in the thymus, spleen, and pancreatic islets. Thus, IL-4 treatment favors the expansion of regulatory CD4+ Th2 cells in vivo and prevents the onset of insulitis and IDDM mediated by autoreactive Th1 cells.

Post partum thyroiditis in Saudi women.

Two hundred and seventy seven Saudi women were prospectively evaluated post-partum to determine the frequency of post-partum thyroiditis. Four to six weeks after delivery, 12 (4.3%) had positive antimicrosomal antibodies and 8 (2.9%) had positive antithyroglobulin antibodies. At 6-8 weeks post-partum, out of 82 subjects followed up, 4 (4.9%) had positive antimicrosoMal antibodies and 1 (1.2%) had positive antithyroglobulin antibodies. At 8-12 weeks post-partum, out of 70 subjects, antimicrosomal antibodies were detected in 5 (3.5%) subjects and antithyroglobulin in 2 (1.4%). Their routine thyroid function tests (T3, T4, and TSH) remained within the normal range. There was no clinical evidence of hyper- or hypothyroidism in any of the patients during the follow up. Post-partum thyroiditis, appears to be relatively uncommon in Saudi Arabia. It does not produce any clinical illness or cause significant subclinical thyroid dysfunction.

Frequency of thyroiditis and postpartum thyroiditis in a 10-year consecutive hyperthyroid Danish population.

In a retrospective study 716 consecutive newly diagnosed and untreated hyperthyroid patients were examined in regard to the frequency of silent thyroiditis and postpartum thyroiditis. Six patients (0.8%) had possible silent thyroiditis (24-hour radioiodine uptake less than or equal to 5% and hyperthyroidism without anterior neck pain). None occurred within one year postpartum. We conclude that silent thyroiditis is a rare cause of hyperthyroidism in our thyroid clinic. The fact that none occurred postpartum suggests that postpartum thyroiditis is oligosymptomatic and that screening programmes are needed if one wants to diagnose the earliest phases of this condition.

In vivo prevention of thyroid and pancreatic autoimmunity in the BB rat by antibody to class II major histocompatibility complex gene products.

Evidence is accumulating that the development of insulin-dependent diabetes mellitus involves autoimmune phenomena, both in the human and in the BB rat model. A strong association is observed in both cases with alleles of the class II major histocompatibility complex (MHC). Results of the present study show that autoimmune phenomena, as assessed by the presence of clinical diabetes or histological thyroiditis, are prevented by the injection of monoclonal antibodies to class II gene products in the BB rat. Immunosuppression was specifically obtained with a monoclonal antibody to the murine I-E equivalent, as opposed to the murine I-A equivalent, of the rat major histocompatibility complex. This represents indirect evidence for I-E subregion control of immune responses to islet cell and thyroid antigens in the BB rat model. The frequent occurrence of anaphylactic type deaths in young (1 month old) animals receiving more than six weekly injections of partially purified homologous (rat) monoclonal antibodies to rat class II gene products underscores the potential risks of this type of immunotherapy. The presumed immunologic mechanism (IgE antibody) and its specificity (anti-allotype, anti-idiotype, or anti-impurity) must be clarified to assess the risks and feasibility of this type of therapy.

Effects of testosterone on the development of autoimmune thyroiditis in two strains of chicken.

The effect of testosterone on organ-specific spontaneous autoimmune thyroiditis (SAT) was examined in two strains of chicken: the Obese (OS) strain, which develops SAT at several weeks of age and the control Special C (Sp. C) strain. Both were originally selected from the C strain and are homozygous for the B13 major histocompatibility haplotype. Testes development and testosterone levels in the OS strain were considerably less than those found in comparably aged birds of the Sp. C strain. Testosterone supplementation of the OS strain significantly decreased thyroid infiltration by lymphocytes while castration of the Sp. C strain significantly enhanced infiltration. These results suggest that testosterone reduces SAT and that the hormonal constitution in both strains of chicken affect the frequency of occurrence and severity of this disorder.

The influence of cyclosporin A on the induction of experimental autoimmune thyroid disease in the PVG/c rat.

Using an experimental model of autoimmune thyroid disease we have investigated the influence of cyclosporin A (CyA) on the induction of the disease and its potential ability to prevent disease development. PVG/c rats (n = 80) neonatally thymectomized (day 21) and thence sublethally irradiated were divided into eight groups and received either no CyA or oral CyA (10 mg/kg body weight) for varying periods prior to and during disease induction. Serial serum measurements of thyrotropin (TSH) by radioimmunoassay and anti-thyroglobulin autoantibody by enzyme linked immunosorbent assay showed a progressive rise in untreated animals. The rise in serum TSH levels from 349 +/- 15 ng/ml (mean +/- s.e., normal less than 400 ng/ml) at 7 weeks of age to 526 +/- 61 ng/ml at 11 weeks and 820 +/- 54 ng/ml at 15 weeks was not significantly different in animals treated with CyA for periods ranging from 24 h prior to thymectomy to 7 days post-thymectomy. In contrast animals treated for 28 days post-thymectomy showed significantly lower levels of TSH at both 11 weeks (391 +/- 26; P less than 0.02) and 15 weeks (587 +/- 37; P less than 0.005) as compared with untreated animals. Similar though less dramatic changes were seen in intermediate groups. Autoantibody levels in untreated animals rose from initially undetectable levels to 0.451 +/- 0.07 OD (mean +/- s.e.) at 11 weeks and 0.581 +/- 0.041 OD at 15 weeks. Animals treated for at least 4 weeks after thymectomy with CyA had significantly lower levels of antibody at both 11 weeks (0.213 +/- 0.01; P less than 0.001) and 15 weeks (0.337 +/- 0.03; P less than 0.001) of age. Intermediate groups ranged in antibody levels depending on the duration of CyA treatment. Thyroid gland weight (12.7 +/- 2.4 mg/100 g body weight, mean +/- s.e.) and histological grade of thyroiditis (1.8 +/- 0.4, mean +/- s.e.) in the animals treated with CyA for 4 weeks, assessed when the animals were killed at 15 weeks, were smaller and had less severe thyroiditis than untreated thymectomized and irradiated animals (23.8 +/- 2.8 mg/100 g, P less than 0.02 and 2.9 +/- 0.2, P less than 0.05) killed at the same time. CyA given for long enough during induction of experimentally-induced autoimmune thyroid disease delayed the onset of disease and reduced its severity but could not prevent it given over time courses ranging from 48 h prior to thymectomy to 4 weeks after.(ABSTRACT TRUNCATED AT 400 WORDS)

Prevention of diabetes mellitus in the BB/W rat with Cyclosporin-A.

Autoimmune diabetes mellitus occurs spontaneously in 40-60% of a colony of BioBreeding/Worcester rats. Pretreatment of susceptible animals for 10-day intervals prior to 70 days of age with Cyclosporin-A (CSA) significantly reduced the frequency and delayed the onset of diabetes. The relatively narrow time frame of successful treatment suggests that effector cells responsible for beta cell destruction in this model of Type I diabetes may be activated during this period of time prior to the onset of overt hyperglycemia. CSA administration did not protect against the occurrence of lymphocytic thyroiditis or autoantibodies directed against smooth muscle or thyroid colloid, suggesting that these BB immunologic phenomena may be controlled by a distinct series of immunologic events.

The effects of female sex steroids on the development of autoimmune thyroiditis in thymectomized and irradiated rats.

Female PVG/c strain rats are more susceptible to the induction of autoimmune thyroiditis initiated by thymectomy and irradiation (Tx-X) than similarly treated males. Pre-pubertal ovariectomy was found to further augment this susceptibility. The administration of oestrogen or progesterone to groups of 4 week old ovariectomized Tx-X animals over a period of 15 weeks significantly altered the course of the events leading to the induction of this condition. Thus oestrogen administered repeatedly at dose levels of 1 microgram and 10 micrograms/100 g body weight resulted in partial suppression of thyroiditis with a corresponding change in the incidence of antibodies to thyroglobulin. Similarly, oestrogen administered by a single implantation had a suppressive effect on the development of autoimmunity in ovariectomized Tx-X females. Oestrogen given by either of these procedures also reduced the incidence of both thyroiditis and autoantibody induction in orchidectomized male Tx-X rats. In contrast to the inhibitory effects of oestrogen, the repeated administration of progesterone at a dose of 250 ng and 1,500 micrograms/100 g body weight appeared to augment the levels of autoimmunity. It is concluded that the differential susceptibility to the induction of autoimmunity by thymectomy and irradiation is the direct consequence of sex hormonal influences. Furthermore, the higher incidence of the disease in the female would appear to be determined by the balance between the activity of oestrogen and progesterone which would further appear to have antagonistic influences in this particular situation.

The influence of testosterone on the development of autoimmune thyroiditis in thymectomized and irradiated rats.

Orchidectomy was found to potentiate the development of autoimmune thyroiditis induced by thymectomy and irradiation (Tx-X) in male PVG/c strain rats. Conversely, testosterone administration to orchidectomized Tx-X rats markedly reduced or inhibited the development of this condition. When given in varying quantities by injection in oil over a period of 15 weeks the inhibitory effect on the development of both thyroiditis and thyroglobulin autoantibodies was found to be directly related to dose. Levels between 150 ng and 150 micrograms/100 gm body weight reduced the incidence and severity of the disease whilst levels of 500 micrograms and 5000 micrograms abrogated these autoimmune effects. Testosterone in implant form had a similar effect. Low doses of testosterone administered by either procedure were also found to be beneficial to entire female Tx-X rats. These results indicate that sex steroid hormones have an important modulatory influence on the genesis of autoimmune thyroiditis. Furthermore, it is also apparent in this particular model that this influence can be demonstrated in the absence of the thymus gland

Spontaneous autoimmune thyroiditis in the rat accelerated by thymectomy and low doses of irradiation: mechanisms implicated in the pathogenesis.

Factors involved in the production of autoimmune thyroiditis in thymectomized and sublethally irradiated rats were investigated. The study suggested that a gene linked to RT1 of the rat major histocompatibility complex (MHC), a selective depletion of suppressor T cells and high radiosensitivity of the thyroid gland were required in varying degrees to initiate the autoimmune thyroiditis in these rats. K cells in the spleen markedly increased at the initial stage and subsequently decreased at the appearance of the thyroid lesion, suggesting the consumption of K cells by thyroid antigen--antibody complexes formed in situ and in the circulation. Our data generally support the three genes concept proposed by Rose et al. (1976, 1980) that at least three genetically determined defects participate in triggering the production of autoimmune thyroiditis--namely, Ir genes within the MHC of the species, diminished ability of T cells to suppress autoimmune responses and a genetic defect in the thyroid gland.

Prevention of autoimmune thyroiditis in T cell-depleted rats by injections of crude thyroid extract.

The effect of intraperitoneal injections of crude allogeneic thyroid extract on the development of autoimmune thyroiditis in PVG/c rats subjected to thymectomy and repeated sublethal irradiation has been examined. Treatment with rat thyroid extract during the course of irradiation and before the onset of thyroiditis prevented the expected development of thyroid lesions and autoantibodies to thyroglobulin in these animals. Rats treated with crude rat liver extract under the same conditions developed thyroid disease similar to that of untreated controls. Treatment of thymectomized and irradiated rats with thyroid extract after the completion of the irradiation schedule failed to reduce the incidence and severity of thyroiditis in these animals as compared to that of untreated controls. The possible significance of these findings in relation to the pathogenesis of autoimmune thyroiditis in T cell-depleted rats is discussed.

The role of the thymus in spontaneous autoimmune thyroiditis.

In two models of genetically determined, spontaneous autoimmune thyroiditis, neonatal thymectomy increases the incidience and severity of disease. The simpliest explanation is that the thymus, or thymus-derived cells, normally exert a suppressive effect on the autoimmune response to thyroglobulin in addition to the helper function that is necessary to initiate the autoimmune reaction.