Context: Familial longevity is associated with higher circulating levels of thyrotropin (TSH), in the absence of differences in circulating thyroid hormones, and a lower thyroid responsivity to TSH... Show moreContext: Familial longevity is associated with higher circulating levels of thyrotropin (TSH), in the absence of differences in circulating thyroid hormones, and a lower thyroid responsivity to TSH, as previously observed in the Leiden Longevity Study (LLS). Further mechanisms underlying these observations remain unknown.Objective: We hypothesized that members from long-lived families (offspring) have higher thyroid hormone turnover or less negative feedback effect on TSH secretion compared to controls.Methods: In a case-control intervention study, 14 offspring and 13 similarly aged controls received 100 mu g 3,5,3'-triiodothyronine (T3) orally. Their circulating T3, free T3 (fT3), and TSH levels were measured during 5 consecutive days. We compared profiles of circulating T3, fT3, and TSH between offspring and controls using general linear modeling (GLM) and calculated the percentage decline in TSH following T3 administration.Results: Circulating T3 and fT3 levels increased to supraphysiologic values and normalized over the course of 5 days. There were no serious adverse events.T3 and fT3 concentration profiles over 5 days were similar between offspring and controls (T3 GLM P= .11, fT3 GLM P= .46).TSH levels decreased in a biphasic manner and started returning to baseline by day 5. TheTSH concentration profile over 5 days was similar between offspring and controls (GLM P= .08), as was the relativeTSH decline (%).Conclusions: Members of long-lived families have neither higherT3 turnover nor diminished negative feedback of T3 on TSH secretion.The cause and biological role of elevated TSH levels in familial longevity remain to be elucidated. Show less
Roelfsema, F.; Boelen, A.; Kalsbeek, A.; Fliers, E. 2017
A subgroup of patients with thyroid cancer (10-15% of patients with DTC) with distant metastases have high remission rates after conventional RaI-treatment. We have explored several routes which in... Show moreA subgroup of patients with thyroid cancer (10-15% of patients with DTC) with distant metastases have high remission rates after conventional RaI-treatment. We have explored several routes which in time may help to improve the prognosis for this subset of patients, focussing on the TSHR. The combination of troglitazone and lovastatin may have potential use in DTC as we observed a strong reduction of growth and distinct changes in morphology in the follicular thyroid carcinoma cell-line FTC-133 at clinically achievable concentrations. Furthermore, the combination of troglitazone and lovastatin was able to increase the expression of NIS and the TSHR which may prove to be beneficial in sensitizing thyroid tumor cells to conventional RaI therapy. Secondly, we explored the possibility of thyroid specific membrane associated therapy by using the TSHR as a target. We succeeded in modifying TSH into a potential vehicle for toxins by converting it into a single chain protein with improved binding to the TSHR. The fusion of short proteins to our modified single chain TSH did not impair binding thus confirming the potential in using modified TSH as a vehicle for therapeutic proteins. We have demonstrated in our studies that a balanced attitude is feasible in commonly used TSH suppressing thyroxine replacement therapy, thus preventing those patients from the potential negative effects of long term TSH suppression on other organs. Show less
The evolutionary advantage to conserve energy in the form of adipose issue in order to survive long periods of food shortage in the past, turned into a major health problem in current times of... Show moreThe evolutionary advantage to conserve energy in the form of adipose issue in order to survive long periods of food shortage in the past, turned into a major health problem in current times of plenty. Excess accumulation of body fat, or "obesity", is associated with severely increased co-morbidity and mortality risks and is a global epidemical medical condition which is difficult to manage. The exact pathophysiologic mechanism of obesity remains elusive and various factors such as genetic, social, behavioral and physiological cues are involved in its development. From a biological point of view, obesity might be partly explained by differences in the regulation of energy intake, expenditure and storage (energy homeostasis) between obese and lean individuals. The neuroendocrine system provides a source of humoral messengers, which modulate energy homeostasis. This thesis will focus on changes of the neuroendocrine environment of obese women. First of all, spontaneous diurnal plasma hormone concentrations and secretion of different hormonal systems were studied. Secondly, the effect of weight loss on neuroendocrine perturbations of some of these hormonal axes was evaluated. Finally, the impact of modulation of potential physiological cues (increased circulating FFAs and deficit dopaminergic signaling), which might be involved in the neuroendocrine changes and metabolic alterations, was investigated. Show less
