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Context: The utility of thyroglobulin (Tg) in the follow-up of differentiated thyroid cancer (DTC) patients has been well-documented. Although third-generation immunoassays have improved accuracy, limitations persist (interfering anti-Tg antibodies and measurement variability). Evolving treatment strategies require a reevaluation of Tg thresholds for optimal patient management., Objective: To assess the performance of serum Tg testing in two populations: patients receiving total thyroidectomy and radioiodine remnant ablation (RRA), or treated with thyroidectomy alone., Design: Prospective observational study. Setting. Centers contributing to the Italian Thyroid Cancer Observatory (ITCO) database., Patients: We included 540 patients with 5 years of follow-up and negative anti-Tg antibodies., Interventions: Serum Tg levels assessed at 1-year follow-up visit., Main Outcome Measure: Detection of structural disease within 5 years of follow-up., Results: After excluding 26 patients with structural disease detected at any time point, the median Tg did not differ between patients treated with or without radioiodine. Data-driven Tg thresholds were established based on the 97th percentile of Tg levels in disease-free individuals: 1.97 ng/mL for patients undergoing thyroidectomy alone (lower than proposed by the MSKCC protocol and ESMO Guidelines, yet demonstrating good predictive ability, with a negative predictive value (NPV) of 98%) and 0.84 ng/mL for patients receiving post-surgical RRA. High sensitivity and NPV supported the potential of these thresholds in excluding structural disease., Conclusions: This real-world study provides evidence for the continued reliability of 1-year serum Tg levels. The data-driven Tg thresholds proposed offer valuable insights for clinical decision-making in patients undergoing total thyroidectomy with or without RRA., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Skeletal fragility is observed in 30% to 60% of acromegaly patients, representing an emerging complication of the disease that increases disability. Despite several studies having investigated the clinical and hormonal prognostic factors for the occurrence of vertebral fractures (VFs) in acromegaly, very few data are available on their prevention/treatment including the effect of vitamin D (VD) supplementation, which has been reported to have a fracture-protective effect in several studies in patients with osteoporosis., Objective: We aimed to investigate the role of cholecalciferol (D3) supplementation in the prevention of incident VFs (i-VFs) in acromegaly., Methods: A longitudinal, retrospective and multicenter study was performed on 61 acromegaly patients treated and untreated with D3 supplementation., Results: Twenty-six patients were treated with D3 supplementation according to clinical guidelines. The median D3 weekly dosage was 8500 IU (interquartile range [IQR]: 3900). The median duration of D3 supplementation was 94 months (IQR: 38). At last follow-up, i-VFs were diagnosed in 14 patients (23%). I-VFs were less prevalent in patients on D3 supplementation (14.3% of cases) compared to patients not treated with D3 (85.7%; P = .02). The final level of serum V25OH-D was significantly lower in patients who developed i-VFs (28.6 ng/mL, IQR: 4.1) compared to patients who did not develop i-VFs (34.2 ng/mL, IQR: 9.6; P = .05). The logistic regression confirmed the protective role of D3 supplementation on the occurrence of i-VFs (odds ratio: 0.16; 95% CI, 0.03-0.79; P = .01)., Conclusion: It is likely that D3 supplementation could lead to a reduction in i-VFs in acromegaly., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Prolactinomas are the most frequent pituitary adenomas. Prolactinoma may occur in different clinical settings and always require an individually tailored approach. This is the reason why a panel of Italian neuroendocrine experts was charged with the task to provide indications for the diagnostic and therapeutic approaches that can be easily applied in different contexts. The document provides 15 recommendations for diagnosis and 54 recommendations for treatment, issued according to the GRADE system. The level of agreement among panel members was formally evaluated by RAND-UCLA methodology. In the last century, prolactinomas represented the paradigm of pituitary tumors for which the development of highly effective drugs obtained the best results, allowing to avoid neurosurgery in most cases. The impressive improvement of neurosurgical endoscopic techniques allows a far better definition of the tumoral tissue during surgery and the remission of endocrine symptoms in many patients with pituitary tumors. Consequently, this refinement of neurosurgery is changing the therapeutic strategy in prolactinomas, allowing the definitive cure of some patients with permanent discontinuation of medical therapy.

Objectives: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in Western populations, being rarer in Asian and African people. It has been suggested that patients with CLL from Africa might have a more aggressive disease compared with white patients. In this study, we aimed to identify genetic factors that may account for this difference., Methods: We analyzed immunoglobulin heavy chain (IGH) genes' mutational status by performing next-generation sequencing in 25 Senegalese and 50 Italian patients with CLL., Results: We found that Senegalese patients more frequently had adverse prognostic factors and an unmutated profile. Furthermore, we documented that IGHV1 (IGHV1-69), IGHD3, and IGHJ6 were significantly more frequent in Senegalese patients, whereas IGHV3-30 was common and limited to the Italian cohort. Stereotyped receptors commonly detected in the white population were not recorded in our Senegalese series., Conclusions: The different IGH repertoire we observed in the Senegalese cohort may reflect the diverse genetic and microenvironmental (ie, polymicrobial stimulation) background., (© American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Objectives: Establish and validate optimal minimal immunohistochemistry panels for usage in a staged algorithmic manner for precise diagnosis of B-cell lymphomas in countries with limited resources. Suggest short panels of immunostains to be used in referring units that refer suspected lymphomas to specialist diagnostic centers in resourceful countries., Methods: Significant proportion of six B-cell lymphomas has characteristic morphology requiring a short panel of confirmatory immunostains. The rest would go through five different algorithms., Results: 812 cases in which a B-cell lymphoma or an HIV-associated lymphoma was suspected on morphological grounds were evaluated. This led to arriving at a specific diagnosis of 799 B-cell lymphomas. A correct diagnosis was achievable in 69% cases with the application of three to five antibodies; others required additional work-up., Conclusions: The panels/algorithms assist pathologists in practicing lymphoma diagnostics in countries with limited resources and in making lymphoma referrals to specialist centers., (© American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Recent studies using next-generation sequencing (NGS) analysis disclosed the importance of the intrinsic activation of the B-cell receptor (BCR) pathway in the pathogenesis of sporadic Burkitt lymphoma (sBL) due to mutations of TCF3/ID3 genes. Since no definitive data are available on the genetic landscape of endemic Burkitt (eBL), we first assessed the mutation frequency of TCF3/ID3 in eBL compared with sBL and subsequently the somatic hypermutation status of the BCR to answer whether an extrinsic activation of BCR signaling could also be demonstrated in Burkitt lymphoma., Methods: We assessed the mutations of TCF3/ID3 by RNAseq and the BCR status by NGS analysis of the immunoglobulin genes (IGs)., Results: We detected mutations of TCF3/ID3 in about 30% of the eBL cases. This rate is significantly lower than that detected in sBL (64%). The NGS analysis of IGs revealed intraclonal diversity, suggesting an active targeted somatic hypermutation process in eBL compared with sBL., Conclusions: These findings support the view that the antigenic pressure plays a key role in the pathogenetic pathways of eBL, which may be partially distinct from those driving sBL development., (© American Society for Clinical Pathology, 2016.)

Objectives: Epstein-Barr virus (EBV)-induced lymphoproliferative disorders (LPDs) are lymphoid proliferations arising as a result of the loss of an effective EBV-specific cytotoxic T-cell response. LPDs may occur for primary or acquired impairment of the immune system, as well as in some persons without documented immunodeficiency., Methods: In this article, we describe the case of a human immunodeficiency virus-positive patient affected by an EBV-LPD of the stomach who developed a nodal diffuse large B-cell lymphoma with complex morphologic and molecular features., Results: GeneScan analysis of the gastric specimen identified two different heavy-chain immunoglobulin gene (IGH) rearrangements characterized by a dominant peak of 285 base pairs (bp) in length and a smaller peak of 266 bp in length. In the lymph node sample, IGH evaluation also demonstrated two different peaks; however, the main peak corresponded to the minor peak detected in the EBV-LPD specimen at the diagnosis. In addition, a monoclonal immunoglobulin light chain gene (IGL) rearrangement was also found. We also demonstrated that the major peak in the stomach corresponded to the EBV-positive population observed in the histologic sections., Conclusions: This case may provide additional insights to better understanding the "hit-and-run" role for EBV in lymphomagenesis. However, we could not exclude that our findings represent the co-occurrence of two unrelated B-cell neoplasms rather than a progression from an EBV-positive neoplasm to an EBV-negative one., (Copyright© by the American Society for Clinical Pathology.)

Everolimus is a valid therapeutic option for neuroendocrine tumors (NETs); however, data in a real-world setting outside regulatory trials are sparse. The aim of this study was to determine everolimus tolerability and efficacy, in relation to previous treatments, in a compassionate use program. A total of 169 patients with advanced progressive NETs treated with everolimus were enrolled, including 85 with pancreatic NETs (pNETs) and 84 with nonpancreatic NETs (non-pNETs). Previous treatments included somatostatin analogs (92.9%), peptide receptor radionuclide therapy (PRRT; 50.3%), chemotherapy (49.7%), and PRRT and chemotherapy (22.8%). Overall, 85.2% of patients experienced adverse events (AEs), which were severe (grade 3-4) in 46.1%. The most frequent severe AEs were pneumonitis (8.3%), thrombocytopenia (7.7%), anemia (5.3%), and renal failure (3.5%). In patients previously treated with PRRT and chemotherapy, a 12-fold increased risk for severe toxicity was observed, with grade 3-4 AEs reported in 86.8% (vs. 34.3% in other patients). In addition, 63.3% of patients required temporarily everolimus discontinuation due to toxicity. Overall, 27.8% of patients died during a median follow-up of 12 months. Median progression-free survival (PFS) and overall survival (OS) were 12 months and 32 months, respectively. Similar disease control rates, PFS, and OS were reported in pNETs and non-pNETs. In the real-world setting, everolimus is safe and effective for the treatment of NETs of different origins. Higher severe toxicity occurred in patients previously treated with systemic chemotherapy and PRRT. This finding prompts caution when using this drug in pretreated patients and raises the issue of planning for everolimus before PRRT and chemotherapy in the therapeutic algorithm for advanced NETs., (©AlphaMed Press.)

Context: Antipituitary antibodies (APA) but not antihypothalamus antibodies (AHA) are usually searched for in autoimmune hypopituitarism., Objective: Our objective was to search for AHA and characterize their hypothalamic target in patients with autoimmune hypopituitarism to clarify, on the basis of the cells stained by these antibodies, the occurrence of autoimmune subclinical/clinical central diabetes insipidus (CDI) and/or possible joint hypothalamic contribution to their hypopituitarism., Design: We conducted a cross-sectional cohort study., Patients: Ninety-five APA-positive patients with autoimmune hypopituitarism, 60 without (group 1) and 35 with (group 2) lymphocytic hypophysitis, were studied in comparison with 20 patients with postsurgical hypopituitarism and 50 normal subjects., Main Outcome Measures: AHA by immunofluorescence and posterior pituitary function were evaluated; then AHA-positive sera were retested by double immunofluorescence to identify the hypothalamic cells targeted by AHA., Results: AHA were detected at high titer in 12 patients in group 1 and in eight patients in group 2. They immunostained arginine vasopressin (AVP)-secreting cells in nine of 12 in group 1 and in four of eight in group 2. All AVP cell antibody-positive patients presented with subclinical/clinical CDI; in contrast, four patients with GH/ACTH deficiency but with APA staining only GH-secreting cells showed AHA targeting CRH- secreting cells., Conclusion: The occurrence of CDI in patients with lymphocytic hypophysitis seems due to an autoimmune hypothalamic involvement rather than an expansion of the pituitary inflammatory process. To search for AVP antibody in these patients may help to identify those of them prone to develop an autoimmune CDI. The detection of AHA targeting CRH-secreting cells in some patients with GH/ACTH deficiency but with APA targeting only GH-secreting cells indicates that an autoimmune aggression to hypothalamus is jointly responsible for their hypopituitarism.

Context: GH and IGF-I play a role in breast cancer (BC) development. We previously demonstrated that GH protects the estrogen receptor (ER) positive BC-derived MCF7 cell line toward the cytotoxic effects of doxorubicin (D), independently of IGF-I. This issue may be important in ER negative BC cells that are more aggressive and more likely to develop chemoresistance., Aim of the Study: The aim of this study was to evaluate whether GH may impact chemoresistance phenotype of ER-negative BC-derived MDA-MB-231 cell line and investigate the possible mechanisms implicated in the protective action of GH toward the cytotoxic effects of D in both ER-positive and ER-negative BC-derived cell lines., Results: GH protects ER-negative MDA-MB-231 cells from the cytotoxic effects of D and GH receptor antagonist pegvisomant reduces GH-induced DNA synthesis also in these cells. In both MDA-MB-231 and MCF7 cells, GH does not revert D-induced G2/M accumulation but significantly reduces basal and D-induced apoptosis, an effect blocked by pegvisomant. Glutathione S-transferase activity is not implicated in the protective effects of GH, whereas D-induced apoptosis depends on c-Jun N terminal kinase (JNK) activation. GH reduces both basal and D-stimulated JNK transcriptional activity and phosphorylation., Conclusions: In human BC cell lines, GH directly promotes resistance to apoptosis induced by chemotherapeutic drugs independently of ER expression by modulating JNK, further broadening the concept that GH excess may hamper cytotoxic BC treatment. These findings support the hypothesis that blocking GH receptor may be viewed as a potential new therapeutic approach to overcome chemoresistance, especially in ER-negative BC.

Background: Stroke is a leading cause of death in industrialized countries, representing the main cause of long-term disability. Recent studies indicate that hypopituitarism may be observed after an acute stroke., Objective: The aim was to prospectively investigate incidence and pattern of pituitary dysfunction in patients suffering ischemic stroke and to assess the predictive value of different clinical and radiological parameters for hypopituitarism., Patients and Methods: We assessed endocrine, clinical, radiological, and functional parameters in 56 patients (34 males; mean age, 64.8 ± 1.3 yr; mean body mass index, 25.8 ± 0.45 kg/m(2)) at 1-3 months (visit 1) and 12-15 months (visit 2) after an ischemic stroke., Results: At visit 1, hypopituitarism was detected in 20 (35.7%) of 56 stroke patients, with multiple deficits in three and isolated deficits in 17. At visit 2, hypopituitarism was detected in 18 (37.5%) of 48 stroke patients, with multiple deficits in two. Four patients with previously diagnosed isolated GH or LH/FSH deficit exhibited normal pituitary function, whereas GH deficiency was newly diagnosed in three cases. Hypopituitarism was associated with worse outcome. We identified both clinical (preexisting diabetes mellitus, medical complications during hospitalization) and radiological (Alberta Stroke Programme Early CT Score ≤ 7) parameters as major risk factors for developing hypopituitarism after ischemic stroke., Conclusions: Hypopituitarism may associate with ischemic stroke in one third of cases and persist in a long-term period, aggravating the functional outcome. We identified specific risk factors for hypopituitarism after stroke, which may help to select patients needing an accurate endocrine evaluation to improve stroke outcome.

Mitotane therapy is associated with many side effects, including thyroid function perturbations mimicking central hypothyroidism, possibly due to laboratory test interference or pituitary direct effects of mitotane. We investigated whether increasing concentrations of mitotane in the therapeutic range might interfere with thyroid hormone assays and evaluated the effects of mitotane on a mouse TSH-producing pituitary cell line. TSH, free T(4), and free T(3) levels do not significantly change in sera from hypo-, hyper-, or euthyroid patients after addition of mitotane at concentrations in the therapeutic window. In the mouse TalphaT1 cell line, mitotane inhibits both TSH expression and secretion, blocks TSH response to TRH, and reduces cell viability, inducing apoptosis at concentrations in the therapeutic window. TRH is not capable of rescuing TalphaT1 cells from the inhibitory effects of mitotane on TSH expression and secretion, which appear after short time treatment and persist over time. Our results demonstrate that mitotane does not interfere with thyroid hormone laboratory tests but directly reduces both secretory activity and cell viability on pituitary TSH-secreting mouse cells. These data represent a possible explanation of the biochemical picture consistent with central hypothyroidism in patients undergoing mitotane therapy and open new perspectives on the direct pituitary effects of this drug.

Context: Pituitary adenomas can cause specific syndromes due to hormone excess and/or determine sellar mass symptoms. Pituitary cell growth can sometimes be influenced by medical therapy, such as for somatotroph adenomas treated with somatostatin analogs or prolactinomas treated with dopaminergic drugs. However, nonfunctioning pituitary adenomas (NFAs) are still orphans of medical therapy. Everolimus (RAD001), a derivative of rapamycin, is a well-known immunosuppressant drug, which has been recently shown to have antineoplastic activity in several human cancers., Objective: The objective of the study was to investigate the possible antiproliferative effects of RAD001 in human NFAs., Design: We collected 40 NFAs that were dispersed in primary cultures, treated without or with 1 nm to 1 microm RAD001, 10 nm cabergoline, 10 nm SOM230 (a somatostatin receptor multiligand), and/or 50 nm IGF-I. Cell viability and apoptosis were evaluated after 48 h, and vascular endothelial growth factor (VEGF) secretion was assessed after an 8-h incubation. Somatostatin and dopamine subtype 2 receptor expression was investigated by quantitative PCR., Results: In 28 cultures (70%), Everolimus significantly reduced cell viability (by approximately 40%; P < 0.05 vs. control), promoted apoptosis (+30%; P < 0.05 vs. control), inhibited p70S6K activity (-20%), and blocked IGF-I proliferative and antiapoptotic effects. In selected tissues cotreatment with SOM230, but not cabergoline, exerted an additive effect. Everolimus did not affect VEGF secretion but blocked the stimulatory effects of IGF-I on this parameter., Conclusions: Everolimus reduced NFA cell viability by inducing apoptosis, with a mechanism likely involving IGF-I signaling but not VEGF secretion, suggesting that it might represent a possible medical treatment of invasive/recurrent NFAs.

Context: GH and IGF-I are known to promote breast carcinogenesis. Even if breast cancer (BC) incidence is not increased in female acromegalic patients, mortality is greater as compared with general population., Objective: The objective of the study was to evaluate whether GH/IGF-I excess might influence BC response to chemotherapy., Design: We evaluated GH and IGF-I effects on cell proliferation of a BC cell line, MCF7 cells, in the presence of doxorubicin (Doxo), frequently used in BC chemotherapy, and the possible mechanisms involved., Results: GH and IGF-I induce MCF7 cell growth in serum-free conditions and protect the cells from the cytotoxic effects of Doxo. GH effects are direct and not mediated by IGF-I because they are apparent also in the presence of an IGF-I receptor blocking antibody and disappear in the presence of the GH antagonist pegvisomant. The expression of the MDR1 gene, involved in resistance to chemotherapeutic drugs, was not induced by GH. In addition, c-fos transduction was reduced by Doxo, which prevented GH stimulatory effects. Pegvisomant inhibited basal and GH-induced c-fos promoter transcriptional activity. Autocrine GH action is ruled out by the lack of endogenous GH expression in this MCF7 cell strain., Conclusions: These data indicate that GH can directly induce resistance to chemotherapeutic drugs with a mechanism that might involve GH-induced early gene transcription and support the hypothesis that GH excess can hamper BC treatment, possibly resulting in an increased mortality.

Purpose: The aim of the study was to define the frequency of hereditary forms and the genotype/phenotype correlations in a large cohort of Italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas., Design: We examined 501 consecutive patients with pheochromocytomas and/or paragangliomas (secreting or nonsecreting). Complete medical and family histories, as well as the results of clinical, laboratory, and imaging studies, were recorded in a database. Patients were divided into different groups according to their family history, the presence of lesions outside adrenals/paraganglia considered syndromic for VHL disease, MEN2, and NF1, and the number and types of pheochromocytomas and/or paragangliomas. Germ-line mutations in known susceptibility genes were investigated by gene sequencing (VHL, RET, SDHB, SDHC, SDHD) or diagnosed according to phenotype (NF1). In 160 patients younger than 50 yr with a wild-type profile, multiplex ligation-dependent probe amplification assays were performed to detect genomic rearrangements., Results: Germline mutations were detected in 32.1% of cases, but frequencies varied widely depending on the classification criteria and ranged from 100% in patients with associated syndromic lesions to 11.6% in patients with a single tumor and a negative family history. The types and number of pheochromocytomas/paragangliomas as well as age at presentation and malignancy suggest which gene should be screened first. Genomic rearrangements were found in two of 160 patients (1.2%)., Conclusions: The frequency of the hereditary forms of pheochromocytoma/paraganglioma varies depending on the family history and the clinical presentation. A positive family history and an accurate clinical evaluation of patients are strong indicators of which genes should be screened first.

Context: Ki-67 is a marker of proliferation activity associated with invasiveness and prognosis in human tumors., Objective: The aim of the study was to evaluate the Ki-67 index prognostic relevance in a group of acromegalic patients who underwent transsphenoidal surgery for a GH-secreting pituitary adenoma., Material and Methods: We selected 68 consecutive acromegalic patients referred to our hospital during a 5-yr period. The Ki-67 index was determined by immunohistochemistry on tissue samples obtained from each adenoma after surgery. Those patients who were not completely cured after surgery began medical therapy with somatostatin analogs (SSAs). Periodical pituitary magnetic resonance imaging and hormonal evaluation were performed during the follow-up., Results: Twenty-eight of 68 patients were cured after surgery (41%). Among the 40 patients treated with SSAs, 13 were considered uncontrolled. Pituitary magnetic resonance imaging showed residual/recurrent disease in 25 of 68 patients after 6 months. No correlation was found between Ki-67 index and age, tumor size, GH, or IGF-I plasma levels. Tumors described as having cavernous sinus invasion had a higher mean Ki-67 index as compared with noninvasive tumors (P < 0.01). The Ki-67 index was significantly lower in tumors in patients cured after surgery as compared with patients considered not cured (P < 0.01) and in tumors in patients controlled by SSA therapy as compared with patients considered as uncontrolled (P < 0.05)., Conclusion: The Ki-67 labeling index may predict clinical outcome in postsurgical management of acromegalic patients. We suggest routine Ki-67 evaluation in GH-secreting pituitary adenomas.

The antisecretory effects of somatostatin (SRIH) and its analogs are widely recognized and provide the basis for treatment of hormonal hypersecretion in patients with pituitary adenomas, especially in the settings of acromegaly. Dopamine (DA) agonists have also been used for medical treatment of prolactin and/or GH hypersecretion, and recent evidence points to an even greater antisecretory effect for a chimeric molecule, having high affinity for both SRIH and DA receptors. Evidence for an antiproliferative effect of these compounds has also been provided. This review focuses on the antiproliferative effects of SRIH and its analogs, of DA and chimeric compounds on pituitary adenomas, and on the clinical consequences on tumor volume of pharmacological treatment of pituitary adenomas with these drugs.

Context: Cerebrovascular disease is highly prevalent in the general population, frequently leading to permanent invalidity and reduced quality of life. IGF-I is recognized as an important neuroprotective factor against cerebral hypoxic insult., Objective: The objective of the study was to evaluate pituitary function, in particular GH-IGF-I axis, in adult patients receiving rehabilitation after an ischemic stroke., Subjects and Methods: We studied 42 patients (12 females; age range, 50-88 yr) during rehabilitation after stroke, evaluating the relationship between the GH-IGF-I axis and the severity (National Institutes of Health stroke scale) and outcome [Rancho Los Amigos Scale of Cognitive Functioning (LCFS); Functional Independence Measure (FIM); modified Ranking Scale] from stroke., Results: GH deficiency was demonstrated in five patients (11.9%). Peak GH after GHRH + arginine test and IGF-I levels did not correlate with severity of stroke. IGF-I was positively correlated with LCFS (r = 0.305, P < 0.05) and the difference between FIM on admission and at discharge from rehabilitation (DeltaFIM; r = 0.361, P < 0.02). Outcome indexes (LCFS, FIM at discharge, DeltaFIM) and occurrence of favorable outcome (modified Ranking Scale 0-1) were significantly (P < 0.05) higher in patients with IGF-I levels 161.8 mug/dl or greater (50th percentile of the patient distribution). LH-FSH deficiency (three cases), ACTH deficiency (one case), and hyperprolactinemia (two cases) were detected. One patient had primary hypogonadism, and six males had low testosterone with normal LH and FSH levels. By multivariate analysis, IGF-I level was the main significant predictor of DeltaFIM and LCFS., Conclusions: Ischemic stroke may be associated with pituitary dysfunction, particularly GH and gonadotropin deficiencies. The higher IGF-I levels observed in patients with better outcome suggest a possible neuroprotective role of IGF-I. Circulating IGF-I may predict functional performance during rehabilitation and ischemic stroke outcome.

Context: The recognition of thyroid microcarcinoma has increased due to the widespread use of ultrasound-guided fine-needle aspiration biopsies., Objective: The objective of this study was to describe histological and clinical characteristics of papillary thyroid microcarcinoma (PTMC) less than or equal to 1 cm., Design: This study was a retrospective cohort., Setting: This study was conducted at a university hospital endocrine clinic., Patients: Over a 9-yr period, 243 consecutive patients with PTMC were studied., Results: PTMC was an incidental finding at surgery in 21.4% of the PTMC cases. There were no differences in the clinical characteristics between those with incidental PTMC and those with suspected thyroid carcinoma. None of the patients with a cancer less than 8 mm had distant metastases, whereas distant metastases were observed in patients with cancers >/= 8 mm (P

Context: Traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) are conditions at high risk for the development of hypopituitarism., Objective: The objective of the study was to clarify whether pituitary deficiencies and normal pituitary function recorded at 3 months would improve or worsen at 12 months after the brain injury., Design and Patients: Pituitary function was tested at 3 and 12 months in patients who had TBI (n = 70) or SAH (n = 32)., Results: In TBI, the 3-month evaluation had shown hypopituitarism (H) in 32.8%. Panhypopituitarism (PH), multiple (MH), and isolated (IH) hypopituitarism had been demonstrated in 5.7, 5.7, and 21.4%, respectively. The retesting demonstrated some degree of H in 22.7%. PH, MH, and IH were present in 5.7, 4.2, and 12.8%, respectively. PH was always confirmed at 12 months, whereas MH and IH were confirmed in 25% only. In 5.5% of TBI with no deficit at 3 months, IH was recorded at retesting. In 13.3% of TBI with IH at 3 months, MH was demonstrated at 12-month retesting. In SAH, the 3-month evaluation had shown H in 46.8%. MH and IH had been demonstrated in 6.2 and 40.6%, respectively. The retesting demonstrated H in 37.5%. MH and IH were present in 6.2 and 31.3%, respectively. Although no MH was confirmed at 12 months, two patients with IH at 3 months showed MH at retesting; 30.7% of SAH with IH at 3 months displayed normal pituitary function at retesting. In SAH, normal pituitary function was always confirmed. In TBI and SAH, the most common deficit was always severe GH deficiency., Conclusion: There is high risk for H in TBI and SAH patients. Early diagnosis of PH is always confirmed in the long term. Pituitary function in brain-injured patients may improve over time but, although rarely, may also worsen. Thus, brain-injured patients must undergo neuroendocrine follow-up over time.

Traumatic brain injury (TBI) is one of the main causes of death and disability in young adults, with consequences ranging from physical disabilities to long-term cognitive, behavioural, psychological and social defects. Post-traumatic hypopituitarism (PTHP) was recognized more than 80 years ago, but it was thought to be a rare occurrence. Recently, clinical evidence has demonstrated that TBI may frequently cause hypothalamic-pituitary dysfunction, probably contributing to a delayed or hampered recovery from TBI. Changes in pituitary hormone secretion may be observed during the acute phase post-TBI, representing part of the acute adaptive response to the injury. Moreover, diminished pituitary hormone secretion, caused by damage to the pituitary and/or hypothalamus, may occur at any time after TBI. PTHP is observed in about 40% of patients with a history of TBI, presenting as an isolated deficiency in most cases, and more rarely as complete pituitary failure. The most common alterations appear to be gonadotropin and somatotropin deficiency, followed by corticotropin and thyrotropin deficiency. Hyper- or hypoprolactinemia may also be present. Diabetes insipidus may be frequent in the early, acute phase post-TBI, but it is rarely permanent. Severity of TBI seems to be an important risk factor for developing PTHP; however, PTHP can also manifest after mild TBI. Accurate evaluation and long-term follow-up of all TBI patients are necessary in order to detect the occurrence of PTHP, regardless of clinical evidence for pituitary dysfunction. In order to improve outcome and quality of life of TBI patients, an adequate replacement therapy is of paramount importance.

Somatostatin (SRIF) analogs interacting with SRIF receptor (SSTR) subtypes SSTR2 and SSTR5 reduce hormone secretion of pituitary adenomas, but their antiproliferative effects are still controversial. We investigated the in vitro effects of SRIF and SSTR-selective agonists interacting with SSTR1 (BIM-23926), SSTR2 (BIM-23120), SSTR5 (BIM-23206), or both SSTR2 and SSTR5 (BIM-23244) on alpha-subunit and chromogranin A secretion and on cell viability of 12 nonfunctioning pituitary adenomas (NFA) expressing SSTR1, SSTR2, and SSTR5, as assessed by RT-PCR. Treatment with SRIF or BIM-23206 did not modify alpha-subunit and chromogranin A secretion, which was significantly inhibited by BIM-23926, BIM-23120, and BIM-23244. SRIF and BIM-23120 did not influence cell viability, which was significantly promoted by BIM-23206 and BIM-23244 and reduced by treatment with BIM-23926. These results demonstrate that, in the selected NFA, the SSTR1-selective agonist inhibits secretory activity and cell viability, the SSTR2-selective agonist inhibits secretion but not cell viability, and the SSTR5-selective agonist does not influence secretion but promotes cell viability. These data can explain the lack of inhibitory effects of currently used SRIF analogs and suggest that drugs acting potently and preferentially on SSTR1 might be useful for medical treatment of NFA.

Somatostatin (SRIF) analogs interacting with SRIF receptor subtype (SSTR) 2 and SSTR5 are known to reduce secretion in GH-secreting pituitary adenomas. We investigated the effects of SRIF and a SSTR1 selective agonist, BIM-23926, on GH and prolactin (PRL) secretion and cell viability in primary cultures deriving from 15 GH- and PRL-secreting adenomas expressing SSTR1. Quantitative RT-PCR showed SSTR1 mRNA mean levels of 6 +/- 2.2 x 10(4) molecules/ microg reverse-transcribed total RNA. SSTR2 and SSTR5 were frequently expressed (93.3%), on the contrary of SSTR3 (53.3%) and SSTR4 (6.7%). GH secretion was significantly reduced by SRIF and BIM-23926 (45 +/- 8.6% and 32 +/- 18.1% inhibition, respectively) as well as PRL secretion (16.1 +/- 4% and 19.7 +/- 3.5% inhibition, respectively). After treatment with SRIF and BIM-23926, cell viability was significantly reduced by 17.5 +/- 5% and 20 +/- 3.9%, respectively. SSTR1 mRNA levels correlated with the degree of GH and PRL secretion inhibition. These results demonstrate that SSTR1 selective activation inhibits hormone secretion and cell viability in GH- and PRL-secreting adenomas in vitro and suggest that SRIF analogs with affinity for SSTR1 may be useful to control hormone hypersecretion and reduce neoplastic growth of pituitary adenomas.

A substantial proportion of GH circulates bound to high affinity GH-binding protein (GHBP), which corresponds to the extracellular domain of the GH receptor. Current evidence indicates that nutritional status has an important role in regulating plasma GHBP levels in humans. In the present study the relationship among plasma GHBP levels, body composition [by bioelectrical impedance analysis (BIA) and dual energy x-ray absorptiometry (DEXA)] and serum estradiol (E(2)) was evaluated in premenopausal (n = 92) and postmenopausal (n = 118) healthy women with different body weight [three groups according to body mass index (BMI): normal, 18.5-24.99; overweight, 25-29.99; obese, 30-39.99 kg/m(2)]. Plasma GHBP levels were measured by high pressure liquid chromatography gel filtration. GH and insulin-like growth factor I levels were determined by immunoradiometric assay and RIA, respectively. GHBP levels were significantly higher in premenopausal women with BMI above 25 kg/m(2) (overweight, 3.789 +/- 0.306 nmol/L; obese, 4.372 +/- 0.431 nmol/L) than those observed in postmenopausal women (overweight, 1.425 +/- 0.09 nmol/L; obese, 1.506 +/- 0.177 nmol/L). No significant differences were found between normal weight premenopausal (1.741 +/- 0.104 nmol/L) and postmenopausal (1.524 +/- 0.202 nmol/L) women. In premenopausal women GHBP levels correlated positively with BMI (r = 0.675; P < 0.001), fat mass (FM; r = 0.782; P < 0.001; by BIA; r = 0.776; P < 0.001; by DEXA), truncal fat (TF; r = 0.682; P < 0.001), waist to hip circumference ratio (WHR; r = 0.551; P < 0.001), and E(2) (r = 0.298; P < 0.05), whereas no significant correlation was found in postmenopausal women between GHBP levels and BMI, FM, TF, WHR, or E(2). In normal weight pre- and postmenopausal women GHBP levels did not change between the ages of 20 and 69 yr. No statistically significant correlation was found between GHBP and age for all groups studied. Moreover, in two distinct subgroups of pre- and postmenopausal women, aged 40-49 yr, the direct relationship between GHBP levels and all indexes of adiposity were only observed in premenopausal women [BMI: r = 0.836; P < 0.001; FM: r = 0.745 (BIA) and r = 0.832 (DEXA); P < 0.001; TF: r = 0.782; P < 0.001; WHR: r = 0.551; P < 0.05], but not in postmenopausal women. In conclusion, the present data indicate a strong direct correlation between GHBP and body fat in premenopausal, but not in postmenopausal women, whereas they failed to detect a relationship between GHBP and age. Therefore, these results suggest that endogenous estrogen status may be an important determinant of the changes in GHBP levels in women with different body weights.

We investigated the 24-h profiles of the circulating levels of norepinephrine (NE) and epinephrine (E), blood pressure (BP), and heart rate in 14 acromegalic patients, before (A) and 3-6 months after transsphenoidal surgery (C-A, cured; A-A, active), and in 8 age-matched normal subjects (N). In addition, the responses of NE, E, PRA, and aldosterone to upright posture were investigated. No significant differences in the mean 24-h plasma NE and E levels were observed between either group of acromegalics and the N subjects. Analysis of the 24-h profiles indicated a statistically significant 24-h rhythm of both NE and E in N subjects. No evidence of a 24-h rhythm of plasma NE and E and BP was found in A patients. After surgery, a statistically significant 24-h rhythm of NE was detected in the patients with acrophase (13.54 and 13.45 h in C-A and A-A patients, respectively) and mesor (1019.8+/-45.1 and 1017.8+/-54.7 pmol/L in C-A and A-A patients, respectively) similar to those observed in N subjects (acrophase, 13.21 h; mesor, 942.3+/-42.5 pmol/L). After surgery, the plasma concentration of E clearly fluctuated throughout the 24 h in both C-A and A-A patients, even if cosinor analysis failed to reveal a 24-h significant rhythm. A statistically significant 24-h rhythm of BP was restored only in C-A patients. The mean 24-h heart rate was slightly, but significantly (P<0.05), higher in A than in N subjects and decreased after surgery. No significant differences in upright-stimulated NE, E, and plasma aldosterone levels were observed between each group of acromegalics and N subjects. However, basal and upright-stimulated PRA levels were significantly (P<0.001) lower in A patients. In conclusion, our study demonstrates the lack of a clear circadian variation in catecholamine levels and BP in active acromegaly and the return of a significant 24-h rhythm of NE and BP after pituitary surgery, concomitant with the reduction in GH and insulin-like growth factor I serum levels.

There is evidence that endogenous opioid peptides exert an inhibitory effect on pituitary luteinizing hormone (LH) secretion both in animals and in humans, by interacting with mu-opioid receptors. However, a role for delta-opioid receptors in the regulation of gonadotrophin releasing hormone (GnRH) secretion has recently been suggested. In the present study, we evaluated the effect of the highly selective delta-opioid receptor agonist deltorphin on the LH and follicle stimulating hormone (FSH) responses to naloxone in six healthy fertile women during the luteal phase of the menstrual cycle. Deltorphin infusion alone (7 microg/kg/min for 60 min) did not significantly change the basal serum concentrations of LH in this group of women. The intravenous (i.v.) bolus administration of naloxone (15 mg) induced a significant (P < 0.001) increase in serum LH concentrations (from a mean basal value of 4.24+/-1.10 IU/l to a peak of 13.27+/-1.8 IU/l). The LH response to naloxone was significantly (P < 0.001) blunted by preinfusion of deltorphin (13.27+/- 1.80 IU/l versus 4.80+/-1.18 IU/l). No significant changes in FSH concentrations were observed during deltorphin, naloxone or deltorphin plus naloxone administration. These data indicate that activation of delta-opioid receptors can reduce naloxone-induced LH release, suggesting a possible role of delta receptors in opioidergic modulation of LH secretion in women.

There is evidence that withdrawal of SRIH infusion in man promotes a rebound GH response that allegedly has been proposed to be related to the function of GHRH-producing neurons. In the present study we have evaluated whether a reduction in endogenous GHRH activity contributes to the decreased GH secretion of the elderly. Sixteen young (8 women, aged 23-32 yr, and 8 men, aged 18-27 yr) and 13 elderly (8 women, aged 65-82 yr, and 5 men, aged 65-70 yr) healthy subjects volunteered to participate in this investigation. Each subject was tested on 2 separate occasions: 1) a 90-min iv infusion of SRIH was given in 50 mL 0.9% saline delivered at a rate of 9 micrograms/kg.h; and 2) a 90-min iv infusion of isovolumetric amounts of 0.9% saline was given. Plasma GH levels were determined before and up to 180 min after SRIH or saline infusion, whereas plasma insulin-like growth factor I, estradiol, and testosterone levels were measured in basal samples. In elderly women, the mean maximum (delta) GH peak (2 +/- 0.7 micrograms/L) after withdrawal of SRIH infusion was significantly (P < 0.02) lower than that in young women (7.3 +/- 2 micrograms/L). In elderly men, the mean delta GH peak (2.9 +/- 0.6 micrograms/L) after withdrawal of SRIH infusion was lower than that in young men (6.3 +/- 1.6 micrograms/L), although the difference failed to achieve statistical significance. Baseline insulin-like growth factor I levels were significantly lower in elderly compared to young subjects in both men and in women. In women, both age and basal plasma estradiol and testosterone levels significantly correlated with delta GH peak after SRIH withdrawal (r = -0.61, r = 0.61, and r = 0.66, respectively), whereas in men they did not. These findings are compatible with the view that an age-related decrease in endogenous GHRH function may contribute to the defective GH secretion of the elderly. Alterations in plasma concentrations of sex steroids may have important implications in the observed changes.

Human galanin (hGAL) is a neuropeptide with 30 amino acid residues that has been found in the peripheral and central nervous system, where it often co-exists with catecholamines. In order to clarify the possible role of hGAL in the regulation of sympathoadrenomedullary function, the effect of a 60-min infusion of hGAL (80 pmol.kg-1.min-1) on plasma epinephrine and norepinephrine responses to insulin-induced hypoglycemia in nine healthy subjects was investigated. Human GAL administration significantly reduced both the release of basal norepinephrine and the response to insulin-induced hypoglycemia, whereas it attenuated the epinephrine response by 26%, with the hGAL-induced decrease in epinephrine release failing to achieve statistical significance. Human GAL significantly increased the heart rate in resting conditions and clearly exaggerated the heart rate response to insulin-induced hypoglycemia, whereas it had no effect on the blood pressure. We conclude that GAL receptor stimulation exerts an inhibitory effect on basal and insulin-induced hypoglycemia-stimulated release of norepinephrine. These findings provide further evidence that GAL may modulate sympathetic nerve activity in man but that it does not play an important role in the regulation of adrenal medullary function.

The neuropeptide galanin (GAL) is widely distributed in the peripheral and central nervous systems, where it often coexists with catecholamines. To gain insight into the action of human GAL on sympathetic nervous system activity in man, we investigated the effects of a 60-min infusion of human (h) GAL (80 pmol/kg.min) or saline on peripheral norepinephrine (NE) and epinephrine concentrations, heart rate (HR), and systolic and diastolic blood pressure (BP) in the supine position as well as after assumption of the upright posture (UP) in eight healthy male volunteers. hGAL depressed supine plasma NE (0.84 +/- 0.06 vs. 0.33 +/- 0.02 nmol/L) and blunted the NE response to assumption of the UP (1.68 +/- 0.03 vs. 0.44 +/- 0.03 nmol/L), but caused a significant enhancement of the epinephrine response to assumption of the UP (0.22 +/- 0.02 vs. 0.65 +/- 0.06 nmol/L). hGAL significantly increased supine HR (70 +/- 2 vs. 99 +/- 4 beats/min) and potentiated the HR response to assumption of the UP (82 +/- 3 vs. 107 +/- 4 beats/min). hGAL did not alter supine systolic and diastolic BP, but caused a significant decrease in the systolic (121 +/- 3 vs. 98 +/- 2 mm Hg) and diastolic (74 +/- 2 vs. 62 +/- 2 mm Hg) BP responses to assumption of the UP. Our data show that hGAL decreases supine position- and UP-stimulated release of NE, suggesting an inhibitory modulation of hGAL on sympathetic outflow in man. The finding that hGAL induces an increase in HR, both in the supine position and after UP, and an inhibition of the systolic and diastolic BP response to UP provides further support for an involvement of hGAL in regulation of the cardiovascular and autonomic nervous systems in man.

To investigate the influence of the cholinergic system on the modulation of the circulating levels of calcitonin gene-related peptide (CGRP) under basal conditions in normal man, the effects of an acetylcholinesterase inhibitor, pyridostigmine bromide, and a muscarinic receptor blocker, pirenzepine, were studied in 16 normal subjects (8 females and 8 males). Pyridostigmine (120 mg, orally) induced a significant (P < 0.01) rise in basal plasma CGRP, while it reduced systolic and diastolic blood pressure. In all subjects, pirenzepine (0.6 mg/kg, i.v. bolus) was unable to modify the basal CGRP level. In conclusion, a pharmacologically induced enhancement of cholinergic tone resulted in an increase in CGRP, whereas muscarinic receptor blockade had no effect on CGRP levels or blood pressure. Therefore, the cholinergic system seems to be involved in the control of CGRP release in man, acting as a positive modulator. However, the available data do not indicate that there is a tonic cholinergic tone responsible for CGRP secretion under physiological conditions.

To examine the role of delta-opioid receptors in the regulation of the sympathoadrenomedullary system, the effects of the highly selective delta-opioid receptor agonist deltorphin (DT) on plasma catecholamine responses to insulin-induced hypoglycemia (IIH) and cold pressor test (CPT) have been investigated in normal subjects in two separate studies. DT failed to modify basal plasma levels of both norepinephrine (NE) and epinephrine (E). DT completely suppressed the IIH-evoked elevation of NE, whereas it attenuated the E response by 20%, with the DT-induced decrease in E release failing to achieve statistical significance. DT completely blocked the release of both NE and E elicited by CPT. We conclude that specific delta-opioid receptor stimulation exerts an inhibitory effect on NE release induced by both IIH and CPT. These findings provide evidence that delta-opioid receptors may influence the autonomic sympathetic reactivity.

Calcitonin gene-related peptide (CGRP) has positive chronotropic and inotropic effects in animals and humans, and produces the most potent vasodilation known for an endogenous peptide. Yet, a physiological role for CGRP in the regulation of vascular tone and blood pressure has not been demonstrated. We studied the effects of 1) assumption of the upright position and 2) iv infusion of angiotensin-II (sequential doses of 8, 16, and 32 ng/kg.min, each dose for 20 min) in eight normal subjects (four men). Serial venous blood samples were taken to determine the plasma CGRP, epinephrine, norepinephrine, and aldosterone levels and PRA. Blood pressure and heart rate were continuously monitored at the finger with a Finapres 2300 instrument. After assumption of the upright posture, a quick rise in plasma CGRP levels was observed together with the expected increases in plasma norepinephrine and aldosterone and PRA. A transient increment was also observed for diastolic blood pressure and heart rate. Angiotensin-II infusion caused dose-dependent increases in plasma CGRP and aldosterone concentrations, already significant at the lowest infusion rate and parallel with the blood pressure rise. Plasma catecholamines significantly increased only at higher infusion rates. Our data demonstrate that modifications of plasma CGRP concentrations are part of the normal response to postural and vasomotor changes. These findings suggest a physiological role for CGRP in regulation of the peripheral vascular tone and possibly blood pressure in man.

To determine the role of delta-opioid receptors in the modulation of hypothalamic-pituitary-adrenal activity, we studied in normal subjects the effect of the highly selective delta-opioid receptor agonist deltorphin (DT) on the secretion of ACTH, cortisol, and arginine vasopressin in response to insulin-induced hypoglycemia. In an attempt to clarify the site of opiate modulation of ACTH secretion, we also studied in normal subjects the effect of DT on the ACTH response to ovine CRH-41. DT blunted the ACTH, cortisol, and arginine vasopressin responses to insulin-induced hypoglycemia, whereas it had no effect on the ACTH and cortisol responses to CRH. We conclude that DT-induced activation of delta-opioid receptors exerts an inhibitory influence on hypoglycemia-stimulated ACTH secretion. Based on the lack of an effect of DT on the ACTH response to CRH, we postulate that DT may modulate the secretion of ACTH through suprapituitary mechanisms.

Calcitonin gene-related peptide (CGRP) is known to exert potent cardiovascular effects and is presumed to participate in the neural control of circulation and blood flow. It has been assayed in many physiological and disease conditions, yet virtually nothing is known of the normal fluctuations in its circulating levels. We have studied the variability throughout a 24-h period of plasma concentrations of CGRP in eight recumbent healthy volunteers (four men and four women, 25-37 yr old), after careful standardization of their daily diet and routine schedules. A correlation with the circadian rhythms of blood pressure (BP), heart rate (HR), and plasma aldosterone (PA), PRA, plasma cortisol (PC), and atrial natriuretic peptide (ANP) was also made. Plasma CGRP concentrations ranged from a mean peak value of 18.1 +/- 1.5 pmol/L to a mean lowest value of 11.7 +/- 0.4 pmol/L (P less than 0.05). The mean circadian acrophase of CGRP (calculated by cosinor analysis to occur at 2314 h) anticipated the corresponding acrophases of the other hormones (0122, 0528, 0809, and 0840 h for ANP, PRA, PA, and PC, respectively). Instead, BP and HR rhythms seemed to be antiphasic with the ANP rhythm (calculated acrophases occurred at 1356, 1339, and 1314 h for systolic BP, diastolic BP, and HR, respectively). Our data demonstrate that, like many other hormones, CGRP circulates in plasma with a circadian rhythm. There seems to be a temporal sequence starting with the nocturnal rise in plasma CGRP concentrations and progressing with the ensuing elevations of ANP, PRA, PA, and PC, whereas BP and HR are kept to their lowest values. These findings are in favor of a physiological role of CGRP in the complex regulation of BP homeostasis.