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Background Autoimmune Polyglandular Syndrome type 1 (APS-1) is a rare recessive inherited disease, caused by AutoImmune Regulator (AIRE) gene mutations and characterized by three major manifestations: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH) and Addison’s disease (AD). Methods Autoimmune conditions and associated autoantibodies (Abs) were analyzed in 158 Italian patients (103 females and 55 males; F/M 1.9/1) at the onset and during a follow-up of 23.7 ± 15.1 years. AIRE mutations were determined. Results The prevalence of APS-1 was 2.6 cases/million (range 0.5–17 in different regions). At the onset 93% of patients presented with one or more components of the classical triad and 7% with other components. At the end of follow-up, 86.1% had CH, 77.2% AD, 74.7% CMC, 49.5% premature menopause, 29.7% autoimmune intestinal dysfunction, 27.8% autoimmune thyroid diseases, 25.9% autoimmune gastritis/pernicious anemia, 25.3% ectodermal dystrophy, 24% alopecia, 21.5% autoimmune hepatitis, 17% vitiligo, 13.3% cholelithiasis, 5.7% connective diseases, 4.4% asplenia, 2.5% celiac disease and 13.9% cancer. Overall, 991 diseases (6.3 diseases/patient) were found. Interferon-ω Abs (IFNωAbs) were positive in 91.1% of patients. Overall mortality was 14.6%. The AIRE mutation R139X was found in 21.3% of tested alleles, R257X in 11.8%, W78R in 11.4%, C322fsX372 in 8.8%, T16M in 6.2%, R203X in 4%, and A21V in 2.9%. Less frequent mutations were present in 12.9%, very rare in 9.6% while no mutations in 11% of the cases. Conclusions In Italy, APS-1 is a rare disorder presenting with the three major manifestations and associated with different AIRE gene mutations. IFNωAbs are markers of APS-1 and other organ-specific autoantibodies are markers of clinical, subclinical or potential autoimmune conditions.

Type 2 amiodarone-induced thyrotoxicosis (AIT2) is a form of drug-induced destructive thyroiditis, usually treated with oral glucocorticoids (oGCs). Our objective was to investigate the short-term effects of intravenous glucocorticoids (ivGCs) on serum thyroid hormone concentrations in patients with AIT2. Exploratory study of three naive AIT2 patients treated with iv methylprednisolone (two pulses of 400 mg with no interpulse oGCs), followed by oGCs, matched 1:3 with AIT2 patients treated with oGCs alone. Changes in serum thyroid hormone concentrations were evaluated in the short-term period (24 h and 7 days) and after a cumulative dosage of 400 and 800 mg equivalents of methylprednisolone; in addition, healing time and duration of exposure to GCs were calculated. During the first 24 h of treatment, serum FT4 concentrations increased in ivGCs patients, and decreased in oGCs patients (+ 3.3% vs − 10.7%, respectively, p = 0.025). After 7 days, serum FT4 and FT3 concentrations decreased significantly in both groups, with no statistical difference between them (p = 0.439 for FT4 and p = 0.071 for FT3), even though the cumulative GCs dose was higher in ivGCs than in oGCs patients (800 mg vs 280 mg, p = 0.008). Furthermore, the iv administration of single 400 mg pulses of methylprednisolone resulted in a less significant decrease in serum thyroid hormone concentrations when compared to equivalent GCs doses fractionated in several consecutive days (p = 0.021 for FT4 and p = 0.052 for FT3). There were no significant differences in the healing time (p = 0.239) and duration of exposure to GCs (p = 0.099). High-dose ivGCs therapy does not offer advantages over standard oGCs therapy in the rapid, short-term control of AIT2.

Background In 2007, we published an opinion document to review the role of pegvisomant (PEG) in the treatment of acromegaly. Since then, new evidence emerged on the biochemical and clinical effects of PEG and on its long-term efficacy and safety. Aim We here reviewed the emerging aspects of the use of PEG in clinical practice in the light of the most recent literature. Results The clinical use of PEG is still suboptimal, considering that it remains the most powerful tool to control IGF-I in acromegaly allowing to obtain, with a pharmacological treatment, the most important clinical effects in terms of signs and symptoms, quality of life and comorbidities. The number of patients with acromegaly exposed to PEG worldwide has become quite elevated and the prolonged follow-up allows now to deal quite satisfactorily with many clinical issues including major safety issues, such as the concerns about possible tumour (re)growth under PEG. The positive or neutral impact of PEG on glucose metabolism has been highlighted, and the clinical experience, although limited, with sleep apnoea and pregnancy has been reviewed. Finally, the current concept of somatostatin receptor ligands (SRL) resistance has been addressed, in order to better define the acromegaly patients to whom the PEG option may be offered. Conclusions PEG increasingly appears to be an effective and safe medical option for many patients not controlled by SRL but its use still needs to be optimized.

Growth hormone (GH) is fundamental for the maintenance of bone mass and metabolism both during childhood and in adulthood. This effect is due to a complex interaction between circulating GH and IGF-I produced peripherally. In vitro data and experimental animal models have clarified many of the regulatory mechanisms underlying the characteristic skeletal changes occurring in acromegaly. This review focuses on the effects of GH excess on bone metabolism and mass in acromegalic patients and, in particular, on the influence of factors such as hypogonadism, gender, age and therapy on bone metabolism and arthropathy.

Rathke cleft cysts (RCCs) are malformative, benign lesions located in the sellar and/or suprasellar space; they are thought to arise from remnants of the Rathke pouch, where embryonic cells which are going to form the adenohypophysis join the nervous component that will become the neurohypophysis. These remnants may enlarge causing pituitary dysfunction and visual impairment. Cyst content may be a mucinous material of varying texture; the wall of the cyst is characterized by a well-differentiated, ciliated columnar epithelium. Magnetic resonance imaging (MRI) has increased sensitivity in RCCs radiologic diagnosis, even if symptoms related to the cyst are absent, so incidental findings are not unusual; in such cases, surgical therapy is questionable or not indicated. The prevalence of Rathke cleft cysts in children is considered lower than in adult population, in spite of their malformative nature, and young patients are mostly asymptomatic. We report a little series of symptomatic RCCs observed in children during an interval time of 4 years (2005–2008).

Objective: Current therapies for acromegaly are unsatisfactory for some patients. High-dose thiazolidinediones have been reported to reduce serum GH levels in animal models of acromegaly. The objective of the study was to evaluate the effect of increasing doses of rosiglitazone on serum GH and IGF-I concentrations in acromegalic patients. Design: Phase 2 clinical trial. Patients and methods: Five consecutive patients with active and uncontrolled acromegaly under conventional medical therapies were treated with increasing doses of rosiglitazone [4 mg/day every month, starting from 8 up to 20 mg/day] added to previous medical therapies for acromegaly. Results: Mean serum IGF-I concentrations decreased from 547±91 to 265±126 μg/l (p

Summary Introduction and aim: Dopamine agonists have been reported to increase the risk of cardiac valve regurgitation in patients with Parkinson’s disease. However, it is unknown whether these drugs might be harmful for patients with hyperprolactinaemia (HyperPRL). The aim of the study was to evaluate whether HyperPRL patients treated with dopamine agonists had a higher prevalence of cardiac valves regurgitation than that of general population. Methods and patients: One hundred consecutive patients (79 women, 21 men, mean age 41 ± 13 years) with HyperPRL during treatment with cabergoline were enrolled in an observational case–control study and compared with 100 matched normal subjects (controls). Valve regurgitation was assessed by echocardiography according to the American Society of Echocardiography recommendations. Results: Seven HyperPRL patients (7%) and six controls (6%) had moderate (grade 3) regurgitation in any valve (p = 0.980). All were asymptomatic and had no signs of cardiac disease. Mean duration of cabergoline treatment was 67 ± 39 months (range: 3–199 months). Mean cumulative dose of cabergoline was 279 ± 301 mg (range: 15–1327 mg). Moderate valve regurgitation was not associated with the duration of treatment (p = 0.359), with cumulative dose of cabergoline (p = 0.173), with age (p = 0.281), with previous treatment with bromocriptine (p = 0.673) or previous adenomectomy (p = 0.497) in patients with HyperPRL. Discussion: In conclusion, treatment with cabergoline was not associated with increased prevalence of cardiac valves regurgitation in patients with HyperPRL. Mean cumulative dose of cabergoline was lower in patients with HyperPRL than that reported to be deleterious for patients with Parkinson’s disease: hence, longer follow-up is necessary, particularly in patients receiving weekly doses > 3 mg.

Cystatin C (Cys C) is a cysteine protease inhibitor produced at a constant rate by nucleated cells, filtered through the glomerular membrane and reabsorbed by kidney tubular cells. Aim of this cross-sectional and longitudinal study was to assess serum Cys C and creatinine (Crea) concentrations in thyroid dysfunction. One hundred and eighty-one patients, 26 with untreated non-toxic nodular goiter, 58 with hyperthyroidism, 31 on L-T4 suppressive therapy for non-toxic nodular goiter, 35 with short-term hypothyroidism after L-T4 withdrawal to perform whole body scan for thyroid cancer, 11 with long-term hypothyroidism due to chronic autoimmune thyroiditis and 20 patients with mild hypothyroidism were enrolled in the study. Fifty-seven age- and sex-matched normal subjects served as controls. Serum Cys C, Crea, free T4 (FT4), FT3 and TSH were assessed. Thirty hyperthyroid patients and 35 short-term hypothyroid patients were followed prospectively until euthyroidism was reached by methimazole or L-T4 therapy. The cross-sectional study showed that mean serum Crea concentrations were significantly reduced in overt hyperthyroid or subclinical hyperthyroid patients, while it was increased in overt hypothyroid patients, but not in mild hypothyroidism. Conversely, serum Cys C levels were significantly increased in overt hyperthyroid patients compared to controls (p

Amiodarone-induced thyrotoxicosis (AMT) is a life-threatening condition, the appropriate management of which is achieved by identifying its different subtypes. Type 1 AIT develops in patients with underlying thyroid abnormalities and is believed to be due to increased thyroid hormone synthesis and release; Type 2 AIT occurs in patients with a normal thyroid gland and is an amiodarone-induced destructive process of the thyroid. Management differs in the two forms of AIT, since Type 1 usually responds to combined thionamides and potassium perchlorate therapy, while Type 2 is generally responsive to glucocorticoids. Mixed forms, characterized by coexistence of excess thyroid hormone synthesis and destructive phenomena, may require a combination of the two therapeutic regimens. In this cross-sectional prospective study, 55 consecutive untreated patients, whose AIT was subtyped according to clinical and biochemical criteria, were evaluated to assess the specificity of color flow doppler sonography (CFDS) and thyroidal radioiodine uptake (RAIU) in the differential diagnosis of AIT. Sixteen patients (6 men, 10 women, age 66+/-13 yr), who had diffuse or nodular goiter with or without circulating thyroid autoantibodies, were classified as Type 1 AIT; 39 patients (27 men, 12 women, age 65+/-13 yr) with apparently normal thyroids were classified as Type 2 AIT. All Type 1 patients had normal or increased thyroidal vascularity on CFDS, while Type 2 AIT patients had absent vascularity (p

Dopamine agonists are considered as the first line therapy in prolactin (PRL) secreting pituitary adenomas inducing a normalization of serum PRL and reduction of tumor size. It is known that serum PRL levels, obtained during treatment, are a predictor of tumor shrinkage. Whether PRL suppression below the lower limit of the normal range is related to a greater chance of tumor shrinkage than just its normalization has not been established. This retrospective cohort study was carried out in a tertiary center. Clinical records of 151 patients with PRL-secreting pituitary adenomas (73 micro-, 78 macroadenomas) treated with cabergoline for at least 24 months were analyzed. The adenoma size was analyzed by MRI before and after 24 months of treatment. PRL levels were evaluated every 6 months, assigning a score at each time point (PRL 0 = suppressed; 1 = normal; 2 = above normal). The total score, after 24 months of treatment, was expressed as the sum of the score at each time point and ranged between 0 and 8. A tumor shrinkage was observed in 102/151 patients (67.5%) and it was significantly associated to a lower PRL total score (p = 0.021, OR = 0.85, CI = 0.73-0.97), being significantly more frequent in patients with suppressed PRL than in those with normal PRL (p = 0.045, OR = 0.42, CI = 0.18-0.98) at 24 months. Cabergoline therapy with the goal of achieving PRL levels below the lower limit of normal range can increase the chance to obtain tumor shrinkage of PRL-secreting pituitary adenomas.

ContextHepatotoxicity is one of the most serious adverse effects in acromegalic patients treated with pegvisomant (PEG-V). Recent studies have found an association between this adverse event and the UGT1A1 allele 28 polymorphism associated with Gilbert's syndrome.ObjectiveTo determine whether UGT1A1*28 and alcohol dehydrogenase (ADH) polymorphisms influence liver toxicity during PEG-V treatment.Design and settingMulticenter observational retrospective study conducted in 13 tertiary care endocrinology units in Italy.PatientsA total of 112 patients with active disease resistant to somatostatin analogs (SSTa) and 108 controls were enrolled.InterventionsClinical and biochemical data were recorded by electronic clinical reporting forms. Blood or DNA samples were sent to the coordinating center for genotyping.ResultsNo differences in genotypes between patients and controls were found. During PEG-V therapy liver function tests (LFT), abnormalities and overt hepatotoxicity developed in 17 and 4.5% of patients respectively. Logistic and linear regression analyses showed an association between LFT abnormalities during the follow-up visit and prior events of LFT abnormalities in medical history (odds ratio=1.25;P=0.04) and the number of concomitant medications, other than SSTa (B=3.9;P=0.03). No correlation between LFT alterations and UGT1A1 allele 28 as well as ADH1C and B polymorphisms was found.ConclusionsUGT1A1 allele 28 and ADH1C and B polymorphisms do not predict increased risk of hepatotoxicity during PEG-V therapy. Conversely, patients with multi-therapies and with previous episodes of liver disease should be carefully managed, due to the observed association between these conditions and LFT abnormalities during PEG-V therapy.

Acromegaly management is a significant challenge for endocrinologists. The Acromegaly Consensus Group developed several statements on the management of acromegaly and specifically on its medical treatment [1–3]. Acromegaly is a quite rare condition generally caused by a growth hormone (GH)-secreting pituitary adenoma [4]. Delayed diagnosis leads to prevalent presentation of the disease at the stage of macroadenoma (two-thirds of patients) and frequent persistence of active disease after surgery which remains in many patients the primary treatment option [5]. However, active acromegaly is potentially a life threatening condition due its severe systemic complications [6, 7] Therefore, elevated GH and insulin-like growth factor (IGF)-1 levels need to be strictly controlled after failure of surgery with medical or radiation treatments [8]. Furthermore, criteria for disease control may not be fulfilled in a considerable proportion of patients undergoing medical treatment with somatostatin receptor ligands (SRLs) after unsuccessful surgery [9, 10]. Accordingly, some acromegaly patients require the administration of GH antagonist Pegvisomant [11]. Pegvisomant has been introduced in clinical practice more than a decade ago as a medical therapy of acromegaly. However, specific guidelines for Pegvisomant use in acromegaly are lacking. Therefore, the Italian Society of Endocrinology constituted a task force with the objective of assessing the published literature and the clinical experience with Pegvisomant. This group involved endocrinologists recognized experts in the field of acromegaly management and their understanding of the data reported so far worldwide as well as their recommendations for Pegvisomant use in clinical practice are presented here. Biochemical and clinical results of Pegvisomant, indications, treatment modalities, combination therapies, safety and regulatory and cost/efficacy issues were evaluated. Evidences were graded with GRADE system [1–3, 12, 13] based on the quality of evidence as very low quality (VLQ; expert opinion with one or a small number of small uncontrolled studies in support), low quality (LQ; large series of small uncontrolled studies), moderate quality (MQ; one or a small number of large uncontrolled studies or meta-analyses), or high quality (HQ; controlled studies or large series of large uncontrolled studies with sufficiently long follow-up). Recommendations were defined discretionary (DR) if based on VLQ-LQ evidence, or strong (SR) if supported by MQ-HQ evidence.

Insulin, 25-hydroxy vitamin D3 [25(OH)D3] and folate have been differently associated with a risk of colonic neoplasms in the general population. Acromegalic patients have an increased risk of colorectal tumors and an association between fasting insulin concentrations and colonic lesions has been reported. However, it is unknown whether insulin, 25(OH)D3, folate, and homocysteine interact to determine the risk of colonic tumors in acromegaly.To investigate whether serum insulin, 25(OH)D3, folate, and homocysteine concentrations were associated with precancerous colonic lesions in acromegalic patients.A cohort of 146 consecutive acromegalic patients was evaluated for colonoscopy findings and fasting insulin, 25(OH)D3, folate, and homocysteine levels. A preliminary study was conducted in 9 naïve acromegalic patients to evaluate the effect of somatostatin analogues (SSA) on serum levels of those factors.Insulin reduced during SSA whereas the other factors did not change. In the cohort study, colonic lesions (14 adenomas; 32 hyperplastic polyps) were detected in 46 patients. Fasting insulin, 25(OH)D3, folate, and homocysteine levels did not differ in patients with or without colonic adenomas. High folate levels were associated with a lower risk of developing precancerous colonic lesions at the multivariate analysis, when corrected by age, gender, disease activity and SSA therapy.Serum insulin, 25(OH)D3 and homocysteine serum concentrations do not seem to influence the development of precancerous colonic lesions in acromegalic patients, while higher folate levels may be associated with a lower risk of colonic lesions.

FSH receptor (FSHR) expression is restricted to gonads, where it drives FSH-dependent cell differentiation; in addition, FSHR plays an important role in the regulation of ovarian angiogenesis. Recently, FHSR expression has been shown in blood vessels of various tumors. However, pancreatic neuroendocrine tumors (p-NET), which have high-degree blood supply, were not included in that study. The aim of this study was to evaluate FSHR expression in p-NET. FSHR expression was evaluated in tumor samples from 30 patients with p-NET by immunohistochemistry and Western blot; fluorescence microscopy was used to localize FSHR in specific cells from tissue samples. von Willebrand factor (vWF) and chromograninA (chrA) was used as blood vessel and NET cells marker, respectively, to co-localize FSHR. FSHR expression was detected in all p-NET by immunohistochemistry. Western blot confirmed FSHR expression on p- NET although different FSHR isoforms, ranging from 240 kD to 55 kD were found in the samples studied. Surprisingly, FSHR co-localized with chrA but not with vWF, suggesting that neoplastic cells of neuroendocrine origin rather than blood vessels expressed FSHR. No relationship was found between degree of FSHR expression and histology of p-NET. FSHR may be aberrantly expressed in neoplastic cells from p-NET and not in tumor blood vessels; however, its biological significance as well as its clinical relevance remains to be elucidated.

Amiodarone-induced thyroid dysfunction occurs in 15-20% of amiodarone-treated patients. Amiodarone-induced hypothyroidism (AIH) does not pose relevant problems, is easily controlled by L-thyroxine replacement, and does not require amiodarone withdrawal. Most frequently AIH develops in patients with chronic autoimmune thyroiditis. Amiodarone- induced thyrotoxicosis (AIT) is most frequently due to destructive thyroiditis (type 2 AIT) causing discharge of thyroid hormones from the damaged, but otherwise substantially normal gland. Less frequently AIT is a form of hyperthyroidism (type 1 AIT) caused by the iodine load in a diseased gland (nodular goiter, Graves' disease). A clearcut differentiation between the two main forms is not always possible, despite recent diagnostic advances. As a matter of fact, mixed or indefinite forms do exist, contributed to by both thyroid damage and increased thyroid hormone synthesis. Treatment of type 1 (and mixed forms) AIT is based on the use of thionamides, a short course of potassium perchlorate and, if treatment is not rapidly effective, oral glucocorticoids. Glucocorticoids are the first-line treatment for type 2 AIT. Amiodarone should be discontinued, if feasible from a cardiac standpoint. Continuation of amiodarone has recently been associated with a delayed restoration of euthyroidism and a higher chance of recurrence after glucocorticoid withdrawal. Whether amiodarone treatment can be safely reinstituted after restoration of euthyroidism is still unknown. In rare cases of AIT resistance to standard treatments, or when a rapid restoration of euthyroidism is advisable, total thyroidectomy represents a valid alternative. Radioiodine treatment is usually not feasible due to the low thyroidal iodine uptake.

Context: The influence of full-length GH receptor (GHR) and exon 3-deleted GHR (d3GHR) on responsiveness to pegvisomant (PEG-V) in acromegalic patients is uncertain. Objective: The aim of the study was to assess the distribution of GHR genotypes in a large series of patients on PEG-V therapy and their influence on treatment efficacy and adverse effects. Design and Setting: A cross-sectional multicenter pharmacogenetic study was conducted in 16 Italian endocrinology centers of major universities and tertiary care hospitals. Patients: The study included 127 acromegalic patients enrolled from 2009 to 2010 not cured by previous surgery, radiotherapy, and long-acting somatostatin (SST) analogs, treated with PEG-V. Intervention and Main Outcome Measure: Sixty-three of 127 patients received combined PEG-V + SST analog therapy. Clinical and hormonal data at diagnosis and before and during PEG-V therapy were inserted in a database. GHR exon 3 deletion and other polymorphisms were genotyped by the coordinator center. Differences in PEG-V dosage required for IGF-I normalization and occurrence of adverse effects between carriers and noncarriers of GHR variants were evaluated. Results: d3GHR variants were not in Hardy-Weinberg equilibrium (P = 0.008). No association of these variants with PEG-V dose required for IGF-I normalization, adverse effects occurrence, and tumor regrowth was found in patients on PEG-V and on PEG-V + SST analog treatment. Similar data were obtained considering the GHR variant rs6180. Conclusions: This study did not confirm a better response of d3GHR to PEG-V treatment in acromegaly. Other studies are needed to determine whether deviation from Hardy-Weinberg equilibrium may indicate an association of d3GHR genotype with poor response to usual treatments.

Some evidence suggests that late stage autoimmune hypophysitis (AH) may result in empty sella (ES). Aim of the study was to assess the prevalence of serum pituitary antibodies (PitAb) and their correlation with pituitary function in patients with ES.In this casecontrol study 85 patients with primary ES, 16 patients with ES secondary to head trauma, 214 healthy controls, and 16 AH were enrolled in a tertiary referral center.PitAb were assessed in all cases and controls. Endocrine function was assessed by basal hormone measurement and dynamic testing in all ES cases.PitAb prevalence was higher in primary ES (6%) than in healthy subjects (0.5% p=0.003) and lower than in AH patients (50%, p0.0001). PitAb were not found in patients with secondary ES. Hypopituitarism was found in 49% of primary ES and in 62% of secondary ES (p=0.34). A positive correlation between the presence of PitAb and hypopituitarism was found in primary ES (p=0.02).The significant association between pituitary autoimmunity and hypopituitarism suggests that ES, in selected cases, could be the final result of AH.

Medical therapy of autoimmune hypophysitis with immunosuppressive drugs can be effective to induce remission of the disease by treating both pituitary dysfunction and compression symptoms. We describe the case of a 41-yr-old man with autoimmune hypophysitis in whom prednisone therapy induced remission of the disease but was followed by a sudden relapse after withdrawal. A second trial of corticosteroid was started and succeeded in inducing remission of the disease. Eight months after the second withdrawal pituitary function was restored, pituitary mass had disappeared, only partial diabetes insipidus remained unchanged. Review of the literature identified 30 articles, among case reports and case series, reporting a total of 44 cases of autoimmune hypophysitis treated with glucocorticoids and/or azathioprine. Combining all the cases, medical therapy resulted to be effective in reducing the pituitary mass in 84%, in improving anterior pituitary function in 45%, and in restoring posterior pituitary function in 41%. Clinical aspects of autoimmune hypophysitis are discussed and a possible algorithm for the diagnosis and treatment of the disease is proposed.

The aim of the study was to evaluate whether vitamin D [25-(OH) D3] status affects serum IGFI concentrations in healthy subjects.Two hundred and forty-one consecutive healthy subjects were included in the present study.Serum IGF-I and 25-(OH) D3 concentrations.As expected, serum IGF-I concentrations progressively decreased with age (r=-0.55, p0.0001); on the contrary, gender was not related to serum IGF-I levels. A positive relationship was identified between serum 25-(OH) D3 and IGF-I concentrations (r=0.33, p0.0001); the 25-(OH) D3-dependent changes of serum IGF-I concentrations were observed also when subjects were divided on the basis of vitamin D deficiency; in fact, those with severe 25-(OH) D3 deficiency (20 ng/ml) had lower (185 ± 83 μg/l) IGF-I values than those with mild-to absent 25-(OH) D3 deficit (225 ± 83 μg/l, p=0.0004).25-(OH) D3 status may contribute to determine serum IGF-I levels in healthy population.

Background: Voice changes are common clinical findings of acromegaly, although scanty data are available so far. Objective: To analyze features and quantify changes of voice in patients with untreated active acromegaly. Design and methods: This was a pilot case-control study. Voice was analyzed using the Multi Dimensional Voice Program software, which generates 33 parameters related to fundamental frequency (F0), micro-perturbation of F0 and amplitude, noise, tremor, voice breaks and irregularities, and diplophony. Patients: Thirteen consecutive patients (8 women, 5 men, mean age 48±9 yr) with active acromegaly, at first diagnosis, and 13 sex- and age-matched normal subjects (controls). Results: Patients with untreated active acromegaly had mean values of parameters related to F0 significantly lower than those of controls, although mostly remaining in the normal range. Most acromegalic patients had micro-perturbation of F0, as indicated by higher mean of absolute or percentage jitter values than those of controls; micro-perturbation of amplitude was a common feature of voice in most acromegalic men. Noise-related parameters were also affected by acromegaly, being higher in male acromegalic patients than in controls and acromegalic women. On the contrary, parameters related to tremors, voice breaks, voice irregularities and diplophony did not differ in acromegalic patients and controls. Conclusions: Patients with untreated active acromegaly had low-pitched voice characterized by lowering F0 and increased values related to noise, micro perturbation of frequency, and amplitude.

Objective: Left ventricular (LV) hypertrophy is the main finding of patients with active acromegaly at cardiac magnetic resonance (CMR). The aim of the study was to evaluate heart changes in acromegalic patients treated with somatostatin analogues (SMSA) using CMR. Design and patients: This was a prospective study. Fourteen consecutive patients (8 women, mean age 46±10 yr) with untreated active acromegaly were submitted to CMR and 2D-color Doppler echocardiography before and after a 6-month SMSA course. Measurements: LV volume, mass (LVM) and wall thickness. Results: CMR: Mean LVM and LVM index (i) decreased from 151±17 g and 77±9 g/m2, to 144±24 g and 70±12 g/m2, respectively (p=0.047 and p

Objective: To evaluate efficacy and safety of lanreotide autogel (ATG) 120 mg injections every 4–8 weeks in somatostatin analogue-na"ive patients with acromegaly. Design: Open, non-comparative, phase III, multicenter clinical study. Methods: Fifty-one patients (28 women, aged 19–78 yr): 39 newly diagnosed (de novo) and 12 who had previously undergone unsuccessful surgery (post-op, 11 macro and 1 micro) were studied. ATG 120 mg was initially given every 8 weeks for 24 weeks and subsequently changed according to GH levels: if ≤2.5 μg/l every 8 weeks (group A, 17 patients); if 2.5–5 μg/l every 6 weeks (group B, 15 patients); and if >5 μg/l every 4 weeks (group C, 19 patients). Treatment duration was 48–52 weeks. The primary objective was to control GH and IGF-I levels (GH≤2.5 μg/l and IGF-I normalized for age/gender). Secondary objectives were to assess GH, IGF-I, and acid-labile subunit (ALS) decrease, improvement of clinical symptoms and quality of life (QoL). Results: GH levels normalized in 32 patients (63%), similarly in de novo and post-op patients (72% vs 50%, p=0.48); in 100% of group A, in 73% of group B and in 21 % of group C (p

Background: Results of circulating Ghrelin levels in hyper- or hypothyroidism are conflicting and only overt thyroid dysfunction has been evaluated. Aim: To evaluate in a large number of patients with thyroid disfunction whether: a) hyper- and hypothyroidism (clinical or subclinical) are associated with variations in both acylated (AG) and total Ghrelin (TG) concentrations, and b) correction of thyroid dysfunction is followed by variations in Ghrelin concentrations. Subjects and methods: Seventy-six hyperthyroids, 52 hypothyroids, 144 euthyroids with chronic autoimmune thyroiditis, and 109 euthyroid healthy controls were evaluated cross-sectionally and longitudinally. Results: TG and AG were significantly lower in hyperthyroids than in controls or hypothyroids; the latter 2 groups did not differ. TG was significantly lower in overt than in subclinical hyperthyroids. with a trend to a reduction also in AG levels. No differences were found between subclinical hyperthyroids and controls. After thionamide treatment, TG and AG levels in hyperthyroids did not differ from controls. L-thyroxine management of hypothyroidism was not associated with significant Ghrelin variations. Plasma Ghrelin was independent of either thyroid or gastric autoimmunity. Plasma TG was negatively correlated with serum free thyroid hormone levels in hyperthyroids but not in hypothyroids. Conclusions: Plasma Ghrelin concentrations are reduced in overt but not in subclinical hyperthyroidism and normalize after restoration of euthyroidism. Hypothyroidism is not accompanied by significant changes in circulating Ghrelin.

We have carried out a prospective study to investigate whether orbital radiotherapy combined with high dose systemic glucocorticoids is more effective than orbital radiotherapy alone for Graves' ophthalmopathy. Thirty consecutive patients with relevant and active Graves' ophthalmopathy were randomly assigned to treatment either with orbital radiotherapy combined with systemic glucocorticoids (Group 1, n = 15) or with orbital radiotherapy alone (Group 2, n = 15). The final evaluation was made 6-9 months after beginning treatment. Two patients in each group were lost to follow-up. Ocular involvement and response to treatment were evaluated by the ophthalmopathy index and by clinical assessment. Mean ophthalmopathy index values were 5.85 in Group 1 and 5.46 in Group 2 (p = NS) before treatment, and 2.46 in Group 1 and 3.61 in Group 2 after treatment (p = 0.0001 and p = 0.003 vs initial value, respectively). The mean ophthalmopathy index decrease in Group 1 (-3.39) was significantly greater (p = 0.043) than that in Group 2 (-1.85). Favorable responses on clinical ground occurred in 9 patients (69%) in Group 1 and in 5 patients (38%) in Group 2. The difference was particularly evident on soft tissue changes and extraocular muscle involvement. Severe eye muscle restriction was substantially unaffected by either treatment. In conclusion, the association of orbital irradiation and high dose systemic glucocorticoids in the treatment of severe Graves' ophthalmopathy provides more favorable responses than orbital radiotherapy alone.

Neurodegenerative diseases are a major focus of scientific and clinical interest because of their increasing medical and social importance. Due to the intimate connections between central nervous and endocrine systems, it is reasonable to suspect that important, and in some cases clinically relevant, endocrine modifications may accompany the progression of neurodegenerative diseases. Data on endocrine modifications in different neurodegenerative diseases have been reported, but results have often been non-conclusive, or conflicting. Accumulating evidence suggests that the GH/IGF-I axis is involved in the regulation of brain growth, development, and metabolism and in the regulation of muscle function. Dysfunctions in GH/IGF-I axis in most of neurodegenerative diseases are therefore reviewed. Alterations of this system could be actors in the complex network leading to (at least some) neurodegenerative diseases. A thorough effort in investigating every possible involvement is warranted, in the light of future therapeutic strategies.

Impaired GH secretion is a common finding in patients with primary hyperparathyroidism (PHP). Ghrelin displays strong GH-releasing action, mainly at the hypothalamic level.To evaluate secretory response of GH to ghrelin in PHP patients.Fifteen patients [11 women/4 men, mean age 54 years, range 32-70 years, body mass index (BMI) 25.0 +/- 0.7 kg/m(2)] affected with PHP due to single parathyroid adenoma and 35 normal age-matched subjects (23 women/12 men, mean age 58 years, range 35-68 years, BMI 24.1 +/- 1.1 kg/m(2)).A measure of 1 microg/kg body weight i.v. acylated ghrelin or 1 microg/kg body weight i.v. GH releasing hormone (GHRH) followed by 0.5 g/kg body weight i.v. arginine (ARG) hydrochloride were administered to all subjects on alternate days in order to evaluate GH response.Mean serum GH peak after GHRH + ARG was 32.6 +/- 7.8 and 17.4 +/- 4.0 microg/l, in controls and PHP patients, respectively (P0.05). Mean serum GH peak after ghrelin was 70.4 +/- 31.5 and 16.8 +/- 1.9 microg/l, in controls and PHP patients, respectively, (P0.001). Using ROC curves, a serum GH peak22 microg/l after ghrelin stimulation might be considered as a cut-off value for identifying normal subjects. Ten (67%) PHP patients have impaired GH response to GHRH + ARG and 13 (87%) to ghrelin. Serum GH peak after ghrelin or GHRH + ARG was unrelated to serum IGF-1, PTH or ionized calcium concentrations.The present data confirm that GH secretion is impaired in PHP patients using the potent GH secretagogue ghrelin and suggest that impaired GH secretion is likely due to a deleterious effect of hypercalcaemia at the hypothalamic level in PHP patients.

Context: Amiodarone-induced hypothyroidism (AIH) may occur in patients with or without underlying thyroid disorders. In the latter, restoration of euthyroidism, after amiodarone discontinuation, can be facilitated and accelerated by a short course of potassium perchlorate (KClO4). However, it is unknown whether KClO4 may exert similar effects on thyroid function of AIH patients if amiodarone treatment is continued. Objective: To evaluate the effects of KClO4 on thyroid function in AIH patients (without underlying thyroid disease) while continuing amiodarone treatment. Design and patients: An open, prospective study of 10 consecutive AIH patients without underlying thyroid abnormalities referred to a tertiary referral center, and treated with KClO4 (600 mg/day) for a period of 26±13 days (range, 15–45 days). An additional, historical group of 12 consecutive patients with subclinical AIH left untreated while continuing or after withdrawing amiodarone was retrospectively evaluated as to the outcome of thyroid function. Measurement: Serum free T4, free T3, and TSH concentrations were measured at booking, during KClO4 treatment and after withdrawing the drug. Results: In the prospective study, KClO4 treatment restored euthyroidism in all patients within 28±11 days (range, 15–45 days). After KClO4 with drawal, however, all patients became hypothyroid again after 45±15 days (range, 30–60 days). Two patients developed mild leukopenia (1 case) or a slight increase in serum creatinine levels (1 case), which promptly normalized after KClO4 withdrawal. In the historical group, followed for at least 12 months, euthyroidism was spontaneously and stably achieved after an average of 6 months in 5 patients in whom amiodarone could be discontinued, while subclinical hypothyroidism persisted in 7 patients in whom amiodarone had to be continued. Conclusions: KClO4 very effectively restores normal thyroid function in AIH patients without underlying thyroid abnormalities, despite the fact that amiodarone therapy is continued. However, euthyroidism does not persist after KClO4 is withdrawn; in addition, spontaneous recovery of euthyroidism does not seem to occur in this subset of AIH patients, unless amiodarone is discontinued. Therefore, also in view of its potential side-effects, KClO4 cannot be recommended as a first-line treatment for AIH if amiodarone needs to be continued, while LT4 replacement is recommended under these circumstances, with periodical reassessment of thyroid function.

GH has a pivotal role in maintaining bone mass and metabolism both during childhood and in adult life. This effect depends on a complex interaction between circulating and peripherically produced GH and IGF-I. In vitro data and the use of genetically modified animals have greatly expanded the understanding of regulatory mechanisms underlying the well known skeletal changes featuring acromegalic disease. The present review focuses on the effects of GH excess on bone metabolism and mass in acromegalic patients with particular attention to the influence on bone metabolism as well as arthropathy of factors such as concomitant hypogonadism, gender, age of patients and therapy.

Background: Heart abnormalities are frequent findings in patients with acromegaly: systolic abnormalities are considered to be secondary to diastolic changes. Aim: The aim of the study was to evaluate whether early systolic abnormalities might be revealed in acromegalic patients using the high sensitive color Doppler myocardial imaging (CDMI) technique. Patients and methods: Twenty-two consecutive acromegalic patients with active untreated disease (ACROUNTR) were evaluated at baseline and after a 6-month course with SS analogs (SSa) (ACROSSa); 25 healthy subjects served as controls. All subjects underwent conventional 2D-color Doppler echocardiography, pulse wave tissue Doppler imaging (PW-TDI) and CDMI. Results: Mean left ventricular (LV) ejection fraction did not differ in ACROUNTR and in controls; at variance, ACROUNTR patients had reduced mean LV diastolic function (E/A ratio: 0.96±0.3 vs controls: 1.6±0.3; p

Background: Two main forms of amiodarone-induced thyrotoxicosis (AIT) exist: type 1 AIT is a condition of true hyperthyroidism developing in patients with pre-existing thyroid disorders, and usually requires thyroid ablative treatment. On the other hand, type 2 AIT is a form of destructive thyroiditis occurring in normal thyroids, the management of which usually consists in glucocorticoid treatment. Aim: To assess the long-term outcome of thyroid function in a prospective study of type 2 AIT patients, as compared to patients with De Quervain’s subacute thyroiditis (SAT). Patients and Methods: Sixty consecutive patients with type 2 AIT were evaluated during oral glucocorticoid treatment (oral prednisone 30 mg/day, gradually tapered and withdrawn over a 3-month period) and followed for 38±4 months (range 6–72) thereafter. Sixty consecutive patients with SAT, referred to our Institutes during the same period and treated with the same therapeutic schedule, served as controls. Results: Type 2 AIT patients were older (p

Primary hyperparathyroidism (PHP) is associated with impaired GH secretion. Whether this effect is due to hypercalcemia or to increased serum PTH concentration is unclear. However, patients with familial hypocalciuric hypercalcemia (FHH), who have normal PTH and increased serum calcium concentrations, also have an impaired GH secretion, suggesting that calcium rather than PTH is responsable for this effect on GH secretion. To further investigate this issue, 10 consecutive patients with secondary hyperparathyroidism (SHP) due to vitamin D deficiency were evaluated by the GH response to GHRH+arginine (Arg) test. A group of 60 consecutive untreated PHP patients served as controls. Mean GH response to GHRH+Arg test was 15.8+/-14 microg/l and 37.5+/-16 microg/l (p0.001) in PHP and in SHP patients, respectively. Forty-two out of 60 (70%) PHP patients had a suppressed or blunted GH response, whereas all SHP patients had normal GH response. The results of the present study confirm and extend our previous observations that PHP is associated with an impaired GH secretion in the majority of cases, and indicate that SHP patients have no abnormality of GH secretion. Thus, hypercalcemia rather than increased serum PTH is responsible for the abnormality of GH secretion.

Prostate-specific antigen (PSA) is a serine proteases produced by prostatic epithelial cells detectable in male serum and seminal plasma. PSA is also expressed in some female tissues and fluids and is increased in hirsute women showing a positive correlation with androgens. Accordingly, it has been suggested that PSA might be a marker of androgen action in women. The aim of this observational study was to assess serum PSA concentration in acro megalic women with active disease, in remission or during somatostatin analogs therapy. Forty-four acromegalic women, 15 with active disease, 10 in remission and 19 under long-acting somatostatin analogs therapy were enrolled in the study; 273 normal women matched for age, body mass index, with no signs of hirsutism, served as controls. Serum PSA, 3a-androstanediol (3alpha-AG), total testosterone (T), DHEAS, LH, FSH and estradiol were assessed. No patient or control had been given estrogen or antiandrogen drugs; no acromegalic women had hyperprolactinemia or hypopituitarism. Serum PSA concentration was significantly higher in acromegalic patients than in control subjects (p < 0.0001). Patients with active acromegaly or under somatostatin analogs therapy had significant higher serum PSA concentration than controls, while patients in remission after adenomectomy did not differ. Serum PSA was detectable in serum of 75% acromegalic women and 45% of controls. In addition 24% of acromegalic women had serum PSA concentrations higher than the mean +/- 2SD of control subjects. Differences in serum PSA levels did not reach statistical significance in the different acromegalic subgroups possibly because of the small number of subjects, but patients with active acromegaly had higher serum PSA levels than patients under somatostatin analogs therapy or in remission. Acromegalic women had significantly higher serum PSA concentrations than controls both before and after menopause (p < 0.01). 3alpha-AG (p < 0.05) and T (p < 0.01) were higher in acromegalic than in control subjects in pre-menopause (PM) but not in post-menopause (M). A correlation was found in the whole group of acromegalic patients between serum PSA and 3a-AG concentrations (r = 0.3, p < 0.01). In conclusion, acromegalic is associated with an increase in serum PSA concentrations as a group, although this increase is observed, at an individual level, in only 24% of cases. Patients whose disease is controlled by somatostatin analogs or has been cured by pituitary adenomectomy tend to have lower serum PSA levels than patients with active disease. M patients tend to have lower PSA values than PM women, consistent with the main androgen control of PSA production. However, the observation that M women still have higher serum PSA levels than controls suggest that in acromegaly PSA is regulated not only by androgens but also by the GH/IGF-I system itself.

Polychlorinated biphenyls (PCBs) are environmental contaminants which may affect thyroid function. PCBs may reduce serum thyroid hormone (TH) concentrations by either displacing T4 from TH transport proteins or increasing its hepatic metabolism. The reduced serum T4 causes neurological and growth defects in animals exposed to PCBs during the perinatal period, which can partially be reverted by T4 administration. In addition to a hypothyroid-like syndrome, a direct action of PCBs on TH-sensitive genes has been postulated. In the present study the effects of Aroclor 1254 (ARO), a mixture of PCBs, on transcription of TH-dependent genes were investigated. A reporter plasmid containing the TH-responsive element (TRE) of malic enzyme (ME) gene was used in transient transfections to assess the responsiveness to ARO. ARO (10 microM) reduced the CAT activity by about 50% and competed with T3 to reduce the induction of transcription. Cotransfection of TH receptor (TR) and a wild type TRE was required to reveal ARO inhibitiry effect, which was abolished by a mock reaction not containing TR or by a mutated TRE. ARO reduced the 125I-T3 binding to TR by 30%, but did not affect the interaction of TR with a 32P-labeled TRE in gel shift assay. ARO is likely to produce a conformational change in in vitro translated TR, leading to its increased proteolysis by trypsin. These results demonstrate that ARO interacts with TR, thereby affecting the transcription of TH-sensitive genes, and provide a molecular basis to further explain the complex effects of PCBs on TH disruption.

Prostate-specific antigen (PSA) is a serine protease with chymotripsine-like enzymatic activity, produced primarily by the prostate gland. It is widely used as a marker of androgen sensitive-prostate cancer. Likewise, women with androgen-dependent hirsutism have increased serum PSA levels. The aim of the present study was to investigate whether female patients with Cushing's disease had increased serum PSA concentrations. We studied 22 patients with active Cushing's disease. Twelve out of 22 patients were also evaluated after remission of the disease. Forty normal women with no signs of hirsutism served as controls. Mean serum PSA levels were higher in patients with active Cushing's disease than controls (p=0.005). Mean serum PSA levels decreased after remission of the disease (33.7+/-63.3 pg/ml vs 2.2+/-3.0 pg/ml, p0.002, in active and cured patients, respectively). All patients with high serum PSA levels had a normalization of this parameter after the disease was cured. Serum T, DHEAS and delta4 concentrations decreased after the remission of Cushing's disease. A positive correlation was found between serum PSA and T values (r=0.6, p0.05). In conclusion, elevated serum PSA values are markers of androgen activity in female with Cushing's disease and their normalization may represent an additional index of remission of the disease.

Amiodarone, a benzofuranic derivative, iodine-rich drug, has been used in pregnancy for either maternal or fetal tachyarrhythmias. Amiodarone, its main metabolite (desethylamiodarone) and iodine are transferred, albeit incompletely, through the placenta, resulting in a relevant fetal exposure to the drug and iodine overload. Since the fetus acquires the capacity to escape from the acute Wolff-Chaikoff effect only late in gestation, the iodine overload may cause fetal/neonatal hypothyroidism and goiter. Among the reported 64 pregnancies in which amiodarone was given to the mother, 11 cases (17%) of hypothyroidism in the progeny (10 detected at birth, 1 in utero) were reported, 9 non-goitrous (82%) and 2 (18%) associated with goiter. Hypothyroidism was transient in all cases, and only 5 infants were treated short-term with thyroid hormones. Only 2 newborns had transient hyperthyroxinemia, associated with low serum TSH concentrations in one. Neurodevelopment assessment of the hypothyroid infants, when carried out, showed in some instances mild abnormalities, most often reminiscent of the Non-verbal Learning Disability Syndrome; however, these features were also reported in some amiodarone-exposed euthyroid infants, suggesting that there might be a direct neurotoxic effect of amiodarone during fetal life. Breast-feeding was associated with a substantial ingestion of amiodarone by the infant, but in the few cases followed it did not cause changes in the newborn's thyroid function. In conclusion, amiodarone therapy during pregnancy may cause fetal/neonatal hypothyroidism and, less frequently, goiter. Thus, the use of amiodarone in pregnancy should be limited to maternal/fetal tachyarrhythmias which are resistant to other drugs or life-threatening. If amiodarone is used during gestation, a careful fetal/neonatal evaluation of thyroid function and morphology is warranted. It seems prudent to advise that fetal/neonatal hypothyroidism be treated, as soon as the diagnosis is made, even in utero, to avoid neurodevelopment abnormalities, although the latter may occur independently of hypothyroidism. If breast-feeding is allowed, careful evaluation of the infant's thyroid function and morphology is required because of the continuing exposure of the infant to the drug.

Amiodarone (AMD) is one of the most effective antiarrhythmic drugs available. However, its use is often limited by side-effects, mainly hypo- or hyperthyroidism. As AMD displays direct toxic effect on different cell types, we investigated the cytotoxic effect of AMD and its main metabolite, desethylamiodarone (DEA), in thyroid (TAD-2) and nonthyroid (HeLa) cell lines. Both AMD and DEA displayed a dose-dependent toxicity in TAD-2 and HeLa cells, although DEA was more effective. Both TAD-2 and HeLa cells underwent apoptosis, as evidenced by plasma membrane phosphatidylserine exposure and DNA fragmentation. Inhibition of protein synthesis with cycloheximide and inhibition of endogenous peroxidase activity with propylthiouracil did not affect this AMD- and DEA-induced apoptosis in TAD-2 cells. Western blot analysis did not display variations in the expression of p53, Bcl-2, Bcl-XL, and Bax proteins during the treatment with AMD and DEA. Generation of reactive oxygen species, investigated by flow cytometry with dichlorofluorescein diacetate, did not show the production of free radicals during drug treatment. Furthermore, Western blot analysis of cytosolic and mitochondrial fractions prepared from AMD-treated cells demonstrated that AMD induces the release of cytochrome c into the cytosol from the mitochondria. These data indicate that AMD induces cytochrome c release from mitochondria, triggering apoptosis through an iodine-independent mechanism, and that this process is not mediated by modulation of p53, Bcl-2, Bcl-XL, or Bax protein expression and does not involve the generation of free radicals.

Pendred's syndrome is an autosomal recessive disorder characterized by goitre, sensorineural deafness and iodide organification defect. It is one of the most frequent causes of congenital deafness, accounting for about 10% of hereditary hearing loss. It is caused by mutations in the pendrin (PDS) gene, a 21 exon gene located on chromosome 7. The aim of this study was to examine an Italian family affected with Pendred's syndrome at the molecular level.Thirteen subjects belonging to a family from Southern Italy were evaluated for the clinical and genetic features of Pendred's syndrome.Exons 2-21 of the PDS gene were amplified from peripheral leucocytes by the polymerase chain reaction; mutation analysis was performed by single strand conformation polymorphism, direct sequencing and restriction analysis.The index patient had the classical triad of the syndrome and harboured two mutations in the PDS gene in the form of compound heterozygosity. He was found to be heterozygous for a cytosine to adenosine mutation at nucleotide 1523 in exon 13 and for a IVS 1001 + 1G --A mutation. The former is a novel mutation which results in a change of 508 threonine to asparagine in the putative eleventh transmembrane domain. The latter mutation in the donor splice site has already been described in other patients and is thought to lead to aberrant splicing and premature protein truncation. Three subjects who were heterozygous for one mutation had normal phenotypes. Two subjects had sensorineural deafness and were heterozygous for a single mutation. Goitre was found only in patients with Pendred's syndrome and was absent in all other individuals, albeit residing in an iodine-deficient area.We have identified a novel mutation in the pendrin gene causing Pendred's syndrome, and confirm that molecular analysis is a useful tool for a definitive diagnosis. This is particularly relevant in cases such as in the subjects of our family in which the clinical features might be misleading and other genetics factors might be responsible for deafness.

Effectiveness of radioiodine for Graves' hyperthyroidism depends also on its intrathyroidal persistence. The latter is enhanced by lithium by blocking iodine release from the thyroid. One hundred ten patients with Graves' hyperthyroidism were randomly assigned to treatment with radioiodine or radioiodine plus lithium, stratified according to goiter size (or =40 or40 mL) and evaluated for changes in thyroid function and goiter size, at monthly intervals, for 12 months. Cure of hyperthyroidism occurred in 33 of 46 patients (72%) treated with radioiodine and in 45 of 54 patients (83%) treated with radioiodine plus lithium. The probability of curing hyperthyroidism was higher and its control prompter (P = 0.02) in the radioiodine-plus-lithium group. Patients withor =40-mL goiters had similar persistence of hyperthyroidism (13%), but lithium-treated patients had hyperthyroidism controlled earlier (P = 0.04). Among patients with40-mL goiters, hyperthyroidism was cured in 6 of 15 patients (40%) treated with radioiodine alone and in 12 of 16 patients (75%) treated with radioiodine plus lithium (P = 0.07), and cure occurred earlier in the latter (P = 0.05). Goiters shrank in both groups (P0.0001), more effectively and promptly (P0.0005) in the radioiodine-plus-lithium group. Serum free T4 and T3 levels increased shortly after therapy only in the radioiodine group (P0.01). Lithium carbonate enhances the effectiveness of radioiodine therapy, in terms of prompter control of hyperthyroidism, in patients with small or large goiters. In the latter group, lithium also increases the rate of permanent control of hyperthyroidism.

Retinoid-like receptors play a central role in hormonal responses by forming heterodimers with other nuclear hormone receptors. In this study we have identified the peroxisome proliferator-activated receptor (PPAR) as a new thyroid hormone receptor (THR) auxiliary nuclear protein, heterodimerizing with THR in solution. Although these heterodimers do not recognize a classical thyroid hormone response element (TRE) characterized by direct repeat separated by four nucleotides (DR+4), PPAR behaves as a dominant negative regulator of thyroid hormone (TH) action. However, a TH-dependent positive effect is elicited by selective interaction of the THR beta-PPAR but not the THR alpha-PPAR heterodimer with a novel TRE (DR+2). The critical region of THR beta was mapped to 3 amino acids in the distal box of the DNA binding domain. Hence, PPAR can positively or negatively influence TH action depending on TRE structure and THR isotype.

Since many tests to investigate thyroid function are currently available, appropriate selection is required to limit the number of assay needed to establish the correct diagnosis of thyroid dysfunction. The limitations inherent in the different tests, and the interferences caused by nonthyroidal factors, especially drugs, must, therefore, be taken into account. Serum total thyroid hormone (TT4 and TT3) determinations are largely affected by changes in the concentrations of thyroid hormone transport proteins (mainly T4-binding globulin). Thus, in many cases, serum TT4 and TT3 measurements do not reliably establish thyroid status. Serum free thyroid hormone (FT4 and FT3) concentrations are independent of transport proteins and more appropriately reflect thyroid status. Serum FT3 measurement is more appropriate for the diagnosis of hyperthyroidism and drug-overdosage in L-T4-treated patients. Conversely, serum FT4 measurement more correctly identifies hypothyroid patients. Serum TSH determination by the currently available sensitive (low detection limit) assays constitutes an indispensable complementary test in both conditions.

The effects of surgery on TSH secretion, with particular regard to the nocturnal TSH surge, were evaluated in 10 consecutive patients followed for 6 days after surgery. Surgical trauma was associated in all patients with significant decreases in serum total and free T3 and a significant increase in serum rT3 levels, with no variations in serum total and free T4 concentrations. A marked increase in serum cortisol levels was observed, with higher values at night than in the morning. Serum cortisol levels and circadian rhythm normalized on the fifth day. Serum TSH values in the morning significantly decreased on the first day after surgery and returned to normal on the second day. Serum TSH values at night (2400-0200 h) were higher than in the morning preoperatively, but the nocturnal surge was abolished from days 1-5 after surgery and was restored only on the sixth day. Thus, surgery was associated with a prolonged loss of the nocturnal serum TSH surge. This effect on TSH secretion was more marked than predictable on the basis of serum TSH measurements in the morning alone. An inverse relationship was found between serum cortisol and serum TSH values at night, suggesting that the excessive endogenous cortisol secretion might play a role in the derangement of TSH secretion.

Eye disease was associated with hyperthyroidism in 202 of 221 patients with active Graves' ophthalmopathy (91.4%) and was not accompanied by thyroid hyperfunction (euthyroid Graves' disease) in the remaining 19 (8.6%). All the latter patients had some mild thyroid abnormalities (thyroid autoantibodies, negative TRH test, negative T3 suppression test, goitre). Sex distribution analysis evidenced a higher prevalence in females with a female/male ratio of 2.1 which was, however, significantly lower (P < 0.05) than that observed in control (Graves' disease patients without overt ophthalmopathy (female/male ratio = 3.4)). Patients with euthyroid Graves' disease showed a female/male ratio of 0.7. Age distribution revealed a peak prevalence in the 5th decade of life, identical to that of Graves' disease without ophthalmopathy. A close temporal relationship between the onset of hyperthyroidism and the onset of ophthalmopathy was found, since in about 85% of the patients the first ocular manifestations occurred within ±18 months around the onset of hyperthyroidism.