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L Bartalena, F Bogazzi, S Brogioni, L Grasso, and E Martino
E. Martino, S. Grasso, G. Bambini, G. Pardo, P. Vitti, F. Aghini-Lombardi, and A. Pinchera
Abstract. The ontogeny of thyrotropin-releasing hormone (TRH) in pancreata of human foetuses from 15–36 weeks of gestation and of infants has been studied. TRH was detectable in the pancreas of a 15 week old foetus; a progressive increase of pancreatic TRH content was observed until the 34th week of gestation, whereas a progressive decrease was found in the late period of pregnancy and in 1 year old infants. In contrast, the pancreatic insulin content showed a progressive increase during the entire pregnancy and in the first year after birth. These data indicate that TRH and insulin have different ontogenetic patterns in the human pancreas.
F Bogazzi, L Bartalena, S Brogioni, A Burelli, L Manetti, ML Tanda, M Gasperi, and E Martino
OBJECTIVE: Thyroid blood flow is greatly enhanced in untreated Graves' disease, but it is not known whether it is due to thyroid hormone excess or to thyroid hyperstimulation by TSH-receptor antibody. To address this issue in vivo patients with different thyroid disorders were submitted to color flow doppler sonography (CFDS). SUBJECTS AND METHODS: We investigated 24 normal subjects, and 78 patients with untreated hyperthyroidism (49 with Graves' hyperthyroidism, 24 with toxic adenoma, and 5 patients with TSH-secreting pituitary adenoma (TSHoma)), 19 patients with thyrotoxicosis (7 with thyrotoxicosis factitia, and 12 with subacute thyroiditis), 37 euthyroid patients with goitrous Hashimoto's thyroiditis, and 21 untreated hypothyroid patients with Hashimoto's thyroiditis. RESULTS: Normal subjects had CFDS pattern 0 (absent or minimal intraparenchimal spots) and mean intraparenchimal peak systolic velocity (PSV) of 4.8+/-1.2cm/s. Patients with spontaneous hyperthyroidism due to Graves' disease, TSHoma, and toxic adenoma had significantly increased PSV (P<0.0001, P=0.0004, P<0.0001 respectively vs controls) and CFDS pattern. Patients with Graves' disease had CFDS pattern II (mild increase of color flow doppler signal) in 10 (20%) and pattern III (marked increase) in 39 cases (80%). Mean PSV was 15+/-3cm/s. Patients with toxic adenoma had CFDS pattern I (presence of parenchymal blood flow with patchy uneven distribution) in 2 (8%), pattern II in 16 (70%) and pattern III in 5 (22%). Mean PSV was 11+/-2.4cm/s. Patients with TSHoma showed CFDS pattern I in one case (20%) and pattern II in 4 (80%). Mean PSV was 14.8+/-4.2cm/s. Patients with thyrotoxicosis had normal PSV (4.2+/-1. 1cm/s in subacute thyroiditis, 4+/-0.8cm/s in thyrotoxicosis factitia, P=not significant vs controls) and CFDS pattern 0. Untreated euthyroid patients with goitrous Hashimoto's thyroiditis had CFDS pattern 0, and mean PSV (4.3+/-0.9cm/s; P=not significant vs controls). Untreated hypothyroid patients with goitrous Hashimoto's thyroiditis had CFDS pattern I in 14 cases (67%), pattern II in 4 (19%) and pattern 0 in 3 (14%) and mean PSV (5.6+/-1. 4cm/s) was higher than that of controls (P=0.026). CONCLUSIONS: An increase in both intrathyroidal vascularity and blood velocity was observed in patients with spontaneous hyperthyroidism but not in thyrotoxicosis due to either ingestion of thyroid hormones or to a thyroidal destructive process. The slightly increased vascularity and blood velocity observed in patients with hypothyroid Hashimoto's thyroiditis suggests that thyroid stimulation by either TSH-receptor antibody or TSH is responsible for the increased thyroid blood flow.
C Cappelli, I Pirola, M Castellano, E Gandossi, E De Martino, A Delbarba, B Agosti, A Tironi, and E Agabiti Rosei
Objective: To evaluate whether a preliminary aspiration (ASP) of the cystic component and/or using spinal needles in complex thyroid nodules (CTN) could improve the adequacy of cytological sampling.
Methods: Between January 2004 and December 2006, 386 consecutive patients with CTN were enrolled in this prospective investigation. Ultrasound (US) fine needle aspiration cytology (FNAC) of the solid component of the nodule (one nodule per patient) was performed using two different 25 gauge needles, with (Yale Spinal, YS) or without (Neolus, NS) a stylet, in alternate sequence on consecutive patients. In addition, a subgroup of patients presenting larger cystic component (∼50%) was submitted to total aspiration of the cystic component (ASP+) or not submitted (ASP−) before US-FNAC, in alternate sequence within each needle type group. All the samplings were performed by a single endocrinologist.
Results: Adequate specimens were observed in 163 (84.5%) and 183 (94.8%) nodules investigated by NS and YS respectively. Sampling with the stylet needle was associated with an overall significant reduction of non-diagnostic specimens (15.5% vs 5.2% by NS and YS respectively, P < 0.001). The favourable result obtained with YS was independent from preliminary aspiration of the cystic component (ASP+: 14.8% vs 5.7% by NS and YS; ASP−: 16.2% vs 4.8%, not significant). A logistic regression analysis, taking into account nodule size and presence of intranodal vascularity at eco-colour evaluation of the solid component, confirmed that needle type was the only significant predictor of successful sampling (odds ratio 3.6 (95% confidence interval 1.7–7.6), P < 0.001).
Conclusions: Our data show that adopting stylet needles to perform FNAC in CTN may significantly improve the percentage of adequate sampling. On the other hand, preliminary aspiration of CTN with large cystic component does not add any advantage.
E Macchia, M Gurnell, M Agostini, G Giorgilli, C Marcocci, TM Valenti, E Martino, KK Chatterjee, and A Pinchera
We have investigated an Italian family with generalized resistance to thyroid hormone (RTH), consisting of two individuals with elevated serum thyroid hormones (TH) and a non-suppressed TSH, together with unaffected family members, for a mutation in the thyroid hormone receptor beta gene (hTR beta). We have identified a single nucleotide substitution (1321 CTT to GTT) corresponding to a leucine to valine substitution at codon 346 (L346V) in the predicted protein. The index case and her affected child are heterozygous for the receptor defect, with normal sequence in unaffected family members. Furthermore, both parents of the index case were unaffected, suggesting that the mutation had arisen de novo. When expressed in vitro, the L346V mutant receptor showed a marked reduction in its affinity for tri-iodothyronine (T3), impaired ligand-dependent transactivation and potent dominant negative activity. Its functional impairment could not be alleviated, even at supraphysiological concentrations of T3, suggesting that the mutation might interfere with the intrinsic ligand-dependent transactivation function (AF-2) located in the hormone binding domain of hTR beta. Finally, the presence of the L346V mutation in the son of the propositus, who died from complications associated with congenital heart disease, raises the possibility that RTH might have contributed to the pathogenesis or severity of the latter.
E. Martino, L. Bartalena, S. Mariotti, F. Aghini-Lombardi, C. Ceccarelli, F. Lippi, M. Piga, A. Loviselli, L. Braverman, M. Safran, and A. Pinchera
Abstract. Amiodarone, an iodine-rich drug, represents at the present, at least in Europe, one of the most common sources of iodine-induced thyroid dysfunction. The drug may induce both hypothyroidism and thyrotoxicosis. In spite of the large iodine intake occurring during amiodarone therapy, 131I thyroid uptake is detectable in patients with amiodarone-iodine-induced hypothyroidism, irrespective of the presence or absence of underlying thyroid disease. In contrast, in patients with amiodarone-iodine-induced thyrotoxicosis, 131I thyroid uptake is normal or even elevated in those with co-existent underlying thyroid disorders, whereas it is very low in those with an apparently normal thyroid gland. Perchlorate discharge test was performed in 8 patients with hypothyroidism and in 5 patients with hyperthyroidism induced by amiodarone: a positive test was found in all hypothyroid patients and a negative test in all hyperthyroid patients.
C Urbani, C Sardella, A Calevro, G Rossi, I Scattina, M Lombardi, I Lupi, L Manetti, E Martino, and F Bogazzi
Objective
Abnormalities of glucose metabolism are common findings of acromegaly. However, robust evidence on whether therapy with somatostatin analogs (SSAs) or pegvisomant (PEG) differently affects glucose metabolism is lacking. The purpose of this study was to evaluate the effects of therapy with SSAs, PEG, or their combination on glucose metabolism in a large series of acromegalic patients.
Design
This was a historical–prospective study. Among 50 consecutive acromegalic patients under SSA therapy, acromegaly in 19 patients was controlled. PEG used in combination with SSA therapy allowed the control of acromegaly in the remaining 31 patients and was then continued as monotherapy in 18 patients.
Methods
The following parameters were evaluated at the diagnosis of acromegaly and during different treatments: fasting plasma glucose (FPG) and insulin concentrations, insulin sensitivity (QUICK-I), homeostasis model assessment of insulin resistance (HOMA2-IR), and plasma glucose and insulin concentrations during the oral glucose tolerance test (OGTT). Comparison was made using analysis for paired data.
Results
Insulin resistance improved when acromegaly was controlled with therapy with SSAs, PEG, or SSA+PEG. However, FPG concentrations were higher during SSA therapy (alone or combined with PEG) than at the diagnosis of acromegaly, even when corrected for disease activity, whereas they were reduced during PEG therapy. Mean glucose concentrations during the OGTT were higher in patients receiving SSA therapy than in those receiving PEG therapy. In addition, the prevalence of diabetes or impaired glucose tolerance was higher during SSA therapy than at diagnosis or during PEG therapy and was not influenced by disease control.
Conclusions
Medical therapies for acromegaly reduce insulin resistance and increase insulin sensitivity; on the contrary, glucose indexes may be differently affected by SSA or PEG therapy.
Lisa L Morselli, Arlet Nedeltcheva, Rachel Leproult, Karine Spiegel, Enio Martino, Jean-Jacques Legros, Roy E Weiss, Jean Mockel, Eve Van Cauter, and Georges Copinschi
Objectives
We previously reported that adult patients with GH deficiency (GHD) due to a confirmed or likely pituitary defect, compared with healthy controls individually matched for age, gender, and BMI, have more slow-wave sleep (SWS) and higher delta activity (a marker of SWS intensity). Here, we examined the impact of recombinant human GH (rhGH) therapy, compared with placebo, on objective sleep quality in a subset of patients from the same cohort.
Design
Single-blind, randomized, crossover design study.
Methods
Fourteen patients with untreated GHD of confirmed or likely pituitary origin, aged 22–74 years, participated in the study. Patients with associated hormonal deficiencies were on appropriate replacement therapy. Polygraphic sleep recordings, with bedtimes individually tailored to habitual sleep times, were performed after 4 months on rhGH or placebo.
Results
Valid data were obtained in 13 patients. At the end of the rhGH treatment period, patients had a shorter sleep period time than at the end of the placebo period (479±11 vs 431±19 min respectively; P=0.005), primarily due to an earlier wake-up time, and a decrease in the intensity of SWS (delta activity) (559±125 vs 794±219 μV2 respectively; P=0.048).
Conclusions
Four months of rhGH replacement therapy partly reversed sleep disturbances previously observed in untreated patients. The decrease in delta activity associated with rhGH treatment adds further evidence to the hypothesis that the excess of high-intensity SWS observed in untreated pituitary GHD patients is likely to result from overactivity of the hypothalamic GHRH system due to the lack of negative feedback inhibition by GH.
F Bogazzi, L Bartalena, S Brogioni, A Burelli, F Raggi, F Ultimieri, C Cosci, M Vitale, G Fenzi, and E Martino
OBJECTIVE: To evaluate the molecular mechanisms of the inhibitory effects of amiodarone and its active metabolite, desethylamiodarone (DEA) on thyroid hormone action. MATERIALS AND METHODS: The reporter construct ME-TRE-TK-CAT or TSHbeta-TRE-TK-CAT, containing the nucleotide sequence of the thyroid hormone response element (TRE) of either malic enzyme (ME) or TSHbeta genes, thymidine kinase (TK) and chloramphenicol acetyltransferase (CAT) was transiently transfected with RSV-TRbeta into NIH3T3 cells. Gel mobility shift assay (EMSA) was performed using labelled synthetic oligonucleotides containing the ME-TRE and in vitro translated thyroid hormone receptor (TR)beta. RESULTS: Addition of 1 micromol/l T4 or T3 to the culture medium increased the basal level of ME-TRE-TK-CAT by 4.5- and 12.5-fold respectively. Amiodarone or DEA (1 micromol/l) increased CAT activity by 1.4- and 3.4-fold respectively. Combination of DEA with T4 or T3 increased CAT activity by 9.4- and 18.9-fold respectively. These data suggested that DEA, but not amiodarone, had a synergistic effect with thyroid hormone on ME-TRE, rather than the postulated inhibitory action; we supposed that this was due to overexpression of the transfected TR into the cells. When the amount of RSV-TRbeta was reduced until it was present in a limited amount, allowing competition between thyroid hormone and the drug, addition of 1 micromol/l DEA decreased the T3-dependent expression of the reporter gene by 50%. The inhibitory effect of DEA was partially due to a reduced binding of TR to ME-TRE, as assessed by EMSA. DEA activated the TR-dependent down-regulation by the negative TSH-TRE, although at low level (35% of the down-regulation produced by T3), whereas amiodarone was ineffective. Addition of 1 micromol/l DEA to T3-containing medium reduced the T3-TR-mediated down-regulation of TSH-TRE to 55%. CONCLUSIONS: Our results demonstrate that DEA, but not amiodarone, exerts a direct, although weak, effect on genes that are regulated by thyroid hormone. High concentrations of DEA antagonize the action of T3 at the molecular level, interacting with TR and reducing its binding to TREs. This effect may contribute to the hypothyroid-like effect observed in peripheral tissues of patients receiving amiodarone treatment.
Elio Roti, Luigi Bartalena, Roberta Minelli, Mario Salvi, Eliana Gardini, Antonio Pistolesi, Enio Martino, and Lewis E Braverman
Roti E, Bartalena L, Minelli R, Salvi M, Gardini E, Pistolesi A, Martino E, Braverman LE. Circadian thyrotropin variations are preserved in normal pregnant women. Eur J Endocrinol 1995;133:71–4. ISSN 0804–4643
Serum thyrotropin (TSH) concentration circadian rhythm is abolished in many endocrine and nonendocrine diseases. In the present study we have measured serum TSH concentration over 24 h every 2 h in second and third trimester pregnant women. During the 24-h period, serum free thyroxine and free triiodothyronine concentrations did not change significantly. In contrast, serum TSH concentrations demonstrated significant circadian variations both in the second and third trimester pregnant women (p<0.02 and p <0.005, respectively). In summary, second and third trimester pregnancy is associated with a normal circadian TSH rhythm.
Elio Roti, Centro per lo Studio, Prevenzione, Diagnosi e Cura delle Tireopatie, University of Parma, via Gramsci 14, 1-43100 Parma, Italy