A group of 330 overweight or obese children, without thyroid anomalies, were followed for TSH, free T4 versus CVD identifiers; total cholesterol (TChol), LDL-cholesterol (LDL), triacylglycerol (TAG), and monocyte chemotactic protein 1 (MCP1).
Tests were measured before and after one year of lifestyle intervention, including weight loss. Study finds that TSH, but not free T4, correlates positively with CVD markers, suggesting direct involvement of TSH in lipoprotein metabolism.
It is speculated that TSH receptors, present in hepatocytes, are responsible for direct cholesterol synthesis and lower bile acid production under TSH stimulation. Future studies could address interventional outcomes of thyroid hormone on TSH and CVD risk factors.
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Context: Overweight and obese children have an increased risk to develop cardiovascular diseases (CVDs) in which thyroid-stimulating hormone (TSH) has been suggested as an intermediary factor. However, results of cross-sectional studies are inconclusive, and intervention studies investigating changes in TSH concentrations in association with changes in cardiovascular risk parameters in overweight and obese children are scarce.
Objective: To gain insight in associations of circulating TSH concentrations and cardiovascular risk parameters in overweight and obese children.
Design: Nonrandomized lifestyle intervention.
Setting: Centre for Overweight Adolescent and Children’s Healthcare.
Patients: 330 euthyroid overweight and obese children.
Intervention: Long-term lifestyle intervention.
Main Outcome Measures: TSH concentrations, pituitary TSH release in response to thyrotropin-releasing hormone (TRH), and cardiovascular risk parameters.
Results: At baseline, serum total cholesterol (TChol), low-density lipoprotein cholesterol (LDL-C), triacylglycerol (TAG), and monocyte chemotactic protein 1 concentrations were significantly associated with serum TSH concentrations. TSH release by the pituitary in response to exogenous TRH was not associated with cardiovascular risk parameters.
During lifestyle intervention, several cardiovascular risk parameters significantly improved. In children whose BMI z score improved, changes in TSH concentrations were significantly associated with changes in TChol, LDL-C, and TAG concentrations.
In euthyroid overweight and obese children, circulating TSH concentrations are positively associated with markers representing increased CVD risk. Changes in TSH concentrations are also associated with changes in lipid concentrations in children with successful weight loss, which is consistent with TSH being an intermediary factor in modulating lipid and lipoprotein metabolism.
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It is indisputable that overweight and obese children are characterized by an elevated cardiovascular risk profile. Various well-known factors associated with overweight and obesity such as dyslipidaemia, high blood pressure (BP), and decreased insulin sensitivity are associated with low-grade inflammation and oxidative stress, ultimately altogether leading to endothelial dysfunction. It has been suggested that thyroid-stimulating hormone (TSH) is an additional intermediary factor involved in the pathogenesis of cardiovascular diseases (CVDs).
However, results of previous studies evaluating associations between cardiovascular risk parameters and TSH concentrations are inconclusive. Both in children and adults with a normal weight, overweight, and obesity, positive associations between TSH concentrations and cardiovascular risk parameters, including total cholesterol (TChol), low-density lipoprotein cholesterol (LDL-C), triacylglycerol (TAG) concentrations, and insulin sensitivity, have been found. Not all studies were able to show these associations in overweight and obese children.
TSH concentrations in the high normal range or above the normal range are common in overweight and obese children and are often higher compared with TSH concentrations of normal-weight children. Different underlying mechanisms have been postulated trying to explain these frequently found high normal TSH concentrations, including leptin-mediated production of prothyrotropin-releasing hormone and thyroid hormone resistance.
The aim of the current study was to evaluate the associations of TSH concentrations with cardiovascular risk parameters, as well as the associations between changes in TSH concentrations and changes in cardiovascular risk parameters in euthyroid overweight and (morbidly) obese children, before and after 12-month lifestyle intervention. Furthermore, we evaluated whether TSH release by the pituitary in response to exogenous TRH stimulation was associated with increased CVD.
Several hypotheses can be postulated about the interaction between serum TSH concentrations and cholesterol metabolism and the underlying mechanisms. Previous studies demonstrated that TSH receptors (TSH-r) are not merely expressed in thyroid tissue, but also in other tissues, including hepatocytes. TSH binding to hepatic TSH-r stimulates sterol regulatory element-binding proteins (SREBP-2) and consequently transcription of 3- hydroxy-3-methyl-glutaryl coenzyme A reductase, which leads to higher endogenous cholesterol synthesis. Furthermore, TSH-r activation lowers bile acid synthesis.
An inverse association between TSH concentrations and serum total bile acid concentrations was demonstrated in adults with subclinical hypothyroidism. Finally, TSH increases proprotein convertase subtilisin kexin type 9 (PCSK9) transcription, another SREBP-2 target. PCSK9 is considered an important regulator of LDL-receptor (LDL-r) function by inhibiting LDL-r recycling to the cell surface. Recently Ozkan et al. demonstrated a positive association between PCSK9 and TSH concentrations, which suggests that there might also be an effect of TSH on LDL-r function, mediated via PCSK9.
In conclusion, in euthyroid overweight and (morbidly) obese children, serum TSH concentrations are positively associated with markers representing increased CVD risk such as TChol, LDL-C, TAG, and MCP-1 concentrations. The additional observation that changes in TSH are associated with changes in TC, LDL-C, and TAG concentrations in children with successful weight loss after 1 year of participating in a lifestyle intervention strengthens the earlier assumptions that serum TSH is indeed an intermediary factor in modulating lipid and lipoprotein metabolism, although causality could not be demonstrated. It is worth exploring in more depth the potential association between TSH and whole-body cholesterol metabolism, including endogenous cholesterol synthesis, intestinal cholesterol absorption, and receptor-mediated cholesterol clearance.