Effect of Thyroid-Stimulating Hormone Suppression on Muscle Function After Total Thyroidectomy in Patients With Thyroid Cancer

ContextThyroid-stimulating hormone (TSH) suppression is recommended to reduce tumor recurrence following surgery for differentiated thyroid cancer (DTC). However, prolonged subclinical hyperthyroidism caused by levothyroxine treatment has deleterious effects on various organs.ObjectiveTo evaluate the relationships of TSH concentration with muscle mass, muscle strength, and physical performance related to sarcopenia in patients with DTC undergoing TSH suppression following surgery.MethodsWe studied 134 patients of >60 years who were undergoing TSH suppression therapy following surgery for DTC. We evaluated muscle mass and muscle function-related parameters and diagnosed sarcopenia using the threshold for Asian people.ResultsThe participants were 68.3 ± 7.2 years old and 36/134 (26.9%) were diagnosed with sarcopenia. They were allocated to high-TSH and low-TSH groups using a threshold concentration of 0.40 μU/mL, and grip strength was significantly lower in the low-TSH group. The data were further analyzed according to age and sex, and in the low-TSH group, male participants and those of <70 years were found to have significantly lower grip strength.ConclusionsLow-TSH concentrations is associated with low grip strength, and this is most pronounced in individuals of <70 years of age. Therefore, muscle function should be considered an adverse effect of TSH suppression in patients with DTC who undergo TSH suppression therapy, especially in men of <70 years.

Evaluation of adrenal reserve in patients with differential thyroid cancer receiving thyroid hormone suppression therapy- case-control comparative study

Background Patients with differentiated thyroid cancer (DTC) are exposed to subclinical exogenous hyperthyroidism for the suppression of thyroid-stimulating hormone (TSH). In this study, we aimed to evaluate the adrenal reserve in DTC patients receiving suppression therapy. Materials and Methods The study included 55 DTC patients on suppression therapy and 32 healthy volunteers. Basal serum cortisol of all participants and adrenocorticotropic hormone (ACTH) of the patient group were measured. A standard-dose ACTH test (0.25 mg) was performed in patients with a basal cortisol < 14.5 mcg/dL. Results In the patient group, TSH was lower, free thyroxine (fT4) was higher, and free triiodothyronine (fT3) was similar to those of the control group (p < 0.01, p < 0.01, p = 0.140, respectively). The serum cortisol of the patient group was significantly lower than the control group (12.14 ± 5.12 mcg/dL vs 18.00 ± 5.56 mcg/dL, p < 0.001). 34 (61.8%) patients with DTC had a basal cortisol < 14.5 mcg/dL. Prolonged TSH suppression (≥ 5 years vs < 5 years) was associated with lower basal cortisol (7.46 ± 2.63 mcg/dL vs 9.48 ± 2.65 mcg/dL, p = 0.022). The ACTH stimulation test showed that 2 (5.8%) patients had a cortisol response < 18 mcg/dL. The rate of adrenal insufficiency was 3.6% in DTC patients. A moderate negative correlation was found between ACTH and fT3 of patients with low basal cortisol (r = − 0.358, p = 0.038) Conclusion Patients with DTC receiving TSH suppression therapy are at risk for adrenal insufficiency. The duration and severity of suppression might increase this possibility. Dynamic testing with synthetic ACTH can be used to reveal insufficient cortisol response in case of clinical suspicion.

Behandlungsstrategie beim radiojodrefraktären differenzierten Schilddrüsenkarzinom

ZusammenfassungTraditionell besteht das multimodale Therapiekonzept bei den differenzierten Schilddrüsenkarzinomen in der Thyreoidektomie mit Neck-Dissection (bei cN+-Halsstatus) und adjuvanten Radiojodablation mit abschließender risikoadaptierter TSH-Suppression. Das Ausmaß der Radiojodaufnahme beim metastasierten Schilddrüsenkarzinom spielt eine signifikante Rolle bei der Einschätzung der Prognose. Das fehlende Jodspeicherungsvermögen einer Läsion in Zusammenschau mit dem fehlenden Abfall des Tumormarkers Thyreoglobulin sowie radiologische Zeichen einer Tumorprogression charakterisieren den Radiojod-refraktären Patienten. Aufgrund des meistens über einen langen Zeitraum indolenten Verlaufs erscheint in den meisten Fällen ein abwartendes Verhalten in Kombination mit lokaler Metastasenbehandlung sowie Symptomlinderung primär sinnvoll zu sein. Der Nachweis einer Veränderung der Tumordynamik ist der Zeitpunkt, um eine Systemtherapie zu evaluieren. Diese beruht auf Multi-Tyrosinkinase-Inhibitoren (Sorafenib, Lenvatinib). Diese Substanzen sind größtenteils mit einem ungünstigen Nebenwirkungsprofil assoziiert (Diarrhö, Hautauschläge, arterielle Hypertonie mit hypertensiver Entgleisung, lokale Wundheilungsstörungen), welches zu einer nicht vernachlässigbaren Rate einer therapieassoziierten Morbidität sowie einer hohen Anzahl an Therapieunterbrechungen führt. Daher sind im Jahr 2020 2 selektive RET-Inhibitoren (Selpercatinib, Pralsetinib) für die differenzierten Schilddrüsenkarzinome von der FDA zugelassen worden. Eine neue Perspektive für die Zukunft wären die unterschiedlichen Redifferenzierungsstrategien, welche auf die Steigerung der Sensitivität der Tumorzellen auf Radiojod abzielen.

Thyroid Stimulating Hormone Suppression and Recurrence After Thyroid Lobectomy For Papillary Thyroid Carcinoma

Background Thyroid lobectomy is recommended as the primary treatment for low-risk thyroid cancer. However, recurrence and hypothyroidism may develop after lobectomy, necessitating thyroid hormone supplementation. The 2015 American Thyroid Association (ATA) guidelines recommended post-lobectomy thyroid-stimulating hormone (TSH) suppression. This study examined the need for TSH suppression and recurrence after lobectomy for unilateral papillary thyroid carcinoma (PTC). Methods This study involved 369 patients who underwent thyroid lobectomy and ipsilateral central neck dissection for PTC between 2007 and 2015. Thyroid function tests were performed before and regularly after lobectomy. Binary logistic regression analyses were used to find factors predictive of the post-lobectomy need for TSH suppression that was defined by the 2015 ATA guidelines. Results Serum TSH concentrations gradually increased after lobectomy: proportions with TSH > 2 mIU/L at post-lobectomy 1, 3 ~ 6, 12, and 24 months were found in 77.0%, 82.3%, 66.7%, and 59.9%, respectively. After lobectomy, 168 (45.5%) patients received levothyroxine (T4) supplementation. Multivariate logistic regression analyses showed that pre-TSH level > 2 mIU/L was the sole independent variable predictive of the need for post-lobectomy TSH suppression (P = 0.003). During the median follow-up of 72 months, recurrence was found in 4 (1.1%) patients who never received T4 supplementation and had post-lobectomy TSH levels > 2 mIU/L. Conclusions Our data show that thyroid lobectomy for unilateral PTC is associated with a low recurrence rate, but a significant risk of hypothyroidism. Preoperative TSH level can predict the need for post-lobectomy TSH suppression compliant with the 2015 ATA guidelines.

Effect of TSH Suppression Therapy on Bone Mineral Density in Differentiated Thyroid Cancer: A Systematic Review and Meta-analysis

CONTEXT As subclinical hyperthyroidism increases the risk of osteoporosis and fractures, concerns are growing about the long-term skeletal safety of thyrotropin (TSH) suppression therapy after total thyroidectomy in patients with differentiated thyroid cancer (DTC). OBJECTIVE We aimed to determine the effect of TSH suppression therapy on bone mineral density (BMD) in DTC patients. METHODS We searched PubMed, Embase, the Cochrane library, and other sources. Eligible observational studies included DTC patients who underwent TSH suppression therapy and BMD measurement. Two independent reviewers extracted data on the studies’ characteristics and outcomes and determined their risk of bias. Data were extracted from each study for postmenopausal/premenopausal women’s and men’s lumbar spine (LS), femoral neck (FN), and total hip (TH) BMD and summed using a random-effects meta-analysis model. The weighted mean difference (WMD) with 95% confidence intervals (CI) are expressed for the differences in outcome measurements between groups. RESULTS Seventeen studies (739 patients and 1085 controls) were included for quantitative analysis. In postmenopausal women, TSH suppression therapy showed a significant decrease in LS BMD (-0.03; -0.05, -0.02), and a similar trend was seen in TH. In premenopausal women, TSH suppression therapy significantly increased LS BMD (0.04; 0.02, 0.06) and FN BMD (0.02; 0.01, 0.04). In men, there was no significant association between TSH suppression therapy and BMD at any site compared to the controls. CONCLUSION Evidence from observational studies suggests that postmenopausal women treated with TSH suppression therapy are at risk for lower BMD. Attention should be paid to long-term skeletal safety in DTC survivors.

Bone Microarchitectural Changes in Hyperthyroid Women Compared to a Normal Canadian Cohort

Thyroid hormones play a critical role in bone physiology during childhood, but also impacts adult bone metabolism. Hyperthyroidism promotes accelerated bone turnover and bone remodelling which is associated with net loss of bone mineral density over time (BMD) and these changes have been quantitated using the gold standard of measuring BMD, Dual Energy X-ray Absorptiometry (DEXA). Ordinarily, biochemical thyroid hormone normalization restores BMD towards normal, yet an increased risk of fractures remains lifelong. DEXA, therefore, cannot explain the underlying etiology for fracture risk which may be due to undetected changes in bone microarchitecture. Our primary objective was to utilize an investigational 3-dimensional bone imaging technology, High Resolution peripheral Quantitative Tomography (HR-pQCT), to study bone microarchitecture in actively hyperthyroid women to determine if there are changes in cortical and trabecular bone microarchitecture from that of age-matched controls. A subset of women were rescanned using HR-pCT after thyroid hormones had been normalized for at least 6 months to determine if there were cortical/trabecular architectural changes that reversed towards normal in these individual cases. We enrolled 20 hyperthyroid women (age 20–76) for this pilot study who had persistent TSH suppression for &gt;3 months (TSH&lt; 0.5, normal range: 0.5–4.49 mU/L) without secondary causes for bone loss. Their etiology was divided amongst TSH suppression for thyroid carcinoma, Grave’s disease and iatrogenic hyperthyroidism. HR-pQCT scans of the radius were compared to age-matched scans of normal females, available from the robust Canadian Multicentre Osteoporosis Study (CaMOS) control cohort. Four participants were re-scanned after 6 months of TSH normalization to assess reversibility. The observed data showed statistically significant differences in key parameters of bone microarchitecture in hyperthyroidism, independent of etiology. We observed decreased cortical thickness and increased failure load as statistically different from age-matched controls. Increases in cortical bone porosity and decreases in volumetric bone density (cortical, trabecular and total) were notable but did not reach significance in this small study. Repeat scans following normalization of thyroid hormone levels revealed consistent (partial, nonsignificant) normalization of multiple bone microarchitecture elements including increased trabecular number/thickness, and decreased cortical porosity. These findings suggest that there are changes in both cortical and trabecular bone during active hyperthyroidism that may contribute to increased lifelong fracture risk.

Effects of thyroid-stimulating hormone suppression after thyroidectomy for thyroid cancer on bone mineral density in postmenopausal women: a systematic review and meta-analysis

ObjectivesWe assessed thyroid-stimulating hormone (TSH) suppression effects on bone mineral density (BMD) in postmenopausal women who underwent thyroidectomy.Data sourcesPubMed, EMBASE, Cochrane Library, Web of Science and SCOPUS were searched from inception to 24 February 2021.Study selectionCase-control studies were included.Data extraction and synthesisTwo authors independently reviewed the studies, extracted the data and performed meta-analysis of eligible studies.Research design and methodsStudies evaluating BMD in postmenopausal women with thyroid cancer who had thyroidectomy and levothyroxine therapy were included. Differences in BMD were presented as standardised mean differences (SMDs). Meta-analyses were conducted using a random-effects model.ResultsAnalysis of 16 case-control studies (426 patients and 701 controls without thyroid cancer) showed that stringent TSH suppression (TSH <0.10 mIU/L) after thyroidectomy had deleterious effects on the BMD of the lumbar spine in postmenopausal women compared with controls (SMD −0.55; 95% CI −0.99 to −0.10; I2=75.8%). There was no significant difference in patients with moderate TSH suppression (TSH 0.10–0.49 mIU/L). TSH suppression in postmenopausal women was not significantly associated with lower femoral neck BMD. Subgroup analysis of the lumbar spine showed that the association between stringent TSH suppression and lower BMD was consistent among studies with >10 years of follow-up (SMD −0.32; 95% CI −0.50 to −0.14). Subgroup analysis of the femoral neck showed that total thyroidectomy was related to detrimental effects on the BMD of the femoral neck (SMD −0.60; 95% CI −0.89 to −0.31; I2=90.4%), but near-total thyroidectomy was not (SMD 0.00; 95% CI −0.30 to 0.30; I2=55.6%).ConclusionsStringent TSH suppression had deleterious effects on the BMD of the lumbar spine after thyroidectomy in postmenopausal women. Further studies are needed to determine whether stringent TSH suppression after thyroidectomy increases the fracture risk.

The Growth Stimulatory Effects of Thyrotropin and Thyroid Hormones on Thyroid Cancer Depend on Expression of Thyrotropin Receptor and Integrins

Background: The long-term management of metastatic thyroid cancer (TC) consists of thyrotropin (TSH) suppression with supraphysiologic doses of thyroid hormones (TH) via a negative feedback loop. The goal of TSH suppression is to prevent TSH stimulation of the TSH receptor (TSHR), as it has been shown to promote proliferation of cancer cells. However, TH (T3 and T4) have also been shown to stimulate cancer cell proliferation via αvβ3 integrin signaling. Since both TSH and TH have mitogenic potential, we aimed to investigate which one is a more potent growth stimulus-TSH or TH by analyzing its growth stimulatory effects in TC models. Methods: We analyzed the mRNA expression of TSHR and ITGAV (αv), ITGB3 (β3) integrins in 496 human TC tissue samples, including 65 paired samples of normal tissue (NT) and the corresponding tumor included in The Cancer Genome Atlas (TCGA). We used 13 TC cell lines and analyzed the mRNA expression of 24 genes (4 thyroid-specific genes, 2 TH receptor genes, and 18 integrin genes) with an emphasis on the expression of cell surface receptors αv, β3 integrins, and TSHR. The protein expression of αv, β3, and TSHR was analyzed by immunoblotting. To test the effects of TH and TSH on cell proliferation and expression of αv, β3, and TSHR, cells were treated with varying concentrations of TSH (0.01, 0.1, 1, 10 mIU/mL), T3 (0.1, 1, 10 100 nM) and T4 (1, 10, 100, 1000 nM) for 72 h. Results: Analysis of the RNA seq data from TCGA revealed a significantly higher expression of TSHR in NT compared with TC (log fold change 0.59, p&lt;0.001), lower expression of αv integrin in NT compared with TC (log fold change -0.3, p=0.001), and comparable expression of β3 integrin (log fold change 0.20, p=0.3). Based on the mRNA expression data of 13 TC cell lines, we selected 6 cell lines (FTC133, TPC1, XTC1, OCUT2, C643, THJ16T) characterized by variable αv, β3, and TSHR expression. The TPC1 and OCUT2 cells with high to moderate αVβ3 expression responded to T4 (1000nM; p&lt;0.001) and T3 treatment (100nM; p&lt;0.001) respectively, with increased proliferation, while the cell lines characterized by low to no β3 and/or low αV expression (FTC133, XTC1, C643, and THJ16T) did not change their growth rate in response to TH. The C643 and XTC1 cells characterized by a preserved low-to-moderate TSHR expression responded to TSH treatment (10mIU/mL) with increased proliferation (p&lt;0.05), while the growth curve of cell lines with very low to no TSHR expression (FTC133, TPC1, OCUT1, THJ16T) was not affected. Analysis of the effects of TH and TSH on the mRNA expression of αV, β3, and TSHR was observed to be cell-line specific. Conclusion: The growth stimulatory effects of TSH and TH on TC cells depend on its concentration and expression of TSHR and αVβ3, respectively. Since TC is characterized by relatively lower TSHR and higher αV integrin expression than NT, treatment with supraphysiologic doses of TH in patients with metastatic TC needs to be individualized.