Impact of resistance to thyroid hormone on thecardiovascular system in adults.

Sixteen untreated and asymptomatic RTH patients (eight males; aged 33 +/- 12 yr, range 21-45 yr) and 16 controls (nine males; aged 33 +/- 5 yr, range 24-42 yr) were enrolled. Clinical data, thyroid status, and echocardiographic results were recorded.Our results suggest the presence of cardiovascular alterations in asymptomatic and untreated RTH patients similar to those reported in hypothyroid patients. Our strict selection likely created a bias in the inclusion of a particular type of RTH patients, who could represent a minority of patients with RTH. However, no correlation was found between the type of mutation and cardiovascular characteristics of RTH patient

Thyroid function, autoimmunity and nodules in hematological malignancies

Objective Hematological malignancies encompass a large spectrum of disease entities whose treatment by chemo/radiotherapy could lead to thyroid complications. To the best of our knowledge, no study has simultaneously addressed thyroid function, autoimmunity and nodularity. Therefore, we decided to conduct one.Materials and methods We evaluated 82 Caucasian patients (36 women and 46 men), who were treated at our Oncology division for hematological malignancies (multiple myeloma, chronic myeloid leukemia, chronic lymphatic leukemia, non-Hodgkin lymphoma and polycythemia vera) and compared them with a control group of 104 patients. Patients who had received or were receiving external head/neck radiotherapy were excluded. All oncological patients and control individuals underwent thyroid ultrasonography and thyroid function and autoimmunity tests.Results A lower prevalence of enlarged thyroid and nodules were found in patients with respect to controls. The rate of thyroid nodules was the highest in multiple myeloma and polycythemia vera, and the lowest in chronic lymphatic leukemia. Non-Hodgkin lymphoma patients had the smallest thyroid nodules while men with multiple myeloma the biggest ones. No patient had hypothyroidism, while 5.6% of patients had subclinical hyperthyroidism. In contrast, within the control group the rates of hypothyroidism and hyperthyroidism, overt and subclinical, were 3.8%, 20.2%, 0% and 0% respectively. Moreover, the overall rate of thyroid autoantibody positiveness in patients was significantly lower than controls.Conclusion In our experience, we found a significantly lower prevalence of thyroid abnormalities in hematologic patients who underwent chemotherapy, but not radiotherapy, with respect to controls. Arch Endocrinol Metab. 2015;59(3):236-4

The clinical implications of sunitinib-induced hypothyroidism: a prospective evaluation

Sunitinib is approved for the treatment of metastatic renal cell carcinoma (RCC) and imatinib-resistant or -intolerant gastrointestinal stromal tumours (GIST). Several studies have identified unexpected rates of thyroid dysfunction with sunitinib treatment. We performed a prospective observational study with the aim of more accurately defining the incidence and severity of hypothyroidism in RCC or GIST patients receiving sunitinib. Thyroid function was assessed at baseline and on days 1 and 28 of each treatment cycle. Thyroid antibodies were assessed at baseline and during follow-up if abnormal thyroid function tests were recorded. Sixteen patients (27%) developed sub- or clinical hypothyroidism and required hormone replacement and 20 patients (34%) showed at least one elevated thyroid-stimulating hormone not requiring therapeutic intervention. Twenty patients (34%) did not develop any biochemical thyroid abnormality. Thus, sunitinib can induce (sub-) clinical hypothyroidism, warranting close monitoring of thyroid function. We propose a new algorithm for managing this side effect in clinical practise

Antiangiogenic drugs in ovarian cancer

Ovarian cancer continues to be a major cause of morbidity and mortality in women. Antiangiogenic treatments have emerged as a promising strategy to treat ovarian cancer. This article reviews the rationale supporting the use of antiangiogenic treatments in ovarian cancer, the clinical development of this group of drugs and the toxicities specific to this modality of treatment

Pituitary-hormone secretion by thyrotropinomas

Hormone secretion by somatotropinomas, corticotropinomas and prolactinomas exhibits increased pulse frequency, basal and pulsatile secretion, accompanied by greater disorderliness. Increased concentrations of growth hormone (GH) or prolactin (PRL) are observed in about 30% of thyrotropinomas leading to acromegaly or disturbed sexual functions beyond thyrotropin (TSH)-induced hyperthyroidism. Regulation of non-TSH pituitary hormones in this context is not well understood. We there therefore evaluated TSH, GH and PRL secretion in 6 patients with up-to-date analytical and mathematical tools by 24-h blood sampling at 10-min intervals in a clinical research laboratory. The profiles were analyzed with a new deconvolution method, approximate entropy, cross-approximate entropy, cross-correlation and cosinor regression. TSH burst frequency and basal and pulsatile secretion were increased in patients compared with controls. TSH secretion patterns in patients were more irregular, but the diurnal rhythm was preserved at a higher mean with a 2.5 h phase delay. Although only one patient had clinical acromegaly, GH secretion and IGF-I levels were increased in two other patients and all three had a significant cross-correlation between the GH and TSH. PRL secretion was increased in one patient, but all patients had a significant cross-correlation with TSH and showed decreased PRL regularity. Cross-ApEn synchrony between TSH and GH did not differ between patients and controls, but TSH and PRL synchrony was reduced in patients. We conclude that TSH secretion by thyrotropinomas shares many characteristics of other pituitary hormone-secreting adenomas. In addition, abnormalities in GH and PRL secretion exist ranging from decreased (joint) regularity to overt hypersecretion, although not always clinically obvious, suggesting tumoral transformation of thyrotrope lineage cells

Syndromes of thyroid hormone resistance

Thyroid hormone resistance (RTH) is a rare autosomal dominant disorder, characterized clinically by goiter and biochemically by elevated circulating free thyroid hormone levels in the presence of measurable serum TSH concentrations. About 85% of patients with RTH are harboring mutations in thyroid hormone receptor beta (TRbeta). These mutations cluster in three different "hot spot" in the T3 binding domain of the receptor. When mapped to their homologous residues in the TR crystal structure, these three clusters of mutations border the T3-binding pocket. As a consequence, most TRbeta mutations impair the hormone binding to the receptor and interfere with the mechanism(s) of corepressor release and the consequent recruitment of coactivators. Thus, the remodeling of chromatin structure throughout the process of histone acetylation is prevented and the transcriptional activity of the mutant receptor on both positively and negatively regulated genes, severely disrupted. The lack of interaction with coactivators appears to be an additional mechanism for the dominant negative effects of mutant TRbeta on the transcriptional activity of the normal receptor

Resistance to Thyroid Hormone and Cardiovascular Risk

Resistance to thyroid hormone (RTH) is a dominantly inherited syndrome of impaired tissue responsiveness to thyroid hormones (TH) characterised by high circulating TH in the presence of unsuppressed thyroid-stimulating hormone (TSH). TH achieve their action on the heart chiefly via thyroid hormone receptor alpha 1 (TR\u3b11), which is the TH receptor (TR) isoform predominantly expressed in such an organ. Data derived from animal models suggest that in RTH the overstimulation of the TR\u3b11 pathway by the high TH levels could explain the cardiovascular abnormalities seen in these animals, although the discordant cardiac gene expression profile between wild-type (wt) and transgenic mice treated with triiodothyronine (T 3) imply that the effects of RTH on the heart are complex and not completely explicable by the heightened T 3/TR\u3b11 signalling. To date, only a few studies have evaluated cardiovascular risk in RTH, with conflicting results, confirming the large variability of the RTH phenotype. In particular, some reports show that several cardiovascular parameters seem to move towards hyperthyroidism, while others show a pattern that resembles thyroid hormone deficiency. Finally, recent data suggest that in addition to reduced vascular compliance and echocardiographic abnormalities, RTH subjects may exhibit some features of metabolic syndrome, suggesting an overall increased cardiometabolic risk in this disorder

Syndromes of thyroid hormone resistance due to mutations in the T3[beta] receptor: progress in our understanding

Thyroid hormone resistance (RTH) is a rare autosomal dominant disorder, characterized clinically by goiter and biochemically by elevated circulating free thyroid hormone levels in the presence of measurable serum thyroid-stimulating hormone (TSH) concentrations. About 85% of patients with RTH harbor mutations in thyroid hormone receptor \u3b2 (TR\u3b2). These mutations cluster in three different 'hot spots' in the ligand (T3) binding domain of the receptor. When mapped to their homologous residues in the thyroid hormone receptor (TR) crystal structure, these three clusters of mutations border the T3-binding pocket. As a consequence, most TR\u3b2 mutations impair the hormone binding to the receptor and interfere with the mechanisms of corepressor release and consequent recruitment of coactivators. Thus, the remodeling of chromatin structure throughout the process of histone acetylation is prevented and the transcriptional activity of the mutant receptor on both positively and negatively regulated genes is severely disrupted. The lack of interaction with coactivators appears to be an additional mechanism for the dominant negative effects of mutant TR\u3b2 on the transcriptional activity of the normal (wild-type) TRs