TSH Administration Research Articles

FRI488 The Effect Of Thyroid Stimulating Hormone On Brown Adipose Tissue In Humans

Abstract Disclosure: L. Salej: None. S.D. Kodani: None. N. Chaves: None. K.N. Youssef: None. R. Monahan-Earley: None. H. Halle: None. H. Shaelah: None. P. Annie: None. J.A. Parker: None. A.M. Cypess: None. G. Kolodny: None. Y. Tseng: None. B.C. James: None. A. Gavrila-Filip: None. Obesity and diabetes are two main public health concerns due to their high impact on global morbidity and mortality. In an effort to find new treatment strategies, highly active metabolic tissues such as brown adipose tissue (BAT) have been studied as potential targets. Animal studies have shown that TSH may have a direct local effect on BAT mass and activity by stimulating local T3 production via increased deiodinase-2 (DIO2) expression and also by increasing the expression of uncoupling protein-1 (UCP-1), the key molecule in BAT thermogenesis. We hypothesized that high circulating TSH levels could increase BAT activity by increasing local T3 production and generating a local tissue "thyrotoxicosis". We studied 7 patients with thyroid cancer who underwent thyroid surgery and required recombinant TSH (rhTSH) administration for standard follow-up procedures. Each patient underwent 2 PET-CT scans for assessment of BAT volume and activity, first one day after the rhTSH administration (high TSH state) and then 1-3 months later on suppressive thyroid hormone (TH) treatment (low TSH state). Indirect calorimetry and serum thyroid function tests, fasting glucose, insulin, HbA1c, and lipid panel were measured. Our results show that there was a statistically significant difference in TSH levels (p = 0.0095), with stable circulating T4 and T3 between the low and high TSH states. There was no statistically significant difference in the BAT volume and activity (SUVmax) between the high TSH and low TSH states. Age was a significant predictor of BAT SUVmax (p = 0.008; coeff = -0.39, CI = -0.65-0.13), while BMI was a significant predictor for resting energy expenditure (REE) (p = 0.04; coeff = -203.95, CI = -396.12 - -10.78). Based on these findings, along with those from our previous study[1] showing that circulating TH levels may not be directly correlated with BAT function, we have extended our study to assess the intracellular thyroid hormone status in BAT. We have collected deep peri-thyroidal adipose tissue and subcutaneous white adipose tissue (WAT) as a control group from patients undergoing thyroid surgery. In these samples, we will measure mRNA expression of TSH receptors, TH receptors, β-adrenergic receptors, DIO2 and UCP-1 and evaluate for correlations with circulating TSH and TH levels as well as different metabolic parameters to get a deeper insight into BAT function in humans. Reference: 1. Gavrila A et al. Variable Cold-Induced Brown Adipose Tissue Response to Thyroid Hormone Status. Thyroid. 2017 Jan 1;27(1):1-10. Presentation: Friday, June 16, 2023

Absorbed dose coefficients for adult thyroid cancer patients undergoing radioiodine therapy

Use of radioactive iodine (RAI) for thyroid cancer patients is accompanied by elevated risks of radiation-induced adverse effects due to significant radiation exposure of normal tissues or organs other than the thyroid. The health risk estimation for thyroid cancer patients should thus be preceded by estimating normal tissue doses. Although organ dose estimation for a large cohort often relies on absorbed dose coefficients (i.e. absorbed dose per unit activity administered, mGy MBq−1) based on population models, no data are available for thyroid cancer patients. In the current study, we calculated absorbed dose coefficients specific for adult thyroid cancer patients undergoing RAI treatment after recombinant human TSH (rhTSH) administration or thyroid hormone withdrawal (THW). We first adjusted the transfer rates in the biokinetic model previously developed for THW patients for use in rhTSH patients. We then implemented the biokinetic models for thyroid cancer patients coupled with S values from the International Commission on Radiological Protection (ICRP) reference voxel phantoms to calculate absorbed dose coefficients. The biokinetic model for rhTSH patients predicted the extrathyroidal iodine decreasing noticeably faster than in the model for THW patients (calculated half-times of 12 and 15 h for rhTSH administration and THW, respectively). All dose coefficients for rhTSH patients were lower than those for THW patients with the ratio (rhTSH administration/THW) ranging from 0.60 to 0.95 (mean = 0.67). The ratio of the absorbed dose coefficients in the current study to the ICRP dose coefficients, which were derived from models for normal subjects, varied widely from 0.21 to 7.19, stressing the importance of using the dose coefficients for thyroid cancer patients. The results of this study will provide medical physicists and dosimetrists with scientific evidence to protect patients from excess exposure or to assess radiation-induced health risks caused by RAI treatment.

Clinical Outcomes After Radioiodine Therapy, According to the Method of Preparation by Recombinant TSH vs. Endogenous Hypothyroidism, in Thyroid Cancer Patients at Intermediate-High Risk of Recurrence.

Background: To effectively treat differentiated thyroid carcinoma (DTC) with radioiodine therapy (RAI), it is necessary to raise serum thyrotropin levels, either by thyroid hormone withdrawal (THW) or by administration of recombinant human TSH (rhTSH). The use of rh-TSH is controversial in DTC patients at intermediate to high risk of recurrence. Even more controversial is the question of whether is alters progression-free survival rates and overall survival in more aggressive patients. Objective: The primary objective of this study was comparing clinical outcomes according to the method of preparation of RAI in intermediate to high DTC patients who presented progression of structural disease. Methods: This retrospective study included 81 patients with initial intermediate to high DTC and progression of structural disease at the end of follow-up. In 21 patients, all RAI treatments were done with only rhTSH stimulation. In 11, RAI treatments were done either with thyroid hormone withdrawal (THW) or rhTSH. In 49 patients, all RAI treatments were done only THW. Results: After a median follow-up time of 83 months, there were no statistical differences in the clinical outcomes (status of structural disease at the end of the follow-up, death rate, overall survival curve, and progression-free survival curve). Conclusions: Preparation for RAI therapy using either rhTSH stimulation or THW was associated with no inferiority in the clinical outcomes in progressive DTC patients at higher risk of recurrence.

Relationship Between rhTSH Administration and Thyroid Cancer Progression: A Case Report

Abstract Introduction: The relationship between the administration of recombinant TSH (rhTSH) and the progression of thyroid cancer has been described in some case reports (1). There are scant data suggesting that rhTSH acts as a growth factor that stimulates metastatic tumor expansion. Case Report: A 55 year old male patient who 3 years ago reported an evident mass at cervical level. The ultrasound documented a large thyroid mass with an endothoracic component. The FNA reported BETHESDA IV, suspicious for follicular neoplasia. Extension studies showed lytic left parietal bone lesion and liver metastatic compromise. The pathology of the total thyroidectomy showed a follicular carcinoma with a micronodular pattern and capsular invasion, of 19x9x7 cm, vascular and esophageal involvement T4BN0M1. He was sent to radioiodine therapy with 100 MCI with previous suspension of LT4 (Preablative TGL> 300 ng / ml (<50 ng / ml) Abs-TGL 2 IU / ml (<2 IU / ml) TSH 31.3 mIU / L (0.37-4.7 mIU / L) and body scan documenting uptake of the radiotracer at the left parietal, the anterior costal grating, and liver. A second dose of iodine was applied, with 150 MCI after stimulation with thyrotropin (Preablative TGL> 300 ng / ml, Abs-TGL 1.76 IU / ml, TSH 83 mIU / L) Immediately after the administration of rhTSH, the patient described the appearance of alopecic plaques on the scalp, sensation of mass at the right upper quadrant of the abdomen and bone pain in the right rib cage and at the right hip, which progressively worsened the following days until they were incapacitating. The scan report showed a new uptake in dorsal vertebrae, the MRI showed new bone injury at the innominate bone, as well as increase in the sum of its maximum dimensions by 22%, indicative of progression. The cerebral angio-MRI showed hypervascularized metastasis at the left parietal level. Bone scintigraphy documented foci of hyper uptake in both parietals, manubrium and sternal body, 5-8 right anterior costal arches, right scapula, both humeral heads, vertebral bodies T3-T5-T7L4, right acetabulum, left proximal femur and the entire length of the right femur. The clinical and imaging worsening of the bone lesions after the application of rhTSH was striking, for this reason radiotherapy and embolization of the liver lesion was performed. The patient was not a candidate for neurosurgical management due to the vascular component of the cranial lesions. Conclusion: rhTSH is a very well-tolerated method that avoids symptoms associated with severe hypothyroidism. However, it has been associated with neoplastic progression. This is one of the few cases documented in the literature where there is a direct association between the administration of rhTSH and the progression of bone metastases.

Bone Markers Are Diminished in Offspring of Long-Lived Families Compared With Matched Controls, but Respond Equally to T3 and rhTSH

Objective: We explored the effects of T3 and rhTSH administration on bone turnover in subjects of the Leiden Longevity Study. Design: Twenty-six subjects (13 offspring and 13 matched controls), mean age 68 y, underwent a rhTSH (0.1 mg i.m) and a T3 challenge (100 µg orally) with an interval of at least 3 m. Bone markers were measured at baseline and hereafter once daily for 3–4 days. Outcome Measures: Bone markers and changes after T3 and rhTSH. The influence of sex, group and time, and relations with incremental changes in TSH, fT4 and T3. Results: CTX (bone resorption) was lower in offspring than controls (mean ± SEM), 0.324±0.026 vs 0.443±0.036 ng/mL, P= 0.02. P1NP (bone formation) was also lower in offspring than in controls (40.3±2.2 vs 59.0± 4.7 ng/mL, P=0.004). No sex differences were found. In offspring, CTX but not P1NP was positively related to TSH and fT4 (R=0.48, P=0.001 and R=0.55, P=0.005). In controls, CTX was negatively related to TSH (R=-0.50, P=0.009), while P1NP was positively related with fT4 (R=0.52, P=0.006). TSH administration increased bone resorption and formation (P<0.0001 and 0.005, respectively). CTX was maximal at 48 h, increasing from 0.415±0.032 to 0.470 ±0.037 ng/mL, P=0.001. P1NP increased from 51.1±4.09 to a maximum of 56.2±3.9 ng/mL at 24 h (P=0.005). T3 also increased bone resorption (P=0.049) and formation (P=0.001). CTX increased from 0.386±0.034 to 0.410± 0.041 ng/mL, P=0.05, and P1NP from 48.9± 4.3 to 55.5±4.2 ng/mL, P=0.007), with maximal values at 48 h. Offspring and controls had similar responses and sex had generally no statistical impact. Significant linear regressions were found between the incremental changes of CTX and TSH at 24 h (R=0.44, P=0.003), but not later. Here, significant linear relation were found for the incremental fT4 and CTX (R=0.60, P=0.001 at 48 h, and R=0.49, P=0.013 at 72 h). For P1NP such relations were not present (R values between from 0.002 to 0.14). T3 changes did not correlate with bone markers at any time point. Conclusion: This study demonstrates that bone turnover is diminished in members of long-lived families where bone resorption was positively related to serum TSH and fT4. Nevertheless, the responses to TSH (and fT4) and T3 were similar in offspring and controls. Interestingly, the maximal effect of TSH increment on bone resorption preceded that of fT4, suggesting that TSH may have an independent stimulatory effect on bone resorption. At physiological TSH concentrations such stimulatory effect on bone resorption may be postulated in offspring, along with many other factors, e.g PTH, vitamin D, GH, sex hormones and cytokines.

Recombinant Human Thyrotropin Worsens Renal Cortical Perfusion and Renal Function in Patients After Total Thyroidectomy Due to Differentiated Thyroid Cancer.

Background: Although thyrotropin (TSH) receptors are found in many nonthyroid tissues, we know little about the direct action of TSH on these receptors. Patients after total thyroidectomy for differentiated thyroid cancer (DTC) provide an interesting model for studying this issue. The administration of exogenous TSH in patients with an established thyroid state on levothyroxine (LT4) treatment allows us to study the effect of elevated TSH concentrations independent of thyroid status on the function of various organs, including the kidneys. The aim of this study was to assess the effects of the administration of recombinant human TSH (rhTSH) on renal perfusion and glomerular filtration in this group of patients. Methods: The study included 24 patients after total thyroidectomy due to DTC, without concomitant diseases, receiving only LT4 who qualified for radioiodine treatment (RIT). For two consecutive days, the patients received rhTSH and subsequently the RIT. Clinical and biochemical evaluation of thyroid and renal function was carried out before and 24 hours after the second dose of rhTSH and before the RIT. On the sixth day of hospitalization, the patients' glomerular filtration rate was re-evaluated. Kidney perfusion was assessed using color Doppler ultrasound imaging before and 24 hours after the second dose of rhTSH and before the RIT. Results: The administration of rhTSH to patients after total thyroidectomy due to DTC caused significant deterioration of renal perfusion after the second dose of rhTSH before the RIT, which was followed by a significant reduction in glomerular filtration. Furthermore, rhTSH did not significantly affect the hemodynamic parameters that could worsen renal function. Conclusions: This study indicates that TSH alone, independent of thyroid hormone concentrations, can influence renal perfusion and renal function.

Effect of rhTSH on Lipids.

Background: Subclinical hypothyroidism is associated with increased blood lipid levels. However, the exact role of thyrotropin (TSH) alone is not clear. In order to clarify this point, we analysed the acute effect of recombinant human TSH (rhTSH) administration on lipid levels. Methods: Sera of 27 premenopausal women with well-differentiated thyroid cancer were analysed. Patients that underwent a total thyroidectomy, ablation with 131I (Iodine 131) and rhTSH administration as a part of routine follow-up American Thyroid Association guidelines were included. The protocol consists of 2 intramuscular injections of 0.9 mg of rhTSH, performed on day 1 day and day 2, with blood collection on day 1 (before rhTSH administration), and day 5. TSH, free thyroxine, total cholesterol, low-density lipoprotein cholesterol (LDLc), high density lipoprotein cholesterol (HDLc), and triglycerides were assessed in all the samples, before and four days after the first administration of rhTSH. Results: Total cholesterol and triglycerides significantly increased after stimulation of rhTSH (respectively, 192 ± 33 vs. 207 ± 26, p = 0.036 and 72 ± 23 vs. 85 ± 23, p = 0.016). LDLc and HDLc showed comparable concentrations before and after the test (respectively, 115 ± 27 vs. 126 ± 22, p = 0.066, and 62 ± 15 vs. 64 ± 15, p = 0.339), while non-HDLc increased after stimulation (130 ± 30 vs. 143 ± 25, p = 0.045). Conclusion: TSH has a direct effect on total cholesterol, triglycerides, and nonHDLc. Explanation of these phenomena will require additional studies.

Malignant struma ovarii with a robust response to radioactive iodine.

SummaryStruma ovarii is a rare, usually benign ovarian tumour with malignancy occurring in <5% of cases. Metastases, particularly seeding to bone, are extremely rare. Presentation is variable but often features local pain and/or ascites and hyperthyroidism may occur. It is not established how to best treat and follow patients with extensive disease. Case reports of radioiodine (I131) ablative therapy following thyroidectomy have shown reduced recurrence. We describe the case of a 33-year-old woman who presented with bone pain and was diagnosed with skeletal metastases with features of follicular thyroid carcinoma. However, thyroid pathology was benign. She recalled that 5 years prior, an ovarian teratoma was excised, classified at that time as a dermoid cyst. Retrospective review of this pathology confirmed struma ovarii without obvious malignant features. The patient was found to have widespread metastases to bone and viscera and her thyroglobulin was >3000 µg/L following recombinant TSH administration prior to her first dose of I131. At 25 months following radioiodine treatment, she is in remission with an undetectable thyroglobulin and clear I131 surveillance scans. This case demonstrates an unusual presentation of malignant struma ovarii together with challenges of predicting metastatic disease, and demonstrates a successful radioiodine regimen inducing remission.Learning points:Malignant transformation of struma ovarii (MSO) is extremely rare and even rarer are metastatic deposits in bone and viscera.MSO can be difficult to predict by initial ovarian pathology, analogous to the difficulty in some cases of differentiating between follicular thyroid adenoma and carcinoma.No consensus exists on the management for post operative treatment of MSO; however, in this case, three doses of 6Gbq radioiodine therapy over a short time period eliminated metastases to viscera and bone.Patients should continue to have TSH suppression for ~5 years.Monitoring thyroglobulin levels can predict recurrence.

Voice Outcome of Total Thyroidectomy in Comparison With Administration of Recombinant Human TSH

The larynx is an end-organ target for hormones, and thyroid hormone may act on the larynx. We objectively compared and analyzed the phonetic characteristics of patients who underwent total thyroidectomy before and after radioiodine therapy (RIT) according to administration of recombinant human TSH (rh-TSH). Ninety-one patients who had undergone a total thyroidectomy participated (50 patients without rh-TSH, 41 patients with rh-TSH). Voice samples were obtained postoperatively (Post-OP), before high-dose RIT (Pre-RIT), and after high-dose RIT (Post-RIT). Frequency-, perturbation-, and noise-related parameters were evaluated for acoustic analysis, and the voice handicap index (VHI) was used for the subjective evaluation. Frequency-related parameters decreased significantly in patients without rh-TSH administration, but not changed at three periods in patients with rh-TSH administration. Pitch perturbation parameters were not changed at each period in two groups, but amplitude perturbation parameters were changed significantly in two groups. The functional scores of the VHI increased significantly at Pre-RIT in two groups and physical scores increased in patients without rh-TSH at Pre-RIT. The hypothyroidism after total thyroidectomy affects phonation significantly. Our results suggest that rh-TSH administration during RIT resulted in improving voice results during RIT in the patients with total thyroidectomy.

Indirect Basal Metabolism Estimation in Tailoring Recombinant Human TSH Administration in Patients Affected by Differentiated Thyroid Cancer: A Hypothesis-Generating Study.

Recombinant human TSH (rhTSH) is currently used in follow-up of patients affected by differentiated thyroid cancer (DTC). Age, sex, weight, body mass index, body surface area (BSA) and renal function are known factors affecting serum TSH peak levels, but the proper rhTSH dose to deliver to single patient remains elusive. In this study, the correlations of basal metabolic rates with serum TSH peak following rhTSH administration were investigated. We evaluated 221 patients affected by thyroid cancer that received a standard dose rhTSH. Blood samples were collected at pre-established time points. Data on body weight, height, and BSA were collected. The Mifflin-St Jeor and Fleisch equations were used to assess basal metabolism. The median value (range) of serum TSH peaks was 142 ± 53 μU/ml. Serum TSH peaks were significantly lower in males than in females (p = 0.04). TSH values also increased with age. Data showed a significant decrease of TSH peak levels at day 3 from the administration of rhTSH when basal metabolic rates increased (p = 0.002 and p = 0.009, respectively). Similar findings were observed at day 5 (p = 0.004 and p = 0.04, respectively). A multivariate analysis of several factors revealed that patients' basal metabolism (obtained using the Mifflin-St Jeor but not Fleisch equation) predicts serum TSH level peak at day 3 (p < 0.001). These results were used to generate a new formula based on Mifflin-StJeor equation which reveals as a promising tool in tailoring rhTSH dose. Basal metabolism appears an improving factor in tailoring diagnostic rhTSH dose in patients affected by DTC.

Adipose TSHB in Humans and Serum TSH in Hypothyroid Rats Inform About Cellular Senescence

Background/Aims: Thyroid hormones have been recently linked to senescence and longevity. Given the recent description of TSHB mRNA in human adipose tissue (AT), we aimed to investigate the relationship between local AT TSH and adipose tissue senescence. Methods: TSHB mRNA (measured by real-time PCR) and markers of adipose tissue senescence [BAX, DBC1, TP53, TNF (real-time PCR), telomere length (Telo TAGGG Telomere Length Assay) and lipidomics (liquid chromatography mass spectrometry)] were analysed in subcutaneous (SAT) and visceral (VAT) AT from euthyroid subjects. The chronic effects of TSH were also investigated in AT from hypothyroid rats and after recombinant human TSH (rhTSH) administration in human adipocytes. Results: Both VAT and SAT TSHB gene expression negatively correlated with markers of AT cellular senescence (BAX, DBC1, TP53, TNF gene expression and specific glucosylceramides) and positively associated with telomere length. Supporting these observations, both rhTSH administration in human adipocytes and increased TSH in hypothyroid rats resulted in decreased markers of cellular senescence (Bax and Tp53 mRNA) in both gonadal and subcutaneous white adipose tissue. Conclusion: These data point to a possible role of TSH in AT cellular senescence.

Does the use of recombinant TSH in preparation for I-131 scintigraphy scan affect hearing function?

ObjectiveThe objective of this study was to examine the effect of hypothyroidism on hearing function in patients surgically treated for differentiated thyroid cancer and subsequently experienced hypothyroidism during preparation for follow up I-131 scintigraphy scan by either recombinant human thyroid stimulating hormone (rhTSH) treatment or thyroid hormone withdrawal (THW). MethodsA total of 55 patients undergoing I-131 scintigraphy scan following surgeries for differentiated thyroid cancer were included in the study, including 25 patients prepared by administration of recombinant TSH (rhTSH Group) and 30 patients by thyroid hormone withdrawal (THW Group). ResultsAir conduction thresholds at 1, 2 and 4 kHz for both ears were higher during hypothyroid period than during euthyroid period for patients in the THW group (p < 0.05) but not for patients in the rhTSH group. ConclusionSensorineural hearing loss was detected, especially at low frequencies, in patients with DTC after surgical treatment whose hormone replacement therapy was withdrawn but not in those receiving rhTSH. It is therefore preferred to use rhTSH when preparing for I-131 scintigraphy scan in patients at risk for hearing loss.

Recombinant human TSH versus thyroid hormone withdrawal in adjuvant therapy with radioactive iodine of patients with papillary thyroid carcinoma and clinically apparent lymph node metastases not limited to the central compartment (cN1b).

To compare the short- and long-term outcomes of adjuvant therapy with radioactive iodine (RAI) preceded by the administration of recombinant human TSH (rhTSH) versus thyroid hormone withdrawal (THW) in patients with papillary thyroid carcinoma and clinically apparent lymph node metastases not limited to the central neck compartment (cN1b). The sample consisted of 178 cN1b patients at intermediate risk who underwent total thyroidectomy with apparently complete tumor resection [including postoperative ultrasonography (US) without anomalies] and who received adjuvant therapy with RAI (30-100 mCi) preceded by the administration of rhTSH (n = 91) or THW (n = 87). One year after RAI, the rates of excellent response to therapy, i.e., nonstimulated thyroglobulin (Tg) ≤ 0.2 ng/mL with negative antithyroglobulin antibodies and negative neck US, and of structural disease were similar for the two preparations (84% and 4.5%, respectively, in both groups). During follow-up (median 66 months), the rate of structural or biochemical (nonstimulated Tg > 1 ng/mL, with increment) recurrence was also similar in the two groups (4.5%). In the last assessment, the percentage of patients without evidence of disease, i.e., nonstimulated Tg < 1 ng/mL and no evidence of structural disease, was similar for the two preparations [92.3% in the rhTSH group and 97.7% in the THW group (p = 0.17)]. Preparation with rhTSH was equally effective (short- and long-term) as THW for adjuvant RAI therapy of cN1b patients at intermediate risk and with apparently complete tumor resection.

Radioiodine therapy after recombinant human tsh administration or hormone withdrawal: Is there a difference in I-131 effective half-life?

Introduction The release of thyroidectomized patients treated with radioactive iodine I-131 from the treating facility is predominantly judged on the basis of the residual I-131 activity which is dictated by the effective half-life of I-131. Purpose To determine the effective half-life of I-131 (Teff1/2 in thyroidectomized patients subjected to radioiodine therapy after either recombinant human TSH administration or hormone therapy withdrawal. Materials and methods A series of 88 consecutive patients administered with I-131 following thyroidectomy was investigated. Recombinant human TSH has been administered in 32 patients (group A), while the rest 56 patients (group B) had been subjected to hormone therapy withdrawal. Measurements of the dose rate emitted by the patient at mid-thoracic height at a distance of 1 m were obtained 0, 6, 24 and 30 h after I-131 administration. The T1/2 was determined from the exponential fit of measured data. Data regarding age, sex, weight, height, diet, administered dose, volume of water drunk, and size of remnant thyroid tissue were recorded. Results The mean I-131 Teff1/2 was found 8.8 h for group A and 12.4 h for group B, with difference being statistically significantly (p Conclusion Administration of recombinant human TSH instead of hormone thyroid withdrawal prior to radioiodine therapy of thyroidectomized patients may enhance elimination rate of residual I-131 activity, and accelerate release from treating facility.

Acute TSH stimulation in vivo does not alter serum PCSK9 levels.

BackgroundIt is now recognized that TSH can act on targets other than the thyroid, including the liver. Elevated serum TSH levels in euthyroid subjects were recently reported to correlate with high values of serum proprotein convertase subtilisin/kexin type 9 (PCSK9). This protein, expressed and secreted by hepatocytes, promotes higher LDL-cholesterol levels. We tested whether an acute increase of TSH levels following administration of TSH in vivo would raise PCSK9 levels in patients who had previously undergone total thyroidectomy and radioablation for thyroid cancer.FindingsTSH levels rose from 0.64 ± 1.02 mU/L on day 1 to 98.66 ± 4.83 mU/L on day 3, following injections of recombinant human TSH (on days 1 and 2). PCSK9 levels were 330 ± 99 ng/ml on day 1, and did not change on days 3 or 5 in response to TSH stimulation.ConclusionsAlthough a positive correlation between TSH and PCSK9 in euthyroid subjects has raised the possibility that TSH might act on the liver to raise PCSK9 values, our data show that PCSK9 levels are not affected by acute elevations of TSH levels. Whether chronic elevations of TSH are needed to upregulate PCSK9 remains to be determined.

Patients With Differentiated Thyroid Cancer Who Underwent Radioiodine Thyroid Remnant Ablation With Low-Activity 131I After Either Recombinant Human TSH or Thyroid Hormone Therapy Withdrawal Showed the Same Outcome After a 10-Year Follow-up

No long-term follow-up data are available for differentiated thyroid carcinoma (DTC) patients prepared with either exogenous or endogenous TSH and treated with low-activity (1.1 GBq [30 mCi]) radioiodine (¹³¹I). The aim of this study was to evaluate the 10-year follow-up of DTC patients who underwent remnant ablation with 1.1 GBq ¹³¹I after l-T4 withdrawal, recombinant human TSH (rhTSH) administration, or both. A total of 159 DTC patients treated with total thyroidectomy and 1.1 GBq (30 mCi) of ¹³¹I for remnant ablation and stimulated with rhTSH and/or endogenous TSH were separated into ablated (n = 115) and not ablated (n = 44) patients and prospectively followed-up for at least 10 years. In addition, we evaluated several features that could correlate with the final status of patients. During the follow-up, 4 of 115 (3.5%) ablated patients showed a recurrence and 1 was successfully cured. Among not ablated patients, 16 of 44 (36.4%) had a persistent disease. At the end of the 10-year follow-up, 140 of 159 (88.1%) patients were disease-free, whereas 19 of 159 (11.9%) remained affected. No correlation was found with the type of TSH stimulation, and no other clinical and pathological features showed any correlation with the final status. However, low levels of stimulated serum thyroglobulin (<5.4 ng/mL) at first control after remnant ablation identified a subgroup of not ablated patients who became spontaneously cured. Long-term outcomes are similar in DTC patients treated with 1.1 GBq (30 mCi) ¹³¹I and prepared either with rhTSH or endogenous TSH. It is of interest that serum thyroglobulin at first control after ablation can have a prognostic role.

Evaluation of whole-body scan, stimulated thyroglobulin after thyroxine withdrawal vs recombinant TSH administration according to the risk groups of tumor recurrence

Evaluation of whole-body scan, stimulated thyroglobulin after thyroxine withdrawal vs recombinant TSH administration according to the risk groups of tumor recurrence

Potential Use of Recombinant Human Thyrotropin in the Treatment of Distant Metastases in Patients with Differentiated Thyroid Cancer

In order to effectively treat differentiated thyroid cancer (DTC) with radioiodine (RAI) it is necessary to raise serum TSH levels either endogenously by thyroid hormone withdrawal (THW) or exogenously by administration of recombinant human TSH (rhTSH). The goal of this review is to present current data on the relative efficacy and side effects profile of rhTSH-aided versus THW-aided RAI therapy for the treatment of patients with distant metastases of DTC. We have searched the PubMed database for articles including the keywords "rhTSH", "thyroid cancer", and "distant metastases" published between January 1, 1996 and January 7, 2012. As references, we used clinical case series, case reports, review articles, and practical guidelines. Exogenous stimulation of TSH is associated with better quality of life because it obviates signs and symptoms of hypothyroidism resulting from endogenous TSH stimulation. The rate of neurological complications after rhTSH and THW-aided RAI therapy for brain and spine metastases is similar. The rate of leukopenia, thrombocytopenia, xerostomia, and pulmonary fibrosis is similar after preparation for RAI treatment with rhTSH and THW. There is currently a controversy regarding RAI uptake in metastatic lesions after preparation with rhTSH versus THW, with some studies suggesting equal and some superior uptake after preparation with THW. Analysis of available retrospective studies comparing survival rates, progression free survival, and biochemical and structural response to a dosimetrically-determined dose of RAI shows similar efficacy after preparation for therapy with rhTSH and THW. The rhTSH stimulation is not presently approved by the FDA as a method of preparation for adjunctive therapy with RAI in patients with metastatic DTC. Data on rhTSH compassionate use suggest that rhTSH stimulation is as equally effective as THW as a method of preparation for dosimetry-based RAI treatment in patients with RAI-avid metastatic DTC.

Value of Diagnostic Radioiodine Whole-Body Scanning After Initial Therapy in Patients with Differentiated Thyroid Cancer at Intermediate and High Risk for Recurrence

Diagnostic radioiodine whole-body scanning (DxWBS) in combination with stimulated thyroglobulin (Tg) (i.e., measurement after levothyroxine [L-T4] withdrawal or recombinant human TSH administration) continues to be recommended for patients with differentiated thyroid carcinoma (DTC) at high or intermediate risk for recurrence with negative basal Tg and ultrasonography (US) after ablation. However, the value of DxWBS has been questioned, even in these cases. The objective of this prospective study was to evaluate the value of DxWBS in these patients. The study consisted of 318 patients who had total thyroidectomy with apparent complete tumor resection for DTC. Further, per inclusion criteria, they had the following characteristics (i) a post-therapy radioiodine whole-body scan (RxWBS) showing no metastases and uptake in the thyroid bed of ≤2%, (ii) classification as high or intermediate risk for recurrence based on the large tumor size, tumor extension beyond the thyroid capsule, and lymph node metastases, (iii) Tg during L-T4 therapy (TgT4) of <1 ng/mL, (iv) negative anti-Tg antibodies (TgAb), and (v) normal US performed 8-12 months after ablation. Tg stimulation combined with DxWBS was performed in all patients. Patients without apparent disease in the initial assessment were followed up for 24 to 96 months. In the initial assessment, stimulated Tg continued to be <1 ng/mL in 253 (79.5%) patients and converted to levels >1 ng/mL in 65 (20.4%). None of the patients had metastases on DxWBS, and 46 (14.4%) had discrete uptake (<0.5%) only in the thyroid bed. (18)F-fluorodeoxyglucose positron-emission tomography and computed tomography (FDG-PET/CT) revealed metastases in three patients with elevated stimulated Tg. Fourteen (4.4%) patients without initially apparent disease relapsed during follow-up, including five (2%) with initial stimulated Tg < 1 ng/mL. There was no disease-related death. Thyroid bed uptake on DxWBS had no prognostic value for recurrence, irrespective of stimulated Tg levels. DxWBS can be avoided in patients with large tumors or extensions beyond the thyroid capsule or lymph node metastases, but who show no apparent disease upon initial RxWBS and US and whose serum TgT4 of <1 ng/mL and negative TgAb after thyroidectomy and ablation.

Inhibited 131I Uptake but Normal Release of Thyroid Hormone by Thyroid Gland in Response to TSH Administration in Subclinical Hypothyroidism

Background: Subclinical hypothyroidism is characterized by normal circulating thyroid hormone levels with super-normal TSH concentrations in absence of clinical manifestations. In majority of subjects, an etiologic factor is often identified. Moreover, therapy with levothyroxine normalizes serum TSH concentration while maintaining normal thyroid hormone concentrations. However, the exact pathophysiology of these thyroid hormone alterations is not well defined. Objective: Major steps in synthesis i.e. iodine uptake and the release of thyroid hormones in response to SC TSH administration were assessed in subjects with subclinical hypothyroidism. Methods: 10 men and 5 women with subclinical hypothyroidism, ages 42 - 76 years and 10 euthyroid men (39 - 70 years) participated. 24 hr 131Iodine thyroid uptake and serum T3, T4 and TSH concentrations were determined prior to and after SC administration of recombinant human TSH, 0.9 mg for two consecutive days. Comparisons were conducted for 24 hour uptake values as well as serum T3, T4 and TSH levels obtained prior to and after TSH administration. Results: In subjects with subclinical hypothyroidism 24 hour 131I thyroidal uptakes were normal (10% - 30%). However, the mean value was significantly lower, (p 3 and T4 concentrations in subjects with subclinical hypothyroidism were not significantly different in comparison to normal subjects. Serum TSH concentrations were supernormal and therefore were significantly higher in subjects with subclinical hypothyroidism in comparison to normal subjects and rose markedly in both groups following TSH administration with no significant difference among groups. Serum T4 and T3 rose significantly from PreTSH levels in both groups (p 131I Thyroid uptake is inhibited prior to as well as following SC TSH administration in comparison to normal subjects with maintenance of normal hormone release.