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Corticosteroid agents (CA) are widely used in the treatment of metastatic castration-resistant prostate cancer (mCRPC) either as concomitant treatment with active agents such as docetaxel, cabazitaxel and abiraterone or in a palliative setting, predominantly due to their anti-inflammatory activity. However, the chronic use of CA has numerous side effects, especially in case of steroid-induced adrenal insufficiency. Furthermore, the latest clinical and preclinical data demonstrate that CA themselves are likely to promote tumour progression in certain populations of patients with mCRPC. Therefore, the role of CA in advanced disease should be carefully weighed for each patient and their withdrawal should be considered in some patients. This is necessary, especially in clinical trials that need good performance status patients to evaluate the activity and the safety of emerging drugs in mCRPC that do not require the concurrent use of CA. In oncology, there is no consensus on an algorithm of gradual steroid tapering and frequently the approach to this procedure is empirical. An algorithm is presented in this article based on clinical observations. Prospective studies are necessary to evaluate the efficacy and safety of the above-proposed algorithm in metastatic castration-resistant prostate cancer.

Thyroid hormone binding autoantibodies have been observed in serum from patients affected by either thyroid disorders or autoimmune nonthyroid diseases.ln most instances, no major involvement of thyroid status of these patients has been reported. However, some authors have attributed the occurrence of hypothyroidism to high capacity thyroid hormone binding autoantibodies.In order to verify such a hypothesis, the effect of these autoantibodies on serum TSH and liver mitochondrial alpha-glycerophosphate dehydrogenase has been investigated in rats, wherein circulating T3-binding antibodies (max cap10−12 10−8 to mol/l) were induced by active immunization.Starting from the 3rd week after antigen injection, the binding of 125I-T3 to serum immunoglobulins was progressively increased, with a peak at the 5th week. In immunized animals considered as a whole group, serum TSH levels were significantly higher and liver mitochondrial alpha-glycerophosphate dehydrogenase activity was significantly lower than in normal rats (m ± SE: 145 ± 15 vs 34 ± 2 ng/dl and 0.0450 ± 008 vs 0.0980 ± 005 ΔA. mg/prot/.min, respectively; p < 0.001) The pattern of both TSH increase and alpha-glycerophosphate dehydrogenase decrease were similar to the evolution of 125-I-T3 binding to serum immunoglobulins, the maximal TSH values and lowest enzyme levels being observed at the 5th week after the beginning of the experiment. These results indicate that high capacity thyroid hormone binding autoantibodies may actually reduce thyroid hormone disposal at cellular level, at least prior to the attainment of steady state T3- antibody hormone binding.

The rate of liver mitochondrial alpha-glycerophosphate dehydrogenase (GPD) induction was compared to the suppression of pituitary thyrotropin (TSH) secretion in thyroidectomized rats submitted to prolonged administration of small amounts of L-thyroxine (T4). With both 350 and 530 ng T4/100 g bw/day, liver alpha-GPD activity remained at post-thyroidectomy level (mean +/- SE: 0.030 +/- 0.002 and 0.034 +/- 0.001 delta A/mg prot/min, respectively) throughout all experiment. A sharp increase in enzyme activity was observed after 3 weeks of treatment in rats receiving 715 ng T4 / 100 g bw / day (mean +/- SE: 0.086 +/- 0.003 delta A/mg prot/min). In contrast, serum TSH levels were lower than pretreatment values (199 +/- 8ng/dI) in rats receiving 350 ng T4/100 g bw/day (mean +/- SE: 104 +/- 15 ng/dI; t = 7.48, p less than 0.001), decreased progressively with increasing T4 doses (m +/- SE:530 ng T4/100 g/day = 36 +/- 7 ng/dI); after only 48 h of treatment and were not significantly modified thereafter. The data are in agreement with the hypothesis of a nonlinear relationship between the degree of thyroid hormone receptor occupancy and the rate of liver mitochondrial alpha-GPD induction.

Thyroid hormones (TH) have been shown to exert a direct stimulatory effect on the Ca++-dependent ATPase from human and other mammalian erythrdcytes. In this in vitro system, T4 has been shown to be more effective than T3. In the present study, TH effects on Ca++-dependent ATPase were investigated, using rabbit and human erythrocyte membranes, after preincubation with 10−10M T4, in the presence or in the absence of exogenous calmodulin (CaM) (5.10−12M to 5.10−9 M). Ca++-dependent ATPase activity was measured as inorganic phosphate (Pi) release from 1 mM ATP. The results showed that basal Ca++-dependent ATPase activity in rabbits was moderately increased by T4 (1.44 ± 0.05 vs 1.32 ± 0.04 μmol Pi/mg protein/90 min, mean ± SE; p

This paper describes the identification of circulating autoantibodies to thyroid hormones in 5 patients with Graves’ disease (n = 2), Hashimoto’s thyroiditis (n = 1), primary myxedema (n = 1) and Sjogren syndrome (n = 1) out of 351 individuals. The 351 patients suffered from different autoimmune thyroid disorders, thyroid cancer or lymphoreticular system disorders as well as autoimmune non thyroid illnesses. Immunoglobulin G (IgG) binding of one or both tracer thyroid hormones and in one case also of reverse triiodothyronine, was demonstrated by radioimmunoprecipitation experiments and by reverse flow zone electrophoresis or cellulose acetate electrophoresis and autoradiography. In all cases the binding of radiolabeled thyroid hormones to IgG was displaced by an excess of the respective non radioactive thyroid hormone. Thyroglobulin displaced the binding in 2 cases but preadsorption with human thyroglobulin was ineffective in other 2 cases. Radioimmunoelectrophoresis and autoradiography of the Immunoelectrophoresis plates indicated that in 2 cases the light chains involved in the binding were k chains of the G3 subclass and to a lesser extent of the G1 subclass, in another case they were λ chains and therefore of restricted heterogeneity. In a case of myxedema coma IgG were polyclonal (k and λ chains of the G1 > G2 > G3 subclasses). The thyroxine (T4) or triiodothyronine (T3) antibodies interfere with the hormone measurement in unextracted serum by falsely lowering their concentrations when non specific separation methods are used and raising their concentrations when double antibody radioimmunoassays are used.In one serum containing anti-T4 antibodies, the association constant (Ka) was 0.63 × 106 l/M and absolute binding (Ab0) was1.54 x10-7 l/M. In another serum with anti-T3 IgG, Ka was 4.44 × 107 l/M and Abo 6.22 × 10-9 l/M. In the case of myxedema coma Ka ranged between 3.1 and 4.3 × 108 l/M.

A 30-yr-old woman with allergic rhinitis and multinodular goiter developed atopic manifestations on different desiccated thyroid extract treatment. Urticaria was observed when the patient was on L-T4 treatment; no atopy was experienced during L-T3 regimen. Serum total immunoglobulin E (IgE) concentration was 390 +/- 7kU/liter (mean +/- SD) prior to any treatment and rose to 850 +/- 7.5 kU/liter when the patient developed urticaria, but declined to baseline figures while she was on L-T3. Intracutaneous testing was positive for desiccated pork thyroid powder, L-T4 and D-T4, but negative for L-T3, DIT and L-tyrosine. Immunoradioligand analyses of mixtures of patient's serum or precipitated immunoglobulin fraction and of 125I-T4 or of 125I-T3 revealed binding of radiolabeled thyroxine to the patient's serum IgE, in turn bound to anti-human-IgE serum covalently coupled to paper discs. This binding was completely inhibited by the preincubation of immunoglobulin fraction with excess unlabeled L-T4 and D-T4, but not with excess nonradioactive L-T3, thus proving the specificity of the binding. Preadsorption experiments performed with desiccated pork thyroid powder solution mixed with the patient's immunoglobulin fraction suggested binding of some unknown component(s) of desiccated thyroid which was apparently not thyroglobulin. This study provides evidence of IgE antibodies to L-T4 cross reacting with D-T4 and capable of binding 125I-T4 in serum. It also suggests a model for the detection of circulating IgE antibodies to thyroid hormones.