Marie-Louise Hartoft-Nielsen

Thyrotropin-Releasing Hormone Stimulation Test in Patients with Pituitary Pathology

Objectives: To evaluate the value of the thyrotropin-releasing hormone (TRH) stimulation test in the diagnostic work-up of the thyroid function in patients with pituitary pathology. Methods: To compare the thyrotropin (TSH) response and the absolute and fold changes after TRH administration in 35 patients with pituitary pathology and 26 normal subjects. Results: Nine of the patients and 2 of the normal subjects had a pathological response. No difference in the thyrotropic response to TRH was found either for the actual values, or for the absolute or fold changes of TSH between the groups. Conclusion: The role of the TRH test in the evaluation of thyroid function in patients with pituitary pathology is modest. The best variables for evaluation of the presence of central hypothyroidism are still a free thyroxine estimate combined with an inappropriately low TSH.

Do Thyroid Disrupting Chemicals Influence Foetal Development during Pregnancy

Maternal euthyroidism during pregnancy is crucial for normal development and, in particular, neurodevelopment of the foetus. Up to 3.5 percent of pregnant women suffer from hypothyroidism. Industrial use of various chemicals—endocrine disrupting chemicals (EDCs)—has been shown to cause almost constant exposure of humans with possible harmful influence on health and hormone regulation. EDCs may affect thyroid hormone homeostasis by different mechanisms, and though the effect of each chemical seems scarce, the added effects may cause inappropriate consequences on, for example, foetal neurodevelopment. This paper focuses on thyroid hormone influence on foetal development in relation to the chemicals suspected of thyroid disrupting properties with possible interactions with maternal thyroid homeostasis. Knowledge of the effects is expected to impact the general debate on the use of these chemicals. However, more studies are needed to elucidate the issue, since human studies are scarce.

Models to study the pathogenesis of thyroid autoimmunity.

In vitro and in vivo models to study the pathogenesis of thyroid autoimmunity are reviewed. Animal models with experimentally induced or spontaneously developed autoimmune thyroid disease as well as transplantation models have been used extensively in these studies, but also the use of thyroid cell cultures from both humans and animals has contributed to the present state of knowledge. Cytokines may play a role in the pathogenic mechanism in thyroid autoimmunity. The major in vitro and in vivo effects of for example interleukin-1, tumour necrosis factor and gamma-interferon on differentiated thyroid cell functions are inhibitory. The advantage of using cell cultures has been the possibility of studying an influence on thyrocytes from a single agent individually, such as cytokines, hormones or growth factors. The disadvantage is that an organism is under the influence of a multitude of factors that can only be investigated in vivo in intact organisms. Both types of models have therefore been important in the understanding of thyroid autoimmunity.

Influence of Phthalates on in vitro Innate and Adaptive Immune Responses

Phthalates are a group of endocrine disrupting chemicals, suspected to influence the immune system. The aim of this study was to investigate the influence of phthalates on cytokine secretion from human peripheral blood mononuclear cells. Escherichia coli lipopolysaccharide and phytohemagglutinin-P were used for stimulation of monocytes/macrophages and T cells, respectively. Cells were exposed for 20 to 22 hours to either di-ethyl, di-n-butyl or mono-n-butyl phthalate at two different concentrations. Both diesters were metabolised to their respective monoester and influenced cytokine secretion from both monocytes/macrophages and T cells in a similar pattern: the secretion of interleukin (IL)-6, IL-10 and the chemokine CXCL8 by monocytes/macrophages was enhanced, while tumour necrosis factor (TNF)-α secretion by monocytes/macrophages was impaired, as was the secretion of IL-2 and IL-4, TNF-α and interferon-γ by T cells. The investigated phthalate monoester also influenced cytokine secretion from monocytes/macrophages similar to that of the diesters. In T cells, however, the effect of the monoester was different compared to the diesters. The influence of the phthalates on the cytokine secretion did not seem to be a result of cell death. Thus, results indicate that both human innate and adaptive immunity is influenced in vitro by phthalates, and that phthalates therefore may affect cell differentiation and regenerative and inflammatory processes in vivo.

Thyrotropin Stimulates Specifically the Expression of the Autoantibody Binding Domains of the Thyroperoxidase Molecule

To get some insight on the in vitro effect of TSH on the expression of two thyroid specific antigens (thyroglobulin (Tg) and thyroid peroxidase (TPO)) on the cell surface of cultured human thyroid cells an indirect immunofluorescence-activated cell sorter (FACStar IV, Becton-Dickinson) was used. Only half of the cultures responded to TSH by increased surface expression of the thyroid specific antigen Tg. In these cells, TSH stimulation of TPO expression showed a difference in epitopes recognized by murine monoclonal antibodies. Epitopes of domain D, recognized by monoclonal antibody 1, 30, 40 and 53 which are not involved in autoimmunity, were unaffected by TSH stimulation, (n = 2-10). In contrast, TSH regulated the surface expression of the TPO epitopes recognized by monoclonal antibody 15, 18, 24 and 60, which are known to be related to the serum autoantibody binding domain of TPO, (n = 6-8; p < 0.05). This indicated that increased activity of the thyroid cells selectively stimulated the expression of autoantigenic epitopes on the cell surface and supports the concept that increased cellular activity might predispose to the autoimmune processes leading to autoimmune thyroid disease.

Iodine and tri-iodo-thyronine reduce the incidence of type 1 diabetes mellitus in the autoimmune prone BB rats

Thyroid hormones modulate the immune system and metabolism, influence insulin secretion, and cause decreased glucose tolerance. Thyroid hormones have been described to change the incidence of spontaneous autoimmune thyroiditis in Bio-Breeding/Worcester (BB) rats but it is unknown how these hormones affect the development of type 1 diabetes mellitus (T1DM). The aim was to investigate the influence of changes in thyroid function during postnatal development on the prevalence of T1DM in BB rats and the influence of T3 on the beta cell mass in non-diabetic Wistar rats. BB rats were treated with sodium iodine (NaI) or thyroid stimulating hormone (TSH) neonatally or with tri-iodo-thyronine (T3) during adolescence. At the age of 19 weeks the incidence of T1DM and the degree of insulitis were evaluated. The influence of T3 treatment on the beta cell mass was evaluated in Wistar rats by unbiased stereological methods. The incidence of T1DM in control BB rats was 68% at the age of 19 weeks. NaI and T3 reduced the incidence, whereas TSH had no effect. In Wistar rats T3 treatment increased the beta cell mass per bodyweight. The modulation of thyroid function during postnatal development may thus affect the precipitation of T1DM in genetically susceptible individuals.

Cytokine production in NOD mice on prophylactic insulin therapy.

We investigated whether cytokines produced primarily by monocytes/macrophages (IL‐1α), Th1‐lymphocytes (IFNγ), or Th2‐lymphocytes (IL‐4) are modulated in diabetes‐prone NOD mice by insulin treatment as used in prophylaxis studies. The cytokines were measured by ELISA in plasma and in supernatants of spleen cells activated ex vivo by lipopolysaccharide plus phytohemagglutinin. Insulin, 0.25–0.50 IU/day, was given subcutaneously for 8 weeks starting in 4‐week‐old female mice. The insulin‐treated and control NOD mice showed similar weight gains and, by the end of the study, both groups exhibited cell infiltration in about 25% of their islets. IL‐la, IFNγ and IL‐4 were generally below detection in plasma of prediabetic animals and controls. Diabetic NOD mice, aged 28–45 weeks, had significantly elevated plasma IL‐la: 154±39 pg/ml (mean±M, p<0.0001). While ex vivo activated NOD splenocytes released similar amounts of IL‐1α, insulin therapy increased the levels from 99±17 to 155±19 pg/106 cells (p<0.05). Supernatants of activated splenocytes from prediabetic NOD mice had lower levels of IL‐4 (<15 pg/106 cells) compared with those from BALB/c mice (88±22 pg/106 cells; p<0.01), and this deficiency was partially compensated for when the NOD mice were given insulin (27±8; p<0.01). The levels of IFNγ were comparable and largely unaffected by insulin treatment. Hence, insulin therapy appears to partially normalize an otherwise deficient Th2 response in NOD mice.