Duration of Exposure to Thyrotoxicosis Increases Mortality of Compromised AIT Patients: the Role of Early Thyroidectomy.

CONTEXT: Patients with amiodarone-induced thyrotoxicosis (AIT) and severely reduced left ventricular ejection fraction (LVEF) have a high mortality rate that may be reduced by total thyroidectomy. Whether in this subset of patients thyroidectomy should be performed early during thyrotoxicosis or later after restoration of euthyroidism has not yet been settled. OBJECTIVES: Mortality rates, including peritreatment mortality and 5-year cardiovascular mortality, and predictors of death, evaluated by Cox regression analysis. METHODS: Retrospective cohort study of 64 consecutive patients with AIT selected for total thyroidectomy from 1997 to 2019. Four groups of patients were identified according to serum thyroid hormone concentrations and LVEF: Group 1 (thyrotoxic, LVEF <40%), Group 2 (thyrotoxic, LVEF ≥40%), Group 3 (euthyroid, LVEF < 40%), Group 4 (euthyroid, LVEF ≥40%). RESULTS: Among patients with low LVEF (Groups 1 and 3), mortality was higher in patients undergoing thyroidectomy after restoration of euthyroidism (Group 3) than in those submitted to surgery when still thyrotoxic (Group 1): peritreatment mortality rates were 40% versus 0%, respectively (P = .048), whereas 5-year cardiovascular mortality rates were 53.3% versus 12.3%, respectively (P = .081). Exposure to thyrotoxicosis was longer in Group 3 than in Group 1 (112 days, interquartile range [IQR] 82.5-140, vs 76 days, IQR 24.8-88.5, P = .021). Survival did not differ in patients with LVEF ≥40% submitted to thyroidectomy irrespective of being thyrotoxic (Group 2) or euthyroid (Group 4): in this setting, peritreatment mortality rates were 6.3% versus 4% (P = .741) and 5-year cardiovascular mortality rates were 12.5% and 20% (P = .685), respectively. Age (hazard ratio [HR] 1.104, P = .029) and duration of exposure to thyrotoxicosis (HR 1.004, P = .039), but not presurgical serum thyroid hormone concentrations (P = .577 for free thyroxine, P = .217 for free triiodothyronine), were independent predictors of death. CONCLUSIONS: A prolonged exposure to thyrotoxicosis resulted in increased mortality in patients with reduced LVEF, which may be reduced by early thyroidectomy.

Comparison Between Total Thyroidectomy and Medical Therapy for Amiodarone-Induced Thyrotoxicosis.

CONTEXT: It is not known whether total thyroidectomy is more favorable than medical therapy for patients with amiodarone-induced thyrotoxicosis (AIT). OBJECTIVE: To compare total thyroidectomy with medical therapy on survival and cardiac function in AIT patients. METHODS: Observational longitudinal cohort study involving 207 AIT patients that had received total thyroidectomy (surgery group, n = 51) or medical therapy (medical therapy group, n = 156) over a 20-year period. AIT types and left ventricular ejection fraction (LVEF) classes were determined at diagnosis of AIT. Cardiac and thyroid function were reevaluated during the study period. Survival was estimated using the Kaplan-Meier method. RESULTS: Overall mortality and cardiac-specific mortality at 10 and 5 years, respectively, were lower in the surgery group than in the medical therapy group (P = 0.04 and P = 0.01, respectively). The lower mortality rate of the surgery group was due to patients with moderate to severely compromised LVEF (P = 0.005 vs medical therapy group). In contrast, mortality of patients with normal or mildly reduced LVEF did not differ between the 2 groups (P = 0.281 and P = 0.135, respectively). Death of patients with moderate to severe LV systolic dysfunction in the medical therapy group occurred after 82 days (interquartile range, 56-99), a period longer than that necessary to restore euthyroidism in the surgery group (26 days; interquartile range, 15-95; P = 0.038). Risk factors for mortality were age (hazard ratio [HR] = 1.036) and LVEF (HR = 0.964), whereas total thyroidectomy was shown to be a protective factor (HR = 0.210). LVEF increased in both groups after restoration of euthyroidism, above all in the most compromised patients in the surgery group. CONCLUSIONS: Total thyroidectomy could be considered the therapeutic choice for AIT patients with severe systolic dysfunction, whereas it is not superior to medical therapy in those with normal or mildly reduced LVEF.

Diabetes insipidus is an unfavorable prognostic factor for response to glucocorticoids in patients with autoimmune hypophysitis.

INTRODUCTION: Autoimmune hypophysitis (AH) has a variable clinical presentation and natural history; likewise, its response to glucocorticoid therapy is often unpredictable. OBJECTIVE: To identify clinical and radiological findings associated with response to glucocorticoids. DESIGN AND METHODS: 12 consecutive patients with AH, evaluated from 2008 to 2016. AH was the exclusion diagnosis after ruling out other pituitary masses and secondary causes of hypophysitis. Mean follow-up time was 30 ± 27 months (range 12-96 months). RESULTS: MRI identified two main patterns of presentation: global enlargement of the pituitary gland or panhypophysitis (n = 4, PH), and pituitary stalk abnormality only, or infundibulo-neuro-hypophysitis (n = 8, INH). Multiple tropin defects were more common in PH (100%) than those in INH (28% P = 0.014), whereas diabetes insipidus was more common in INH (100%) than that in PH (50%; P = 0.028). All 4 PH and 4 out of 8 INH were treated with glucocorticoids. Pituitary volume significantly reduced in all PH patients (P = 0.012), defective anterior pituitary function recovered only in the two patients without diabetes insipidus (50%) and panhypopituitarism persisted, along with diabetes insipidus, in the remaining 2 (50%). In all INH patients, either treated or untreated, pituitary stalk diameter reduced (P = 0.008) but diabetes insipidus persisted in all. CONCLUSIONS: Glucocorticoid therapy may improve anterior pituitary function in a subset of patients but has no effect on restoring posterior pituitary function. Diabetes insipidus appears as a negative prognostic factor for response to glucocorticoids.

Disease activity and lifestyle influence comorbidities and cardiovascular events in patients with acromegaly.

OBJECTIVE: The primary objective of this study is to identify the predictors of comorbidities and major adverse cardiovascular events (MACE) that can develop after diagnosis of acromegaly. The role of therapy for acromegaly in the event of such complications was also evaluated. DESIGN AND METHODS: Retrospective cohort study was conducted on 200 consecutive acromegalic patients in a tertiary referral center. The following outcomes were evaluated: diabetes, hypertension and MACE. Each patient was included in the analysis of a specific outcome, unless they were affected when acromegaly was diagnosed, and further classified as follows: (i) in remission after adenomectomy (Hx), (ii) controlled by somatostatin analogues (SSA) (SSAc) or (iii) not controlled by SSA (SSAnc). Data were evaluated using Cox regression analysis. RESULTS: After diagnosis of acromegaly, diabetes occurred in 40.8% of patients. The SSAnc group had a three-fold higher risk of diabetes (HR: 3.32, P = 0.006), whereas the SSAc group had a 1.4-fold higher risk of diabetes (HR: 1.43, P = 0.38) compared with the Hx group. Hypertension occurred in 35.5% of patients, after diagnosis. The determinants of hypertension were age (HR: 1.06, P = 0.01) and BMI (HR: 1.05, P = 0.01). MACE occurred in 11.8% of patients, after diagnosis. Age (HR: 1.09, P = 0.005) and smoking habit (HR: 5.95, P = 0.01) were predictors of MACE. Conversely, therapy for acromegaly did not influence hypertension or MACE. CONCLUSION: After diagnosis of acromegaly, control of the disease (irrespective of the type of treatment) and lifestyle are predictors of comorbidities and major adverse cardiovascular events.

Divergent Effects of Dioxin- or Non-Dioxin-Like Polychlorinated Biphenyls on the Apoptosis of Primary Cell Culture from the Mouse Pituitary Gland.

Polychlorinated biphenyls (PCBs) can disrupt the endocrine function, promote neoplasms and regulate apoptosis in some tissues; however, it is unknown whether PCBs can affect the apoptosis of pituitary cells. The study evaluated the effect of PCBs on the apoptosis of normal pituitary cells and the underlying mechanisms. Primary cell cultures obtained from mouse pituitary glands were exposed to Aroclor 1254 or selected dioxin-like (PCB 77, PCB 126) or non-dioxin-like (PCB 153, PCB 180) congeners. Apoptosis was evaluated by Annexin V staining, DNA fragmentation, and TUNEL assay. Both the expression and activity of caspases were analyzed. Selective thyroid hormone receptor (TR) or aryl-hydrocarbon receptor (AhR) or CYP1A1 antagonist were used to explore the mechanisms underlying PCBs action. Our results showed that Aroclor 1254 induced the apoptosis of pituitary cells as well as the final caspase-3 level and activity through the extrinsic pathway, as shown by the increased caspase-8 level and activity. On the other hand, the intrinsic pathway evaluated by measuring caspase-9 expression was silent. The selected non-dioxin-like congeners either increased (PCB 180) or reduced (PCB 153) pituitary cell apoptosis, affecting the extrinsic pathway (PCB 180), or both the extrinsic and intrinsic pathways (PCB 153), respectively. In contrast, the dioxin-like congeners (PCB 77 and PCB 126) did not affect apoptosis. The anti-apoptotic phenotype of PCB 153 was counteracted by a TR or a CYP1A1 antagonist, whereas the pro-apoptotic effect of PCB 180 was counteracted by an AhR antagonist. The induced apoptosis of Aroclor 1254 or PCB 180 was associated with a reduction of cell proliferation, whereas the decreased apoptosis due to PCB 153 increased cell proliferation by 30%. In conclusion, our data suggest that non-dioxin-like PCBs may modulate apoptosis and the proliferation rate of pituitary cells that have either pro- or anti-apoptotic effects depending on the specific congeners. However, the impact of PCBs on the process of pituitary tumorigenesis remains to be elucidated.

Clinical and genetic characteristics of a large monocentric series of patients affected by thyroid hormone (Th) resistance and suggestions for differential diagnosis in patients without mutation of Th receptor ß.

OBJECTIVE: The syndrome of resistance to thyroid hormone (RTH) is caused by a mutation of TH receptor ß (TRß) in 80% of cases. Patients without mutation (non-TR-RTH) may have a biochemical pattern that is difficult to differentiate from that of pituitary TSH-secreting adenoma (TSHoma). Herein, we report a large monocentric series of RTH focusing on patients with non-TR-RTH, to evaluate possible clinical or biochemical parameters able to distinguish them from TSHoma. DESIGN AND PATIENTS: We retrospectively reviewed the data of 99 consecutive patients with inappropriate TSH secretion (IST) syndrome referred to our Department between 1983 and 2011, identifying 68 patients with RTH and 31 patients with TSHomas. MEASUREMENTS: Patient records were reviewed for the main clinical, biochemical and imaging characteristics. RESULTS: Of our 68 patients with RTH, 16 (23·5%) did not show a TRß mutation and did not have affected family members. Of these 16 patients, three developed a TSHoma, during follow-up. To distinguish non-TR-RTH from TSHoma, we identified appropriate cut-off values for the main biochemical parameters that demonstrated the greatest sensitivity and specificity (T3 suppression test, α-subunit/TSH molar ratio, α-subunit assay and TRH test) and we calculated the probability for each patient to develop a TSHoma. CONCLUSIONS: The application of the identified cut-offs could become a very useful tool in the challenging differential diagnosis between sporadic non-TR-RTH and TSHoma. It would then be possible to select the patients at higher risk of developing a TSHoma and therefore needing a closer follow-up.

Growth hormone is necessary for the p53-mediated, obesity-induced insulin resistance in male C57BL/6J x CBA mice.

Insulin resistance is a key marker of both obesity and GH excess. The purpose of the study was to assess the role of GH on p53-mediated insulin resistance of male mice with obesity due to a high-fat diet. C57BL/6J × CBA male mice fed on a high-fat diet (Obe) were studied; male mice fed a normal diet (Lean) or transgenic mice for bovine GH under the same genetic background (Acro) served as controls. The convergence of p53 and GH pathways was evaluated by Western blot. Obe mice had insulin resistance, which was sustained by a selective increased expression of p53 in adipose tissue. Normal insulin sensitivity was restored, and adipose p53 expression normalized when the GH pathway was blocked. Only the adipose p53 expression was sensitive to the GH blockage, which occurred through the p38 pathway. Adipose tissue of Obe mice had a coordinate overexpression of suppressors of cytokine signal 1-3 and signal transducers and activators of transcription-1, -3, and -5b, not different from that of Acro mice, suggesting an increased sensitivity of adipose tissue to GH. On the contrary, Lean mice were unaffected by changes of GH action. GH seems to be necessary for the increased adipose p53 expression and for insulin resistance of obese mice.

Comparison of the effects of primary somatostatin analogue therapy and pituitary adenomectomy on survival in patients with acromegaly: a retrospective cohort study.

OBJECTIVE: Acromegalic patients have an increased risk of mortality. The objective of this study was to compare the effect of different therapies for acromegaly on mortality. DESIGN AND METHODS: The mortality rate of 438 consecutive acromegalic patients was compared with that of the general population using the standardized mortality ratio (SMR); the effect of different therapies on survival was evaluated using Cox regression analysis. RESULTS: Twenty patients (4.5%) died between 1999 and 2009. Age- and sex-adjusted SMR was 0.70 (95% CI 0.43-1.08). The Cox regression analysis revealed that, in the whole population, both general risk factors (age and physical status) and specific factors for acromegaly (macroadenoma, hypopituitarism and uncontrolled disease) were associated with death. The most compromised patients at diagnosis had a higher mortality rate (P=0.001), which also occurred in patients with controlled acromegaly. Death occurred in 2.4% (adenomectomy), 2.6% (adenomectomy followed by somatostatin analogue (SSA) therapy) and 11.4% (SSA therapy as the primary therapy) of the patients. The risk of death was higher in patients receiving SSA therapy as the primary therapy (hazard ratio (HR) 5.52, 95% CI 1.06-28.77, P=0.043) than in all patients submitted to adenomectomy; however, a higher risk of death occurred only in diabetic patients treated with SSAs alone (HR 21.94, 95% CI 1.56-309.04, P=0.022). Radiotherapy was associated with an increased risk of mortality, which occurred in patients with the more locally advanced disease. CONCLUSIONS: Therapies for acromegaly and comorbidities have lowered the risk of mortality to the level of the general population; the effect of SSA therapy alone or that following pituitary adenomectomy was comparable to that of curative neurosurgery on survival in non-diabetic patients; on the contrary, SSA therapy as the primary therapy may be less effective than adenomectomy in reducing mortality rate in diabetic patients.

Impact of GH replacement therapy on sleep in adult patients with GH deficiency of pituitary origin.

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 µV(2) 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.

Total thyroidectomy in patients with amiodarone-induced thyrotoxicosis and severe left ventricular systolic dysfunction.

CONTEXT: Patients with amiodarone-induced thyrotoxicosis (AIT) and left ventricular (LV) systolic dysfunction have a high mortality rate. Usually, medical therapy is the first choice for AIT patients, whereas the role of the thyroidectomy is unsettled. OBJECTIVE: The objective of the study was to evaluate the effect of a total thyroidectomy on cardiac function and survival of AIT patients with severe LV systolic dysfunction. DESIGN: This was a retrospective cohort study. SETTINGS: The study was conducted at a tertiary university center. PATIENTS: All AIT patients (n=24; nine patients with type 1 AIT, 15 patients with type 2 AIT) referred to the Department of Endocrinology and submitted to a total thyroidectomy at the Department of Surgery, both at the University of Pisa, during the years 1997-2010. INTERVENTION: The intervention was a total thyroidectomy. MAIN OUTCOME MEASURE: LV ejection fraction (EF) after the thyroidectomy and survival in December 2011 were measured. RESULTS: All enrolled patients had previously undergone to medical treatment for AIT, as appropriate, without achieving euthyroidism. Patients with moderate to severe LV systolic dysfunction (EF<40%, group 1, n=9) or with mild systolic dysfunction (40%≤EF≤50%, group 2, n=5) were compared with patients with normal systolic function (EF>50%, group 3, n=10). Two months after thyroidectomy, under levothyroxine replacement therapy, LVEF improved in patients with LV systolic dysfunction, particularly in those of group 1, in whom it increased from 28.2±7.2 to 38.3±6% (P=0.007). On the contrary, LVEF did not significantly change in group 3 (from 57.1±3.0 to 59.8±6.6%, P=0.242). The mean follow-up was 67±42 months. No death occurred during and 2 months after surgery. One death occurred in one patient of group 1, 30 months after the thyroidectomy, due to acute myocardial infarction. No patient had relevant complications of thyroidectomy. CONCLUSIONS: Total thyroidectomy, by rapidly restoring euthyroidism, may improve cardiac function and reduce the risk of mortality in AIT patients with severe LV dysfunction.

Hashimoto's thyroiditis in a benign cystic teratoma of the ovary: case report and literature review.

Ectopic thyroid tissue in ovarian teratoma or in struma ovarii appears to be histologically identical to the thyroid gland tissue and may virtually exhibit all the pathological patterns found in the thyroid gland. However, the concurrent lymphocytic infiltration of the thyroid gland, as found in Hashimoto's thyroiditis, and of the ectopic thyroid tissue is extremely rare. We describe the case of an 18-years old patient, in which a right ovarian 4 cm cyst has been found during pelvic ultrasound exam. The cyst was resected and microscopic examination of the mass revealed a mature cystic teratoma in which epidermal-like lining with skin adnexa, admixed with respiratory type epithelium, and areas of mature fatty, chondroid and dentigerous tissues were found. In a peripheral area of 0.7 cm  × â€Š0.5 cm, a prominent lymphocytic infiltrate surrounding thyroid follicles was identifiable. Thyroid function evaluation at different time points after surgery, revealed the development of mild hypothyroidism. Anti-TPO and anti-Tg autoantibodies were elevated, at fine needle aspiration biopsy a lymphocytic infiltrate, compatible with Hashimoto's thyroiditis, was present. We report here a rare case of Hashimoto's thyroiditis occurring both in the thyroid and in the ectopic thyroid tissue in the context of a benign cystic teratoma of the ovary.

A functioning FSH-secreting pituitary macroadenoma causing an ovarian hyperstimulation syndrome with multiple cysts resected and relapsed after leuprolide in a reproductive-aged woman.

Bioactive gonadotropin-secreting pituitary adenomas are very rare in fertile women and can cause an ovarian hyperstimulation syndrome (OHSS). A 31-year-old woman with oligo-amenorrhea, severe ovarian cystic swelling and high serum estradiol was submitted to the resection of ovarian cysts and then treated with long-acting leuprolide 11.25 mg. Two months later, the ovarian multicystic hyperplasia relapsed, thus a pituitary MRI was performed and a pituitary macroadenoma was detected. In January 2010, she was referred to our Endocrinology Department where her hormonal evaluation showed high serum estradiol, FSH, α-subunit and inhibin with low LH. In April 2010, she underwent a trans-sphenoidal pituitary adenomectomy, which rapidly regularized the hormonal profile, the ovary and pituitary morphology and the menses. The case presented confirms that gonadotrophinomas occurring in reproductive-aged women frequently produce symptoms of ovarian hyperstimulation and proves that the use of GnRH analogs is not indicated in this condition.

Impact of different cut-off limits of peak GH after GHRH-arginine stimulatory test, single IGF1 measurement, or their combination in identifying adult patients with GH deficiency.

OBJECTIVE: To evaluate the impact of different peak GH cut-off limits after GHRH-Arg test, IGF1 measurement, or their combination in identifying patients with GH deficit (GHD). DESIGN AND PATIENTS: Totally, 894 normal subjects (used for determining IGF1 normative limits) and 302 patients with suspected GHD were included. Different peak GH cut-off limits (used by European (depending on body mass index (BMI)) or North American (4.1 µg/l) Endocrine Societies, by HypoCCs (2.5 µg/l), or with 95% specificity (based on BMI), Method 1, 2, 3, or 4 respectively) and IGF1 were considered. METHODS: Peak GH after GHRH-Arg and IGF1. RESULTS: Different peak GH cut-off limits recognized different proportions of GHD (range, 24.8-62.9%). Methods 1 and 2 with high sensitivity recognized a higher proportion (95.5 and 92.5% respectively) of GHD among patients with three (T) pituitary hormone deficits (HD), whereas Method 4 (with high specificity) identified 96.7% normal subjects among those without pituitary HD; on the contrary, Method 4 identified only 75% GHD among patients with THD, whereas Method 1 recognized a high proportion (40%) of GHD among subjects without HD. Of the total patients, 82% with THD and 84.5% without HD were recognized as GHD or normal respectively by IGF1. Among the remaining patients with THD and normal IGF1, 75% was recognized as GHD by Method 1; among patients without HD and abnormal IGF1, 87.5% was identified as normal by Method 4. Overall, combination of IGF1 and Method 1 or Method 4 identified 95.5% GHD among patients with THD and 98.1% normal subjects among those without HD. CONCLUSIONS: Single peak GH cut-offs have limits to sharply differentiate GHD from normal subjects; IGF1 may be used for selecting patients to be submitted to the GHRH-Arg test; the peak GH cut-off limits to be used for identifying healthy or diseased patients depend mainly on the clinical context.

Changes in coagulation indexes and occurrence of venous thromboembolism in patients with Cushing's syndrome: results from a prospective study before and after surgery.

OBJECTIVES: To evaluate whether patients with Cushing's syndrome (CS) had i) changes in coagulative and fibrinolytic parameters associated with CS activity and ii) higher prevalence of venous thromboembolic events (VTE). DESIGN: Prospective study conducted on patients with CS evaluated at diagnosis and 12 months after surgery. PATIENTS AND METHODS: Forty patients with active CS (36 with Cushing's disease (CD) and 4 with an adrenal adenoma) were evaluated. Forty normal subjects and 70 patients with non-ACTH-secreting pituitary adenomas served as controls. All patients and controls underwent an assessment of coagulation and fibrinolysis indexes before and after surgery. RESULTS: CS patients at baseline had a hypercoagulative phenotype when compared with normal subjects (activated partial thromboplastin time (aPTT), fibrinogen, D-Dimer, von Willebrand factor (VWF), plasminogen activator inhibitor 1 (PAI-1 or SERPINE1), antithrombin III (ATIII or SERPINC1), P<0.0001, α(2) antiplasmin, P=0.0004, thrombin-antithrombin complex (TAT), P=0.01, factor IX (F9), P=0.03). Patients with still active disease after surgery had higher coagulative parameters than those in remission (VWF (P<0.0001), PAI-1 (P=0.004), TAT (P=0.0001), ATIII (P=0.0002) and α(2) antiplasmin (or SERPINF2; P=0.006)), whereas aPTT levels (P=0.007) were significantly reduced. VTE occurred in three patients with CD (7.5%): one had a pulmonary embolism and two patients had a deep venous thrombosis; no patients submitted to transsphenoidal surgery for non-Cushing's pituitary adenoma had VTE (P=0.04). CONCLUSIONS: Patients with CS have a procoagulative phenotype due to cortisol-associated changes in haemostatic and fibrinolytic markers, leading to increased incidence of VTE. Thromboprophylaxis seems to be appropriated in patients with active disease, particularly in the postoperative period.

Impact of lithium on efficacy of radioactive iodine therapy for Graves' disease: a cohort study on cure rate, time to cure, and frequency of increased serum thyroxine after antithyroid drug withdrawal.

CONTEXT: Radioactive iodine (RAI) is a common therapy for hyperthyroidism due to Graves' disease. A small but significant proportion of patients have recurrence of hyperthyroidism after RAI therapy. Lithium might increase RAI effectiveness by increasing RAI retention in the thyroid. However, whether lithium favorably affects the long-term outcome of RAI therapy is still a matter of argument. OBJECTIVE: The objective of the study was to compare the efficacy of RAI given with or without concomitant lithium treatment. DESIGN: This was a retrospective cohort study. SETTING: The study was conducted at a tertiary university center. PATIENTS: Six hundred fifty-one patients with newly diagnosed Graves' disease participated in the study. INTERVENTION: Two hundred ninety-eight patients were treated with RAI plus lithium (900 mg/d for 12 d) and 353 with RAI alone. MAIN OUTCOME MEASURES: Proportion of cured patients and time to achieve cure of hyperthyroidism during 1 yr of follow-up was measured. RESULTS: PATIENTS treated with RAI plus lithium had a higher cure rate (91.0%) than those treated with RAI alone (85.0%, P = 0.030). In addition, patients treated with RAI plus lithium were cured more rapidly (median 60 d) than those treated with RAI alone (median 90 d, P = 0.000). Treatment with lithium prevented the serum free T(4) increase after methimazole withdrawal and RAI therapy. Side effects after RAI therapy occurred in a subset of patients and were mild, transient, and without differences in the two groups. CONCLUSIONS: RAI combined with lithium is safe and more effective than RAI alone in the cure of hyperthyroidism due to Graves' disease.

Tumor infiltrating lymphocytes but not serum pituitary antibodies are associated with poor clinical outcome after surgery in patients with pituitary adenoma.

CONTEXT: Serum pituitary antibodies (Pit Abs) and tumor-infiltrating lymphocytes (TILs) have been described in pituitary adenomas, but their clinical significance remains unknown. OBJECTIVE: The objective of the study was to assess Pit Abs and TILs prevalence in pituitary adenomas and their influence on clinical outcome. DESIGN: This was a prevalence case-control study. PATIENTS AND SETTING: Two hundred ninety-one pituitary adenoma cases (110 non-secreting, 30 ACTH-69 GH-71 prolactin- and 13 TSH-secreting adenoma; 177 operated and 114 untreated), 409 healthy controls, and 14 autoimmune hypophysitis were enrolled in a tertiary referral center. INTERVENTION: Pit Abs were measured using immunofluorescence in all cases and controls (n = 714). The presence of TILs was evaluated using CD45 staining in a subset of adenomas surgically treated (n = 72). MAIN OUTCOME MEASURE: Clinical response of pituitary adenoma after surgery was evaluated. RESULTS: Pit Abs prevalence was higher in adenomas (5.1%) than healthy subjects (0.7%, P < 0.0001) and lower than in autoimmune hypophysitis patients (57%, P < 0.0001). Similarly, TILs prevalence was higher in adenomas than normal pituitary (P = 0.01) and lower than in autoimmune hypophysitis (P < 0.0001). No correlation between Pit Abs and TILs was found (P = 0.78). A poor clinical outcome was more common in adenoma patients with TILs (11 of 18, 61%) than in those without (17 of 54, 31%, P = 0.026). Multivariate regression analysis identified the presence of TILs as independent prognostic factor for persistence/recurrence of pituitary adenoma. CONCLUSIONS: TILs and Pit Abs are present in a significant number of pituitary adenoma patients. Cell-mediated immunity appears to be predictive of a less favorable clinical outcome.

Reduced colonic apoptosis in mice overexpressing bovine growth hormone occurs through changes in several kinase pathways.

OBJECTIVE: Growth hormone (GH) has antiapoptotic effects in several cell lines, including human colonic adenocarcinoma cells. In addition, it has been reported that patients with acromegaly have reduced apoptosis in colonic mucosa. The aim of the study was to investigate colonic apoptosis and underlying molecular mechanisms in transgenic mice overexpressing bovine GH (Acro) aged 3 months (young) or 9 months (elder). DESIGN AND METHODS: Apoptosis in colonic epithelial cells was evaluated by TUNEL and Annexin V; expression of pro- and anti-apoptotic proteins was assessed by Western blot. GH action was blocked treating Acro with a selective GH receptor antagonist. RESULTS: Young and elder Acro had lower colonic apoptosis [driven by GH through p38, p44/42 and PI3 kinase pathways], than littermate controls; changes were abolished by treating Acro with a selective GH receptor antagonist. The effects of GH were consistent with an anti-apoptotic phenotype (reduced cytosolic cytochrome-c, Bad and Bax and increased Bcl-2, and Bcl-XL level) leading to lower activation of caspase-9 and caspase-3. Changes in apoptotic proteins reversed after treatment with a GH receptor antagonist, suggesting a direct effect of GH. In addition, antiapoptotic phenotype of Acro had a protective role against doxorubicin-induced apoptosis. CONCLUSIONS: Our results suggest that GH leads to increased and reduced levels of anti- and pro-apoptotic proteins, respectively, lowering apoptosis in either young or elder transgenic animals through activation of several kinase pathways.

Changes in the expression of suppressor of cytokine signalling (SOCS) 2 in the colonic mucosa of acromegalic patients are associated with hyperplastic polyps.

BACKGROUND: Acromegalic patients have increased prevalence of colonic polyps. Development of hyperplastic polyps was related to suppressor of cytokine signalling (SOCS) 2 haploinsufficiency in animal models of acromegaly. OBJECTIVE AND PATIENTS: To evaluate whether variations in SOCS2 expression in the colonic mucosa of acromegalic patients might be associated to hyperplastic polyps, patients with active acromegaly or disease in remission with or without hyperplastic polyps were studied; controls were non-acromegalic subjects age- and sex- matched with or without polyps. MEASUREMENTS: Expression of SOCS1-3 was evaluated by RT-PCR, immunofluorescence and Western blot in the colonic mucosa. Coimmunoprecipatiton was used to evaluate multimeric protein complexes. RESULTS: Acromegalic patients with active disease and hyperplastic polyps had higher levels of SOCS2 transcripts; on the contrary, SOCS1 and SOCS3 transcripts did not differ among the study groups. While the expression of SOCS2 and SOCS3 protein was indistinguishable with that of the corresponding transcripts, SOCS1 protein expression was reduced in active acromegalic patients with polyps. SOCS1 protein was reduced owing to its increased proteasome degradation mediated by SOCS2. The increased SOCS2 and reduced SOCS1 led to increased STAT5b expression, suggesting a higher GH signalling transduction. CONCLUSIONS: Acromegalic patients with active disease and hyperplastic polyps have high levels of SOCS2 and increased SOCS1 degradation, leading to reduced negative feedback on GH signalling, likely favouring a hyperplastic polyps phenotype.