The ongoing challenge of discrepant growth hormone and insulin-like growth factor I results in the evaluation of treated acromegalic patients: a systematic review and meta-analysis.

OBJECTIVE: Growth hormone (GH) and insulin-like growth factor I (IGF-I) are the principal biomarkers used to assess disease activity in acromegaly, and any discrepancy between them renders interpretation of results inconclusive. Purpose of this study was to assess the frequency of this discrepancy and identify parameters that might affect its occurrence. DESIGN: A systematic review of MEDLINE and Scopus was performed (1987-2013) followed by a meta-analysis to address the frequency of discrepant results between GH and IGF-I levels. Meta-regression and subgroup analyses were performed assessing the effects of the year of publication, the different types of GH testing and GH assays used, as well as the impact of treatment with somatostatin analogues (SSAs) on the occurrence of this discrepancy. RESULTS: The analysis retrieved 39 eligible studies totalling 7071 patients. The pooled discordance rate between GH and IGF-I was 25·7% (95% CI: 22·3-29·4), and the predominant format was that of elevated IGF-I with normal GH levels (15·3%, 95% CI: 12·5-18·7). No significant correlation between the discordance rate and the year of publication was shown; whereas, the use of ultrasensitive GH assays resulted in higher discordance rates (30·7%, 95% CI: 25·9-35·9 vs 19·8%, 95% CI: 14·1-27·2, P = 0·04) as did treatment with SSAs (32·5%, 95% CI: 27·8-37·4) vs (21·6%, 95% CI: 17·8-25·6, P = 0·001). CONCLUSIONS: Discrepancy between GH and IGF-I results is encountered in a quarter of treated patients with acromegaly, especially when using ultrasensitive GH assays or in patients receiving SSAs, a fact that the clinician should take into consideration when making clinical decisions.

Impact of gsp mutations in somatotroph pituitary adenomas on growth hormone response to somatostatin analogs: a meta-analysis.

OBJECTIVE: Somatic mutations in the GNAS1 gene, which encodes the alpha-subunit of G stimulatory proteins (gsp), are frequently detected in somatotroph pituitary tumors and have been associated to specific clinical and histopathological characteristics. However, the question whether the presence of a somatic gsp mutation affects the response to somatostatin analog treatment remains unresolved. DESIGN: Following a literature search, we performed a meta-analysis, including 8 eligible studies, in order to estimate the effect of gsp mutation on the percent reduction of growth hormone (GH) levels during an acute octreotide suppression test (OST). A total of 310 patients with acromegaly [126 gsp (+) and 184 gsp (-)] were included in the analysis. RESULTS: The presence of the gsp mutation was related with a greater reduction in GH levels on OST [Weighted Mean Difference (WMD): 9.08 % (95 % CI, 2.73, 15.42); p = 0.005; random effects model]. There was significant heterogeneity for this effect estimate (I(2) = 58 %, p value for heterogeneity = 0.02). A sensitivity analysis after exclusion of a study with different methodology of OST provided similar estimates [WMD: 6.93 % (95 % CI, 1.40, 12.46); p = 0.01], albeit with no significant heterogeneity (I(2) = 35 %, p value for heterogeneity = 0.16). CONCLUSIONS: The present meta-analysis suggests a role for gsp mutation as a prognostic factor of treatment response to somatostatin analogs.

Incidence of pituitary incidentalomas in patients with adrenal adenomas.

With the advent of modern imaging modalities, endocrine incidentalomas are increasingly being discovered. We aimed to investigate the presence of pituitary incidentalomas (PI) in patients with adrenal incidentalomas (AI), and identify potential metabolic correlates in this cohort. 26 patients (18 females) with AI discovered on abdominal computerized tomography were studied. All patients underwent pituitary magnetic resonance imaging (MRI) and endocrine investigations to evaluate functional adrenal pathology, anterior pituitary hormonal status, insulin-resistance indices and presence of metabolic syndrome. Pituitary MRI revealed a microadenoma and a 4×5 mm cyst in 1 patient respectively, and an empty sella in 4 (2 partial) patients. Overall, 6/26 (23%) patients with an AI had evidence of pituitary imaging pathology but only 8% had a PI; none had any evidence of abnormalities in pituitary function. Subclinical hypercortisolism was the only hyperfunctional status detected in 4 patients with AI but was unrelated to the pituitary findings. No abnormality of insulin secretion and action was found between patients with or without pituitary pathology. In the present study 23% of patients with AI had some alteration in pituitary morphology, and 2 a PI without accompanying pituitary hormonal deficit or metabolic derangement. Further studies are required to address this issue and identify a potential pathogenetic mechanism.

Response to the article: "primary aldosteronism: are we missing the wood for the trees?".

This letter is a short response to Dr Funder's recent commentary on primary aldosteronism under the title "Primary aldosteronism: are we missing the wood for the trees?". We briefly discuss recent data from our department on autonomous aldosterone secretion (AAS) and the efficacy of mineralocorticoid receptor antagonists in a group of patients with AAS, that would otherwise remain undiagnosed.

Azathioprine as an alternative treatment in primary hypophysitis.

Primary hypophysitis (PH) is an unusual disorder characterized by inflammatory infiltration of the pituitary gland with various degree of pituitary dysfunction. Glucocorticoids are the treatment of choice in the majority of patients. Still, in patients with poor response in glucocorticoids or when their administration is accompanied with serious side effects, the use of alternative agents should be considered; up to now, data on other therapeutic approaches remains scant mainly due to the rarity of the disease. Among them, the immunosuppressant azathioprine could represent an effective and safe alternative. In this article, we present our clinical experience of two cases with PH successfully treated with azathioprine following serious side effects after initial treatment with glucocorticoids and provide a brief review of the existing literature.

The effect of iodine administration on the development of thyroid autoimmunity in patients with nontoxic goiter.

OBJECTIVE: Previous studies, mostly performed in iodine-deficient areas, have suggested that the administration of iodine to patients with endemic goiter may be associated with the development of thyroid autoantibodies (ThAbs); however, this has not been a consistent finding. In this study, we evaluated the effect of iodine on thyroid function and on the development of indices of autoimmunity (ThAbs and lymphocytic infiltration) in an iodine replete area. METHODS: Iodized oil (1 mL) was administered intramuscularly to 40 euthyroid patients with nontoxic goiter, adequate iodine intake, and absent or normal levels of ThAbs. Blood and urinary samples were taken at time 0, 3, 6, and 12 months after iodine administration. Thyroid volume was evaluated and fine-needle aspiration (FNA) was performed at 0, 6, and 12 months. RESULTS: Seven patients developed abnormal levels of ThAbs at some time between 3 and 12 months after iodine administration (p = 0.017). Mean anti-thyroglobulin (Tg) antibody levels increased at 6 months without reaching abnormal levels, but did not reach statistical significance (p = 0.062). Lymphocytic infiltration was detected in FNA smears in 10 cases before and in 27 cases after treatment (p = 0.0003). Triiodothyronine (T3) decreased at 12 months of follow-up, while thyroxine (T4) and thyrotropin (TSH) levels did not change significantly. A decrease in the mean levels of thyroglobulin as well as a small reduction in goiter size was observed at 6 and 12 months. CONCLUSION: The administration of iodized oil to patients with small nontoxic goiter in an iodine-replete area was accompanied by the development of abnormal levels of ThAbs in some cases and by an increase in thyroid lymphocytic infiltration.

Incidence of sideropenia and effects of iron repletion treatment in women with subclinical hypothyroidism.

Sideropenia affects ca. 20% of the world population, and iron dependent anemia is the most frequent type of anemia worldwide. The aim of the study was to investigate the incidence of sideropenia and dependent anemia in patients with subtle changes of the thyroid function, such as subclinical hypothyroidism (SH). 57 women with SH and 61 euthyroid controls (CG) were studied. Serum concentrations of T4, T3, TSH, anti-TPO, anti-Tg, ferrum (Fe), ferritin (Frt) total iron binding capacity (TIBC) and blood count were determined. In SH 17 patients (29.8%) presented low Fe levels (<50 microg/dl). 9 (15.7%) also had decreased Frt, confirming iron deficiency, whereas 8 patients presented additionally diminished hematocrit and hemoglobin levels, suggesting manifested sideropenic anemia. In CG, 10 persons (16%) had sideropenia, 6 (9.8%) had low Fe and Frt and only 3 (4.9%) had blood count alterations suggesting manifested sideropenic anemia. In SH, anti-TPO were positive in 39 patients (68%), whereas, in CG only 2 (3.2%) were positive. 8 patients with SH and manifested sideropenic anemia were treated with ironproteinsuccinylate (I-PSL), (80 mg Fe /day, for three months), a new iron compound. The repletion treatment safely led to the clinical and laboratory correction of sideropenia and showed a good tolerability. Furthermore, iron treatment provoked a minor increase of T4 and a mild decline of TSH, but the levels were not significant. These results suggest that sideropenia is a common finding in patients with slightly decreased thyroid activity, and that determination of Frt should be routinely advised. Finally, in the assessment of sideropenia and dependent anemia, evaluation of the thyroid function must be taken into account.

Inhibitory action of oral thyrotropin-releasing hormone on the glucoregulatory response of the oral glucose tolerance test.

Thyrotropin-releasing hormone (TRH) has been found in the gastrointestinal tract, where it mainly exerts an inhibitory action. We used oral TRH, a stable and powerful formulation, to explore the glucoregulatory response of oral glucose tolerance test (OGTT) on obese patients with impaired glucose tolerance (IGT). Seven obese patients with IGT and eight controls were investigated. Three tests were performed on three separate days. On day 1, An oral TRH test: a 40 mg TRH tablet, was given. Blood samples for blood glucose (BG), proinsulin (PI), insulin (INS), C-peptide (CP), thyroxine (T4), triiodothyronine (T3), and thyrotropin (TSH) were collected every 30 minutes for 3 hours. On day 2, an OGTT with 75 g glucose was performed. On day 3, an oral TRH test was administered 30 minutes before the OGTT, and blood was collected every 30 minutes for 3 hours. Oral-TRH had no effect on basal BG and on pancreatic hormone secretion. Oral TRH, coupled with OGTT in both controls and obese patients, led to a significant inhibition of BG (p < 0.01), of CP (p < 0.001), and of INS (p < 0.001) during the first hour of administration, and afterward, there was only a very slight increase, compared with levels after only OGTT treatment. After OGTT, PI peaked at 90 minutes (9.4+/-3 ng/mL) in controls and at 60 minutes (12.7+/-2.5 ng/mL) in obese patients. TRH application prior to OGTT inhibited PI secretion for 90 minutes in controls, whereas in obese patients PI levels were decreased, not inhibited, during the OGTT. The mechanism of the inhibitory TRH action on OGTT-induced increase of BG and pancreatic hormone secretion is not clear. It could be due to inhibition of gastric motility, and on a paracrine effect that enhances secretion of somatostatin that then suppresses INS, CP, and possibly PI levels. The partial escape of PI from the TRH blockade in obese patients with IGT might indicate a diminished functioning capability of beta-cells and that TRH cannot affect the INS processing within the beta-cells in these patients.