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.

The beneficial effect of acromegaly control on blood pressure values in normotensive patients.

OBJECTIVE: Control of acromegaly may ameliorate blood pressure (BP) in hypertensive (HT) patients. We evaluated the impact of acromegaly control on BP values of normotensive (NT) acromegalics. DESIGN: Retrospective cohort study. PATIENTS: Fifty-eight naïve patients with acromegaly (39 F; age range, 30-69 years), including 28 NT and 30 HT subjects, participated in the study. MEASUREMENTS: Blood pressure was measured by clinical measurement and 24-h ambulatory monitoring at diagnosis and after 24 months of medical therapy for acromegaly. RESULTS: Acromegaly was controlled by medical therapy in 15 NT and 17 HT patients at 24 months. In the NT group, systolic (SBP) or diastolic (DBP) BP significantly increased (all P < 0·005) when acromegaly was uncontrolled, but did not change when the disease was controlled. Changes in SBP and DBP were also significantly different between uncontrolled and controlled NT patients. At 24 months, clinical hypertension was detected only in uncontrolled NT patients (46% vs 0%, P < 0·001), whereas ambulatory hypertension was found in 38% of uncontrolled and in 7% of controlled NT subjects (P = 0·035). In the HT group, ambulatory SBP increased in patients with uncontrolled acromegaly (24-h SBP P = 0·046, day SBP P = 0·005, night SBP P = 0·005), whereas ambulatory DBP decreased in subjects with controlled disease (24-h DBP P = 0·008, day DBP P = 0·026). CONCLUSIONS: Control of acromegaly has a beneficial effect on BP regulation either in HT or NT subjects; in the latter, it may prevent progression towards hypertension.

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.

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.

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.

Transgenic mice overexpressing growth hormone (GH) have reduced or increased cardiac apoptosis through activation of multiple GH-dependent or -independent cell death pathways.

GH has antiapoptotic effects in cardiac or noncardiac cell lines; however, increased apoptosis has been found in myocardial samples of patients with acromegaly. The aim of this study was to investigate cardiac apoptosis and underlying molecular mechanisms in transgenic mice overexpressing bovine GH [acromegalic mice (Acro)] aged 3 or 9 months. Cardiomyocyte apoptosis was evaluated by terminal deoxynucleotidyl transferase assay and annexin V; expression of pro- or antiapoptotic proteins was assessed by Western blot. Specificity of GH action was confirmed using a selective GH receptor antagonist. Apoptosis was lower in 3-month-old Acro than in controls; reduction was abolished by a GH receptor antagonist. The effects of GH were consistent with an antiapoptotic phenotype (increased Bcl2 and Bcl-XL and reduced Bad and cytochrome c levels, leading to lower activation of caspase-9 and caspase-3). In contrast, apoptosis was higher in 9-month-old Acro than in littermate controls; in addition, a GH receptor antagonist was without effect; the proapoptotic phenotype consisted in increased Bad, cytochrome c, caspase-9, and caspase-3. GH reduced apoptosis through p38 and p44/42 kinase pathways at young ages, whereas phosphatidylinositol-3-kinase was silent; on the contrary, the effects of GH on p38 and p44/42 kinase pathways were overcome by GH-independent stimuli in 9-month-old Acro. In addition, the antiapoptotic effect of GH was still present at this age as shown by phosphatidylinositol-3-kinase/Akt pathway activation. In conclusion, chronic GH excess reduced apoptosis at a young age, whereas its antiapoptotic action was overwhelmed in older animals by GH-independent mechanisms, leading to increased cell death.

Novel autoantigens in autoimmune hypophysitis.

BACKGROUND: Pituitary autoantibodies are found in autoimmune hypophysitis and other conditions. They are a marker of pituitary autoimmunity but currently have limited clinical value. The methods used for their detection lack adequate sensitivity and specificity, mainly because the pathogenic pituitary autoantigen(s) are not known and therefore antigen-based immunoassays have not been developed. OBJECTIVES: This study aimed to identify novel pituitary autoantigens using sera as probes in proteomic assays. We also compared immunoblotting and immunofluorescence methods for their accuracy in diagnosing autoimmune hypophysitis. STUDY DESIGN AND SUBJECTS: Twenty-eight sera from autoimmune hypophysitis cases (14 histologically proven and 14 clinically suspected) were compared to 98 sera from controls, which included 14 patients with pituitary adenomas, 48 with autoimmune thyroiditis (15 Graves' disease and 33 Hashimoto's thyroiditis) and 36 healthy subjects. METHODS: All sera were tested against human pituitary cytosolic proteins separated by one-dimensional (1D) gel electrophoresis. The band recognition was analysed statistically to detect molecular weight regions preferentially recognized by hypophysitis sera. 2D gel immunoblotting and mass spectrometry were then used to sequence the protein spots of interest. Sera were also tested by immunofluorescence for their recognition of Macaca mulatta pituitary sections. RESULTS: A single region in the 25-27-kDa range was recognized more often by hypophysitis cases than healthy subjects (P = 0.004) or patients with pituitary adenomas (P = 0.044). This region contained two novel candidate autoantigens: chromosome 14 open reading frame 166 (C14orf166) and chorionic somatomammotrophin. Immunoblotting positivity for the 25-27-kDa region yielded greater sensitivity (64%vs. 57%) and specificity (86%vs. 76%) than immunofluorescence in predicting histologically proven hypophysitis, although the performance was still inadequate to make immunoblotting a clinically useful test. CONCLUSION: The study reports two novel proteins that could act as autoantigens in autoimmune hypophysitis. Further studies are needed to validate their pathogenic role and diagnostic utility.

High prevalence of cardiac hypertophy without detectable signs of fibrosis in patients with untreated active acromegaly: an in vivo study using magnetic resonance imaging.

OBJECTIVE: Left ventricular (LV) hypertrophy and myocardial fibrosis are considered the main pathological features of acromegalic cardiomyopathy. The aim of the study was to evaluate the proportion of LV hypertrophy and the presence of fibrosis in acromegalic cardiomyopathy in vivo using cardiac magnetic resonance (CMR). DESIGN AND PATIENTS: Fourteen consecutive patients (eight women, mean age 46 +/- 10 years) with untreated active acromegaly were submitted to two-dimensional (2D) colour Doppler and integrated backscatter (IBS) echocardiography and CMR. MEASUREMENTS: LV volume, mass and wall thickness and myocardial tissue characterization (IBS and CMR). RESULTS: On echocardiography: mean LV mass (LVM) and LVM index (LVMi) were 209 +/- 48 g and 110 +/- 24 g/m(2), respectively; hypertrophy was revealed in five patients (36%); abnormal diastolic function [evaluated by isovolumic relaxation time (IVRT) or early (E) to late or atrial (A) peak velocities (E/A ratio)] was found in four patients (29%). Systolic function evaluated by measuring LV ejection fraction (LVEF) was normal (mean 72 +/- 12%) in all patients. Six patients (43%) had increased IBS (mean 57.4 +/- 6.2%). On CMR: mean LVM and LVMi were 151 +/- 17 g and 76 +/- 9 g/m(2), respectively; 10 patients (72%) had LV hypertrophy. Contrastographic delayed hyperenhancement was absent in all patients; on the contrary, mild enhancement was revealed in one patient. Systolic function was normal in all patients (LVEF 67 +/- 11%). LVMi was not related to serum IGF-1 concentrations or the estimated duration of disease. CONCLUSIONS: CMR is considered to be the gold standard for evaluating cardiac hypertrophy, fibrosis and systolic function. Using CMR, 72% patients with untreated active acromegaly had LV hypertrophy, which was only detected in 36% patients by echocardiography. However, cardiac fibrosis was absent in all patients irrespective of the estimated duration of disease. Although a very small increase in collagen content (as suggested by increased cardiac reflectivity at IBS), not detectable by CMR, could not be ruled out, it is unlikely that it would significantly affect cardiac function.

Diagnosis and management of amiodarone-induced thyrotoxicosis: similarities and differences between North American and European thyroidologists.

OBJECTIVE: To investigate how North American thyroidologists assess and treat amiodarone-induced thyrotoxicosis (AIT) and to compare the results with those of the same questionnaire-based survey previously carried out among European thyroidologists. DESIGN: Members of the American Thyroid Association (ATA) with clinical interests were sent by e-mail a questionnaire on the diagnosis and management of AIT, 115 responses were received from the United States and Canada, representing about one-third of ATA members with clinical interests. RESULTS: The majority of respondents (91%vs. 68% in Europe, P < 0.05) see < 10 new cases of AIT per year, and AIT seems less frequent than amiodarone-induced hypothyroidism (AIH) in North America (34% and 66% of amiodarone-induced thyroid dysfunction, respectively, vs. 75% and 25%, respectively, in Europe, P < 0.001). When AIT is suspected, in North America hormonal assessment is mostly based on serum free T4 (FT4) and TSH measurements, while serum free T3 (FT3) determination is requested less frequently than in Europe; thyroid autoimmunity is included in the initial assessment less than in Europe. Most commonly used additional diagnostic procedures include, as in Europe, thyroid colour-flow Doppler sonography, and to a lesser extent, thyroid radioactive iodine uptake and scan, but Europeans tend to request multiple tests more than North Americans. Withdrawal of amiodarone is more often considered unnecessary by North American thyroidologists (21%vs. 10% in Europe in type 1 AIT, P < 0.05, 34%vs. 20% in type 2 AIT, P < 0.05). In type 1 AIT thionamides represent the treatment of choice for North Americans as well as for Europeans, but the former use them as monotherapy in 65%vs. 51% of Europeans (P < 0.05) who more often consider potassium perchlorate as an useful addition (31%vs. 15% of North Americans, P < 0.01). Glucocorticoids are the selected treatment for type 2 AIT, alone (62%vs. 46% in Europe, P < 0.05) or in association with thionamides (16%vs. 25% in Europe, P = NS). After restoration of euthyroidism, thyroid ablation in the absence of recurrent thyrotoxicosis is recommended in type 1 AIT less frequently by North Americans. If amiodarone therapy needs to be reinstituted, prophylactic thyroid ablation is advised by 76% in type 1 AIT, while a 'wait-and-see' strategy is adopted by 61% in type 2 AIT, similar to behaviour of European thyroidologists. CONCLUSION: Similarities and differences exist between expert North American and European thyroidologists concerning the diagnosis and management of AIT. While differences reflect the frequent uncertainty of the underlying mechanism leading to AIT, similarities may represent the basis to refine the diagnostic criteria and to improve the therapeutic outcomes of this challenging clinical situation.

Glucocorticoid response in amiodarone-induced thyrotoxicosis resulting from destructive thyroiditis is predicted by thyroid volume and serum free thyroid hormone concentrations.

CONTEXT: Amiodarone-induced thyrotoxicosis (AIT) resulting from destructive thyroiditis (type 2) is commonly treated with glucocorticoids, but time needed to restore euthyroidism may be unacceptable for patients with underlying cardiac disorders. OBJECTIVE: The objective of this prospective study was to identify factors affecting the response to glucocorticoids in a large cohort of patients with type 2 AIT followed prospectively. SETTING: This study was conducted at university centers. PATIENTS: Sixty-six untreated patients with type 2 AIT were enrolled in the study. INTERVENTION: All patients were treated with prednisone (initial dose, 0.5 mg/kg.d) as long as needed to restore euthyroidism, defined as cure of AIT. MAIN OUTCOME MEASURE: The main outcome measure was cure time. RESULTS: The median cure time was 30 d (95% confidence interval, 23-37 d). Serum free T4 concentration (picograms per milliliter) and thyroid volume (milliliters per square meter) (and, to a lesser extent, serum free T3 concentration) at diagnosis were the main determinants of response to glucocorticoids, with a cure hazard ratio of 0.97 (95% confidence interval, 0.95-0.99; P = 0.005) and 0.84 (95% confidence interval, 0.77-0.91; P = 0.000) for unit of increment, respectively. AIT was cured in all patients with a complete follow-up; euthyroidism was reached in 30 d or less in 60% of patients but in more than 90 d in 16%. A prompt control of thyrotoxicosis (

Prevalence and functional significance of antipituitary antibodies in patients with autoimmune and non-autoimmune thyroid diseases.

BACKGROUND: Circulating antipituitary antibodies (APA) are markers of autoimmune hypophysitis, which may cause deficient pituitary function. The prevalence of APA in autoimmune thyroid disorders (AITD) is uncertain. OBJECTIVES: The aims of this study were 1) to evaluate APA prevalence in a large series of patients with AITD and non-AITD and 2) to investigate the functional significance of APA by assessing pituitary function in APA-positive patients. DESIGN AND SETTING: We conducted a health survey on consecutive AITD and non-AITD patients at a tertiary referral center (Department of Endocrinology, Pisa). PATIENTS: Subjects, including 1290 consecutive patients with thyroid disorders (961 AITD and 329 non-AITD) and 135 controls, were enrolled in the study. METHODS: APA (indirect immunofluorescence), free T(4), free T(3), TSH, and organ-specific autoantibodies were assayed in all patients. Functional pituitary evaluation was performed in most APA-positive patients. RESULTS: APA frequency was higher in AITD (11.4%) than in non-AITD (0.9%; P < 0.0001) patients; all control subjects had negative APA tests. APA were more frequently found in Hashimoto's thyroiditis (13%) than in Graves' disease (7.1%; P = 0.05). Of 110 APA-positive AITD patients, 20 (18.2%) had autoimmune polyglandular syndrome, whereas 90 (81.8%) had apparently isolated AITD. APA positivity increased percentage of autoimmune polyglandular syndrome in our series from 10.4 to 13.5%. Of 110 APA-positive patients, 102 were submitted to dynamic testing for functional pituitary assessment; 36 patients (35.2%) had mild or severe GH deficiency (GHD). No additional anterior pituitary hormone deficiencies were found; one patient had central diabetes insipidus. Pituitary abnormalities at magnetic resonance imaging were found in most APA-positive GHD patients. CONCLUSIONS: APA are frequently present in patients with AITD. Patients should be tested for APA because positive tests are associated with GHD.

Risk factors for development of coronary heart disease in patients with acromegaly: a five-year prospective study.

BACKGROUND: Data on coronary heart disease (CHD) are scanty and matter of argument in acromegalic patients. OBJECTIVE: The objective of this study was to evaluate risk factors for development of CHD and the occurrence of cardiac events in acromegalic patients during a 5-yr prospective study. DESIGN: Ten-year likelihood for CHD development was estimated by the Framingham scoring system (FS); patients were stratified as having low (FS < 10), intermediate (>or= 10 FS < 20), or high (FS >or= 20) risk. Coronary artery calcium content was measured using the Agatston score (AS) in all patients; those with positive AS were submitted to myocardial single-photon emission computed tomography; cardiac events were recorded during a 5-yr follow-up period. PATIENTS: Fifty-two consecutive patients (31 women, mean age 52 +/- 11 yr) with controlled or uncontrolled acromegaly were followed prospectively for 5 yr. RESULTS: Thirty-seven patients (71%) had low, 14 patients (27%) had intermediate, and one patient (2%) had high CHD risk. CHD risk was unrelated to acromegaly activity or the estimated duration of disease. Among patients with FS less than 10%, 24 had AS equal to 0, eight had AS of 1 or greater and less than 100, and five had AS 100 or greater and less than 300, respectively. Among patients with FS 10 or greater and less than 20%, nine had AS equal to 0, two had AS of one or greater and less than 100, one had AS of 100 or greater and less than 300, and two had AS of 300 or greater; a patient of the latter group, having AS of 400 or greater, increased his CHD risk from 11% to 20% or more. FS or AS did not differ in patients with controlled or uncontrolled acromegaly (P = 0.981). All patients with positive AS had no single photon emission computed tomography perfusion defects. During the 5-yr follow-up period no patient developed ischemic cardiac events. CONCLUSIONS: CHD risk in acromegalic patients, predicted by FS as in nonacromegalic subjects, is low; AS might have adjunctive role only in a subset of patients. However, most patients have systemic complications of acromegaly, which participate in the assessment of global CHD risk.

Cardiac expression of adenine nucleotide translocase-1 in transgenic mice overexpressing bovine GH.

Heart hypertrophy is a common finding of acromegaly, a syndrome due to GH excess. Impairment of adenine nucleotide translocase-1 (ANT-1) gene, the main mitochondrial ADP/ATP exchanger, leads to cardiac hypertrophy. The aim of the study was to evaluate cardiac expression and the functional role of ANT-1 in 1- to 12-month-old transgenic mice overexpressing bovine GH (acromegalic mice, Acro) and littermate controls (wild-type mice, Wt). GH specificity of protein degree variation was assessed treating Acro with pegvisomant, a GH receptor competitor. Tissue levels of ANT-1, NF-kappaB, ATP, and lactic acid were evaluated by western blot, bioluminescence, and Fourier transform infrared spectroscopy respectively. The degree of ANT-1 expression was higher in 1-month-old Acro than in Wt (47+/-5% OD vs 33+/-4% OD, P<0 01). On the contrary, ANT-1 expression was lower in 3- to 12-month-old Acro than in Wt (P<0 03). Changes in ANT-1 expression were associated with consistent changes of cellular ATP content, increasing at 1 month (P<0 05) and reducing thereafter in Acro when compared with Wt (P<0 04). Treatment with pegvisomant abolished ANT-1 and ATP changes observed in 1- and 3-month-old Acro, thus supporting a GH-dependent mechanism. Reduced ATP generation in hypertrophied hearts of older Acro was associated with increased lactic acid levels suggesting that part of energy was due to glycolysis. Variations in ANT-1 expression were linked to GH through changes in NF-kappaB, the levels of which changed accordingly. In conclusion, 1-month-old acromegalic mice had increased ANT-1 expression and higher degree of ATP production. Long-standing disease was associated with a consistent reduction of ANT-1 and ATP tissue levels, which became GH-independent in older animals. This study demonstrated a direct effect of GH on key proteins involved in energy metabolism of acromegalic hearts.