ContextWith age, the prevalence of subclinical hypothyroidism rises. However, incidence and determinants of spontaneous normalization remain largely unknown.ObjectiveTo investigate incidence and... Show moreContextWith age, the prevalence of subclinical hypothyroidism rises. However, incidence and determinants of spontaneous normalization remain largely unknown.ObjectiveTo investigate incidence and determinants of spontaneous normalization of TSH levels in older adults with subclinical hypothyroidism.DesignPooled data were used from the (1) pretrial population and (2) in-trial placebo group from 2 randomized, double-blind, placebo-controlled trials (Thyroid Hormone Replacement for Untreated Older Adults With Subclinical Hypothyroidism Trial and Institute for Evidence-Based Medicine in Old Age thyroid 80-plus thyroid trial).SettingCommunity-dwelling 65+ adults with subclinical hypothyroidism from the Netherlands, Switzerland, Ireland, and the United Kingdom.ParticipantsThe pretrial population (N = 2335) consisted of older adults with biochemical subclinical hypothyroidism, defined as ≥1 elevated TSH measurement (≥4.60 mIU/L) and a free T4 within the laboratory-specific reference range. Individuals with persistent subclinical hypothyroidism, defined as ≥2 elevated TSH measurements ≥3 months apart, were randomized to levothyroxine/placebo, of which the in-trial placebo group (N = 361) was included.Main Outcome MeasuresIncidence of spontaneous normalization of TSH levels and associations between participant characteristics and normalization.ResultsIn the pretrial phase, TSH levels normalized in 60.8% of participants in a median follow-up of 1 year. In the in-trial phase, levels normalized in 39.9% of participants after 1 year of follow-up. Younger age, female sex, lower initial TSH level, higher initial free T4 level, absence of thyroid peroxidase antibodies, and a follow-up measurement in summer were independent determinants for normalization.ConclusionBecause TSH levels spontaneously normalized in a large proportion of older adults with subclinical hypothyroidism (also after confirmation by repeat measurement), a third measurement may be recommended before considering treatment. Show less
Zutinic, A.; Roelfsema, F.; Pijl, H.; Ballieux, B.E.; Westendorp, R.G.J.; Blauw, G.J.; Heemst, D. van 2021
Context: Offspring from long-lived families have a different thyroid status than controls, characterised by higher circulating levels of thyroid stimulating hormone (TSH) and similar levels of... Show moreContext: Offspring from long-lived families have a different thyroid status than controls, characterised by higher circulating levels of thyroid stimulating hormone (TSH) and similar levels of thyroid hormone. Expression of the TSH receptor has previously been observed on various extrathyroidal tissues, including bone. However, potential physiological consequences of differences in circulating TSH as observed in familial longevity on bone tissue remain unclear. Objective: Based on the hypothesis that TSH may inhibit bone resorption, we explored whether offspring of long-lived families have lower bone turnover than controls at baseline as well as following a challenge with recombinant human TSH (rhTSH). Methods: Bone turnover markers CTX and P1NP were measured in fasted morning samples from 14 offspring and 12 controls at baseline and at 24 hour intervals following 0.1 mg rhTSH i.m. administration for four consecutive days. Results: At baseline, mean (SEM) CTX was 0.32 (0.03) ng/ml in offspring and 0.50 (0.04) ng/ml in controls, p < 0.01, whereas mean (SEM) P1NP was 39.6 (3.2) ng/ml in offspring and 61.8 (6.6) ng/ml in controls, p < 0.01. Following rhTSH administration, both CTX and P1NP levels transiently increased over time and normalized towards baseline after 72 h (general linear modelling: CTX time p = 0.01, P1NP time p < 0.01); the response was similar between offspring and controls. Conclusions: Bone turnover markers were lower at baseline in offspring from long-lived families than in controls but increased similarly following an rhTSH challenge. Show less
Zutinic, A.; Blauw, G.J.; Pijl, H.; Ballieux, B.E.; Westendorp, R.G.J.; Roelfsema, F.; Heemst, D. van 2020
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
Zutinic, A.; Pijl, H.; Ballieux, B.E.; Roelfsema, F.; Westendorp, R.G.J.; Blauw, G.J.; Heemst, D. van 2020
Context: Longevity is associated with higher circulating levels of TSH in the absence of differences in circulating thyroid hormones (TH), as previously observed in F2 members of long-lived... Show moreContext: Longevity is associated with higher circulating levels of TSH in the absence of differences in circulating thyroid hormones (TH), as previously observed in F2 members of long-lived families (F2-LLS) and their partners (F2-Con). The mechanism underlying this observed difference remains unknown.Objective: We hypothesized that the thyroid gland of members from long-lived families are less responsive to TSH stimulation, thereby requiring higher circulating TSH levels to maintain adequate TH levels.Methods: We performed a case-control intervention study with a single intramuscular (gluteal) injection with 0.1 mg recombinant human TSH in a subgroup of 14 F2-LLS and 15 similarly aged F2-Con. They were followed for 4 days. No serious adverse events were reported. For analyses, we compared time trajectories of TSH and TH, and the ratio of TH to TSH using area under the curve (AUC) calculations.Results: The AUC free T4/AUC TSH ratio was significantly lower in F2-LLS than in F2-Con (estimated mean [95% confidence interval] 1.6 [1.2-1.9] and 2.2 [1.9-2.6], respectively, P = 0.01). The AUC thyroglobulin/AUCTSH ratio was also lower in F2-LLS than in F2-Con (median [interquartile range] 2.1 [1.4-3.6] and 3.2 [2.7-7.4], respectively, P = 0.04). We observed the same trend with the AUC free T3/AUC TSH ratio, although the difference was not statistically significant (estimated mean [95% confidence interval] 0.6 [0.4-0.7] and 0.7 [0.6-0.8], respectively, P = 0.07).Conclusions: The present findings show that members of long-living families have a lower thyroid responsivity to TSH compared with their partners. Show less
Spoel, E. van der; Jansen, S.W.; Akintola, A.A.; Ballieux, B.E.; Cobbaert, C.M.; Slagboom, P.E.; ... ; Heemst, D. van 2016
The canonical Wnt pathway plays a key regulatory role in osteoblastogenesis and bone mass acquisition through its main effector, beta-catenin Adenomatous polyposis coli (APC) represents the key... Show moreThe canonical Wnt pathway plays a key regulatory role in osteoblastogenesis and bone mass acquisition through its main effector, beta-catenin Adenomatous polyposis coli (APC) represents the key intracellular gatekeeper of beta-catenin turnover, and heterozygous germline mutations in the APC gene cause familial adenomatous polyposis (FAP) Whether APC mutations affect bone mass has not been previously investigated We conducted a cross-sectional study evaluating skeletal status in FAP patients with a documented APC mutation Twenty-two FAP patients with a mean age of 42 years (545% women) were included in this study Mean bone mineral density (BMD) Z-scores were significantly increased above normal at all measured sites lumbar spine (p < 01), total hip (p < 01), femoral neck (p < 05), and trochanter (p < 01) Z-scores were +1 or greater in 14 patients (63 6%) and +2 or greater in 5 (22 7%) Mean values of bone turnover markers were within normal ranges There was a significant positive correlation between procollagen type I N-terminal propeptide (P1NP) and beta-crosslaps (beta-CTX) (r = 0 70, p < 001) and between these markers and sclerostin and BMD measurements We demonstrate that FAP patients display a significantly higher than normal mean BMD compared with age- and sex-matched healthy controls in the presence of a balanced bone turnover Our data suggest a state of "controlled" activation of the Wnt signaling pathway in heterozygous carriers of APC mutations, most likely owing to upregulation of cytoplasmic beta-catenin levels (C) 2010 American Society for Bone and Mineral Research Show less
Background: The long-term effects of perinatal growth and corticosteroid exposure on adrenal steroid concentrations in adults born very preterm are uncertain. Objectives: To examine the effect of... Show moreBackground: The long-term effects of perinatal growth and corticosteroid exposure on adrenal steroid concentrations in adults born very preterm are uncertain. Objectives: To examine the effect of birth weight, early postnatal growth, and pre- and postnatal corticosteroid administration on serum adrenal steroids in 19-year-old subjects born very preterm. Design and methods: Subjects born before 32 weeks of gestation in The Netherlands participating in the Project on Preterm and Small for Gestational Age Infants (POPS) were investigated at 19 years of age. Serum cortisol, DHEA sulfate (DHEAS), and androstenedione (Adione) concentrations were measured in 393 out of 676 eligible subjects, compared with controls, and associated with perinatal growth and pre- and postnatal corticosteroids administration using multiple linear regression analyses. Results: Serum DHEAS and Adione in men and women were higher than in controls. In the multiple regression analyses, birth weight SDS showed a statistically significant negative association with serum DHEAS concentrations in women (beta: -0.865, 95% confidence interval (CI): -1.254 to -0.476) and in men (beta: -0.758, 95% CI: -1.247 to -0.268) and with serum Adione concentrations in women (beta: -0.337, 95% CI: -0.593 to -0.082). Early postnatal weight gain showed no association with any of measured adrenal markers. In women, serum Adione was associated with postnatal dexamethasone exposure (beta: 0.932, 95% CI: 0.022 1.843). Conclusions: Young adults born very preterm show elevated adrenal androgens, particularly when born small for gestational age. Postnatal corticosteroid administration is positively associated with serum Adione in young women. Show less
The purpose of this study was to explore the prevalence and nature of cardiac abnormalities in sporadic inclusion body myositis (sIBM). Fifty-one sIBM patients were cross-sectionally studied using... Show moreThe purpose of this study was to explore the prevalence and nature of cardiac abnormalities in sporadic inclusion body myositis (sIBM). Fifty-one sIBM patients were cross-sectionally studied using history-taking, physical examination, measurements of serum creatine kinase activity, the MB fraction (CK-MB), cardiac troponin T (cTnT) and I (cTnI), a 12-lead electrocardiogram (ECG) and 2-dimensional echocardiography. Present cardiac history was abnormal in 12 (24%) out of 51 patients, 12 (24%) patients had abnormalities on ECG, mostly aspecific, and in 12 (24%) patients the echocardiograph showed abnormalities. Elevated CK-MB was present in 42 (82%) patients and 40 (78%) had an elevated cTnT in the absence of acute cardiac pathology. In contrast, in one patient (2%) cTnI was elevated. There was no apparent association between elevated biomarkers, ECG or echocardiographic abnormalities. The prevalence of cardiac abnormalities in sIBM does not seem to be higher than would be expected in these elderly patients. Elevated CK-MB and cTnT levels are common, in contrast to cTnI, but do not reflect cardiac pathology. Show less
