Pituitary apoplexy represents one of the most serious, life threatening endocrine emergencies that requires immediate management. Gonadotropin-releasing hormone agonist (GnRHa) can induce pituitary apoplexy in those patients who have insidious pituitary adenoma coincidentally.

A 46-year-old woman, with a history of hypertension and menorrhagia was transferred to our hospital from a secondary care hospital after complaints of headache and vomiting, with loss of consciousness 5 min after an injection of GnRHa. The drug was prescribed by her gynecologist due to the presence of uterine myomas. The clinical neurological examination revealed right cranial nerve III palsy, ptosis and movement limitation of the right eye. Our first clinical consideration was a pituitary apoplexy. Blood hormonal analysis revealed mild hyperprolactinemia and high follicle stimulating hormone level; PTH and calcium was high with glomerular filtration rate mildly to moderately decrease. A computed tomography scan, revealed an enlarged pituitary gland (3.5 cm) impinging upon the optic chiasm with bone involvement of the sella. Following contrast media administration, the lesion showed homogeneous enhancement with high-density focus that suggests hemorrhagic infarction of the tumor. Transsphenoidal endoscopic surgery was perfomed and adenomatous tissue was removed. Immunohistochemistry was positive for luteinizing hormone (LH) and follicular-stimulating hormone (FSH). A solid hypoechoic nodule (14 mm x 13 mm x 16 mm) was found in the caudal portion of the right thyroid lobe after a parathyroid ultrasound. A genetic test of Multiple Endocrine Neoplasia type 1 (MEN1) was negative. A right lower parathyroidectomy was performed and the pathologic study showed the presence of an encapsulated parathyroid carcinoma of 1.5 cm. A MEN type 4 genetic test was performed result was negative.

This case demonstrates an uncommon complication of GnRH agonist therapy in the setting of a pituitary macroadenoma and the casual finding of parathyroid carcinoma. It also highlights the importance of suspecting the presence of a multiple endocrine neoplasia syndrome and to carry out relevant genetic studies.

Recent evidence demonstrated an interplay between estrogens and growth hormone (GH) at cellular level. To investigate the possible mechanism/s involved, we studied the effect of 17β-estradiol (E2) on GH signaling pathways in primary culture of human osteoblasts (hOBs). Exposure of hOBs to E2 (10(-8) M) 60 min before GH (5 ng/ml) significantly increased phosphorylated STAT5 (P-STAT5) levels compared with GH alone. E2 per se had no effect on P-STAT5. E2-enhanced GH signaling was effective in increasing osteopontin, bone-sialoprotein, and IGF II mRNA expression to a greater extent than GH alone. We then studied the effect of E2 on the protein levels of the negative regulator of GH signaling, suppressor of cytokine signaling-2 (SOCS2). E2 (10(-11) M-10(-7) M) reduced dose-dependently SOCS2 protein levels without modifying its mRNA expression. The silencing of SOCS2 gene prevented E2 positive effect on GH induced P-STAT5 and on GH induced bone-sialoprotein and osteopontin mRNA expression. Treatment with the inhibitor of DNA-dependent RNA synthesis, actinomycin-D, did not prevent E2 induced decrease of SOCS2, thus suggesting a non-genomic effect. E2 promoted an increase in SOCS2 ubiquitination. To determine if increased ubiquitination of SOCS2 by E2 led to degradation by proteasome, hOBs were pretreated with the proteasome inhibitor MG132 (5 μM) which blocked E2 reduction of SOCS2. These findings demonstrate for the first time that E2 can amplify GH intracellular signaling in hOBs with an essential role played by the reduction of the SOCS2 mediated feedback loop.

Zollinger-Ellison syndrome (ZES) is a rare disorder characterized by gastrin-secreting tumors of the gastrointestinal tract and gastric acid hypersecretion. There is controversy over the best way to manage these patients; we investigated outcomes of patients with different forms of the disease, who did and did not undergo surgery.

We performed a retrospective chart review of patients with ZES associated with multiple endocrine neoplasia type 1 (MEN-1) (n = 16) and those with sporadic ZES (n = 33) seen at a tertiary care center from August 1994 to January 2012. Cox proportional hazards modeling was used to compare survival times among groups, based on treatment with surgery (n = 34) and the presence of MEN-1 (n = 9 with surgery; n = 7 without surgery). Differences were compared using the unpaired Student t test and the Fisher exact test.

Patients with MEN-1 syndrome-associated ZES presented at a younger age than patients with sporadic ZES (34.9 vs 45.7 y, respectively; P < .05) and were diagnosed at a younger age (39.3 vs 49.7 y, respectively; P < .01), yet lived a similar number of years (55.9 vs 55.1 y, respectively; P = .91). None of the patients with MEN-1-associated ZES died of progressive disease, compared with 86% of deaths among patients with sporadic ZES (P < .05). Lymph node involvement, detected during surgery, increased the risk of metastasis to liver (P = .13) and lack of cure by surgery (P = .01). Surgery reduced all-cause mortality (hazard ratio, 0.11; 95% confidence interval, 0.2-0.6; P = .011) and disease-related mortality (hazard ratio, 0.14; 95% confidence interval, 0.2-0.84; P = .032) of patients with sporadic, but not MEN-1 syndrome-associated, ZES.

The presence of MEN-1 is associated with earlier onset and diagnosis of ZES, but a benign clinical course that rarely results in disease-related death; surgery therefore can be deferred for these patients. However, 86% of deaths among patients with sporadic ZES are attributed to disease-related causes, and mortality is reduced by early surgical intervention. Patients with sporadic ZES should undergo surgery soon after diagnosis.

The aim of this study was to evaluate the results of pancreatic resection in pancreatic endocrine neoplasias (PENs) in patients affected by multiple endocrine neoplasia type 1 (MEN1) syndrome.

Since these tumors often show an indolent course, the role of diagnostic procedures and type of surgical approach are controversial. Experience with new diagnostic approaches and more aggressive surgery is still limited.

Sixteen MEN1 patients were referred to our Surgical Unit (1992-2003) and were operated on for the indications of hypergastrinism, hypoglycemia, and/or pancreatic endocrine neoplasias larger than 1 cm. Zollinger-Ellison syndrome (ZES) was present in 13 patients, 2 of whom experienced a recurrence after previous surgery. Preoperative tumor localization was carried out using ultrasonography (US), computed tomography (CT), endoscopic ultrasonography (EUS), somatostatin receptor scintigraphy (SSRS), or selective arterial secretin injection (SASI). Rapid intraoperative gastrin measurement (IGM) was carried out in 8 patients, and 1 patient also underwent an intraoperative secretin provocative test.

Either pancreatoduodenectomy (PD) or total pancreatectomy (TP) or distal pancreatectomy was performed. There was no postoperative mortality; 37% complications included pancreatic (27%) and biliary (6%) fistulas, abdominal collection (6%), and acute pancreatitis (6%). EUS and SSRS were the most sensitive preoperative imaging techniques. At follow-up, 10 of 13 hypergastrinemic patients (77%) are currently eugastrinemic with negative secretin provocative test, while 3 are showing a recurrence of the disease. All patients affected by insulinoma were cured.

MEN1 tumors should be considered surgically curable diseases. IGM may be of value in the assessment of surgical cure. Our experience suggests that PD is superior to less radical surgical approaches in providing cure with limited morbidity in MEN1 gastrinomas and pancreatic neoplasias.

Between 1971 and 2002, 80 patients underwent surgery for insulinoma at the Department of General and Endocrine Surgery of the Lille University Hospitals. The present report deals with 13 patients with proven multiple endocrine neoplasia type I (MEN I) or supposed genetic-related insulinomas. This entity differs from spontaneous insulinoma by the presence of multiple foci in the pancreas. Enucleation is not advised in this setting due to the strong likelihood of persistence or recurrence. Various studies suggest different strategies for preoperative localization and surgical approach. We analyzed retrospectively the surgical strategy proposed by the A.F.C.E. and G.E.N.E.M. The purpose of this study was to validate the strategy, integrate the contribution of genotypic diagnosis, simplify preoperative imaging studies, and re-evaluate the value of intraoperative baseline secretin-stimulated insulin measurements. We recommend preoperative endoscopic ultrasonography of the pancreatic head only and routine left pancreatectomy with enucleation of cephalic tumors under intraoperative hormone monitoring. Preoperative invasive localization studies are proposed only if the endoscopic ultrasonography is negative for the pancreatic head. Intraoperative secretin stimulation test can be useful in difficult cases, especially with concurrent nesidioblastosis or in case of secondary surgery. All but one of the 13 patients achieved long-term cure with this strategy.

Multiple endocrine neoplasia type I is a rare autosomal dominant disorder with many endocrine and nonendocrine manifestations. Hyperparathyroidism, islet cell tumors, and pituitary tumors are diagnosed most commonly in these patients. There is controversy regarding treatment of the different manifestations and screening modalities of this disorder because no large series has determined the best therapeutic approach. Our institution advocates early screening with biochemical and radiographic testing in patients with a definite predilection for this disorder. Patients with hyperparathyroidism should undergo early surgical intervention of at least three and a half glands combined with bilateral upper thymectomy through a cervical incision. Although the recurrence rate is high, disease-free survival can be for as long as 30 years. Pituitary tumors are predominantly prolactinomas and growth hormone-releasing tumors. Prolactinomas usually require pharmacologic therapy, whereas growth hormone-releasing tumors are treated surgically. Enteropancreatic tumors should be treated surgically or medically, depending on the hormone secreted. Insulinomas respond well to distal pancreatectomy, with enucleation of the tumor from the head and uncinate process of the pancreas. However, there is controversy regarding the surgical treatment of gastrinomas. Carcinoid tumors should be treated with early surgical intervention. Adrenal lesions are thought to occur in association with pancreatic lesions and commonly have an indolent course. Adrenocortical cancers are uncommon in patients with multiple endocrine neoplasia type I. Skin lesions can be excised when cosmetically unappealing.

Gastrinoma treatment has evolved considerably in the last 20 years. In particular, the advent of effective acid-reducing pharmacologic agents has changed the primary morbidity of this disease entity from one of acid hypersecretion to one of tumor growth and spread. Thus, while symptoms can be temporized using histamine receptor antagonists, proton pump inhibitors, or somatostatin analogs, cure can be effected only by surgical means. Recent advances in operative techniques and pre- and intra-operative imaging studies, including routine duodenotomy, somatostatin-receptor scintigraphy, and intraoperative ultrasound, have allowed for identification and subsequent resection of more than 95% of gastrinoma tumors. Most experts agree that all sporadic cases of localized gastrinoma should be excised. In addition, debulking of metastatic tumor may improve symptoms and survival when cure cannot be ascertained. There is, however, some controversy as to the surgical approach for gastrinoma found in the setting of multiple endocrine neoplasia, type 1. Because of the usual multiplicity and particular indolence of these tumors, two primary strategies have emerged: aggressive approaches have been advocated in an effort to eradicate all present and potential tumor; and less aggressive, or nonoperative, approaches have been suggested because it is unclear whether intervention offers survival or disease-free benefit in this population. We advocate surgical intervention for patients with gastrinoma and multiple endocrine neoplasia, type 1 when tumors exceed 2.5 cm in size. This tumor size has been associated with a higher likelihood of hepatic metastases, which ultimately affects survival. The role of adjuvant therapies for gastrinoma remains limited.

In a 69-year-old woman with a complicated history of multiple endocrine neoplasia type I (MEN 1), growth hormone overproduction was found without clinical features of acromegaly. Zollinger-Ellison syndrome was diagnosed at the age of 36 years. Total gastrectomy and partial pancreatectomy were performed. Two years later hypercalcaemia occurred, hyperparathyroidism was suspected and three hyperplastic parathyroid glands were removed. In 1994 the plasma gastrin level was elevated and a computerized tomography of the abdomen revealed a 1.5-cm large pancreatic tumour. Screening of the pituitary functions was unremarkable and a magnetic resonance scan of the pituitary gland showed no abnormalities. In 1995 type II diabetes mellitus was diagnosed. In 1997 basal plasma growth hormone levels were raised and plasma IGF-I levels were alternately high and normal. The patient had no clinical signs of acromegaly, but glucose tolerance testing resulted in a paradoxical rise in growth hormone concentration compatible with the diagnosis of growth hormone overproduction. Magnetic resonance imaging of the pituitary gland revealed a microadenoma.

To note that a thyrotropin (TSH)-secreting macroadenoma may be part of the multiple endocrine neoplasia-1 (MEN-1) syndrome and to report the use of octreotide-LAR (OCT-LAR) to treat a TSH-secreting macroadenoma in a patient with MEN-1 with previous surgery for hyperparathyroidism and gastrinoma.

We present a patient with a TSH-secreting pituitary macroadenoma and report the results of her endocrine, genetic, radiologic, and nuclear medicine testing and her response to treatment with octreotide (OCT), octreotide-LAR, and estrogen.

This patient's TSH-induced hyperthyroidism responded to octreotide for 5 months and octreotide-LAR for more than 11 months. Her hypercalcemia normalized while she was taking estrogen. Her genetic testing is reported to show a genetic defect that is typical of patients with MEN-1.

This report describes: (1) The use of octreotide-LAR to treat both a TSH-secreting pituitary tumor and a gastrinoma over 12 months; (2) the importance of including these tumors into the MEN-1 syndrome with its attendant implications; and (3) a genetic defect, typical of patients with MEN-1, associated with this tumor.

The majority of reports describing the natural history and prognosis of multiple endocrine neoplasia type 1 (MEN 1) utilize phenotypic rather than molecular genetic criteria to establish a diagnosis of MEN 1.

We sought to determine the spectrum of endocrine abnormality amongst 152 members (64 gene carriers and 88 noncarriers) of a large MEN 1 family in whom a determination of MEN 1 status had previously been made by phenotype screening. The predictive utility of both clinical and molecular screening techniques are described.

A novel IVS2-3 (C-G) MEN1 mutation was identified in affected members of this family. Seven (10%) of 71 individuals satisfying clinical diagnostic criteria for MEN 1 were found to be genetically negative (excluded by mutation analysis and haplotyping) for MEN 1. These cases of MEN 1 phenocopy comprised four cases of primary hyperparathyroidism, two 'nonsecretory' pituitary adenoma and one case of coincident prolactinoma and hyperparathyroidism. Three of the patients with hyperparathyroidism had previously required parathyroidectomy and each had achieved normocalcaemia following parathyroid resection. Predictive genetic testing prospectively identified three children with the MEN 1 genotype. Serum calcium was normal at the time of their initial molecular genetic diagnosis. In each case hyperparathyroidism subsequently developed during adolescence.

Multiple endocrine neoplasia type 1 phenocopy is an important differential diagnosis in patients exhibiting an multiple endocrine neoplasia type 1 phenotype. This is a relevant consideration, particularly when the diagnosis of multiple endocrine neoplasia type 1 is made using sensitive, but nonspecific, criteria such as mild hyperparathyroidism, pituitary micoadenoma, and hyperprolactinaemia. Confirmatory genetic testing should be undertaken to confirm clinical diagnoses of multiple endocrine neoplasia type 1.

The aim of this retrospective study conducted by the "Groupe d'étude des néoplasies endocriniennes multiples type 1" (GENEM) was to report a series of insulinomas associated with multiple endocrine neoplasias type 1 (NEM 1) and to determine the most appropriate strategy for the topographical exploration and surgical management.

From 1960 to 1996, 44 patients were included, 16 men and 28 women (mean age: 36.4 +/- 13.9 years). This study concerned morphological investigations, tumoral features, modalities and results of the treatment.

Insulinomas were associated with other functional islet tumors in 15 patients: ZE syndrome (n = 8), glucagonoma (n = 6), vipoma (n = 1). Malignant lesions were present in 6 patients: isolated insulinomas (n = 2), insulinomas associated with ZE syndrome (n = 2) and vipoma (n = 1). The sensitivity of the preoperative imaging procedures was less than 70%. Fourty-one patients were operated on: subtotal pancreatectomy (n = 26 including cephalic enucleations in 8), enucleations (n = 8), total pancreatectomy (n = 3), pancreaticoduodenectomy with caudal enucleations (n = 1), and for 3 patients, no details were available. There was no postoperative mortality. Hyperinsulinism disappeared in 27 patients (including 2 after reoperation) with a mean follow-up of 9 years. Among 6 patients with malignant lesions, 3 were alive with a 3, 4 and 10 year-follow-up.

Subtotal pancreatectomy with splenic conservation and enucleation of cephalic lesions is suggested as the procedure of choice in this group of patients. This procedure allows simplification of preoperative imaging investigations because lesions of the pancreatic head have only to be detected. Preoperative endoscopic ultrasonography and intraoperative ultrasonography are the best investigations.

Hyperinsulinemia in multiple endocrine neoplasia type I (MEN-I) is a rare but potentially curable condition that presents difficulties not encountered in sporadic cases.

The present report documents our surgical approach to 3 MEN-I patients with hyperinsulinemia.

Primary hyperparathyroidism was manifested in all 3 patients at the time of presentation. Distal subtotal pancreatectomy with enucleation of tumor at the head of pancreas detected intraoperatively resulted in immediate cure of 2 patients. Persistent disease occurred in 1 patient after enucleation of tumor at the head of the pancreas guided by preoperative imaging elsewhere. The patient was subsequently cured by distal subtotal pancreatectomy. Pathology revealed multiple tumors (4 to 14) in all patients.

A different surgical strategy with an aim of distal subtotal pancreatectomy and enucleation of any tumor identified in the head of pancreas is the treatment of choice for hyperinsulinemia in MEN-I patients.