Medullary Thyroid Carcinoma: Prognostic Variables And Tumour Markers Affecting Survival.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a relatively rare thyroid malignancy and its clinical course varies among patients due to its familial association. A number of prognostic factors have been studied, but the significance of these factors remains controversial. We evaluated the progression free survival (PFS) and overall survival (OS) of MTC and its association with tumour marker rising velocity and serum calcitonin (Ct) doubling time (DT). METHODS: Analysis of 83 (8.7%) consecutive MTC patients registered at a single centre between 1995 and 2015. The impact of tumour respectability, TNM stage, multiple endocrine neoplasia (MEN) syndrome, local recurrence, Ct DT and Ct rising velocity on PFS and OS was analysed. Median follow-up was 4.3 years (range: 1-18 years). RESULTS: Eighty-three (8.7%) of all thyroid cancers registered at our centre were MTC. Fifty-five males, 28 females. Mean age 39 years [range: 17-72 years]. Twenty-two were unresectable and 61 resectable. Five-year and 10-year OS was 84% and 77% respectively. Of 68 with follow up greater than a year; 20 (29.4%) were cured, 15 (22.1%) had biochemical evidence of disease, three (4.4%) had stable macroscopic disease and 30 (44.1%) had recurrent/progressive disease. Sixteen (23.5%) died. On multivariate analysis, T4 tumour, male gender, nodal and distant metastases, tumour resectibility, Ct DT less than two years and tumour marker rising velocity of greater than 0.05pg/ml/month were poor prognostic factors (pvalue <0.05). Age and association with MEN syndrome had no statistically significant survival impact. Radiotherapy reduced local relapse in patients with nodal disease. Total thyroidectomy with nodal clearance lessened relapses. CONCLUSION: Clinical stage and pathological aspects are predictors of disease progression. Persistent biochemical evidence of MTC does not affect OS, however, Ct DT < 2 years and rapid rate of tumour marker rise predict disease progression.

Obesity in MENX Rats Is Accompanied by High Circulating Levels of Ghrelin and Improved Insulin Sensitivity.

Ghrelin, the natural ligand of the growth hormone secretagogue receptor type 1a (GHS-R1a), is mainly secreted from the stomach and regulates food intake and energy homeostasis. p27 regulates cell cycle progression in many cell types. Here, we report that rats affected by the multiple endocrine neoplasia syndrome MENX, caused by a p27 mutation, develop pancreatic islet hyperplasia containing elevated numbers of ghrelin-producing ε-cells. The metabolic phenotype of MENX-affected rats featured high endogenous acylated and unacylated plasma ghrelin levels. Supporting increased ghrelin action, MENX rats show increased food intake, enhanced body fat mass, and elevated plasma levels of triglycerides and cholesterol. Ghrelin effect on food intake was confirmed by treating MENX rats with a GHS-R1a antagonist. At 7.5 months, MENX-affected rats show decreased mRNA levels of hypothalamic GHS-R1a, neuropeptide Y (NPY), and agouti-related protein (AgRP), suggesting that prolonged hyperghrelinemia may lead to decreased ghrelin efficacy. In line with ghrelin's proposed role in glucose metabolism, we find decreased glucose-stimulated insulin secretion in MENX rats, while insulin sensitivity is improved. In summary, we provide a novel nontransgenic rat model with high endogenous ghrelin plasma levels and, interestingly, improved glucose tolerance. This model might aid in identifying new therapeutic approaches for obesity and obesity-related diseases, including type 2 diabetes.

Laboratory approaches for the diagnosis and assessment of hypercalcemia.

Calcium, the fifth most common element in the body, plays major physiological functions. Measurement of blood calcium is one of the most commonly ordered laboratory tests in assessments of calcium homeostasis and disease diagnosis. Hypercalcemia is an increased level of calcium in the blood. This disorder is most commonly caused by primary hyperparathyroidism and malignancy. However, other less common causes of elevated calcium levels need to be considered when making a differential diagnosis. This review is intended to provide readers with a better understanding of calcium homeostasis and the causes and pathophysiology of hypercalcemia. Most importantly, this review describes useful approaches for laboratory scientists and clinicians to appropriately diagnose and assess hypercalcemia.

Hypercalcitoninemia is not pathognomonic of medullary thyroid carcinoma.

Hypercalcitoninemia has frequently been reported as a marker for medullary thyroid carcinoma. Currently, calcitonin measurements are mostly useful in the evaluation of tumor size and progression, and as an index of biochemical improvement of medullary thyroid carcinomas. Although measurement of calcitonin is a highly sensitive method for the detection of medullary thyroid carcinoma, it presents a low specificity for this tumor. Several physiologic and pathologic conditions other than medullary thyroid carcinoma have been associated with increased levels of calcitonin. Several cases of thyroid nodules associated with increased values of calcitonin are not medullary thyroid carcinomas, but rather are related to other conditions, such as hypercalcemias, hypergastrinemias, neuroendocrine tumors, renal insufficiency, papillary and follicular thyroid carcinomas, and goiter. Furthermore, prolonged treatment with omeprazole (>2-4 months), beta-blockers, glucocorticoids and potential secretagogues, have been associated with hypercalcitoninemia. An association between calcitonin levels and chronic auto-immune thyroiditis remains controversial. Patients with calcitonin levels >100 pg/mL have a high risk for medullary thyroid carcinoma (approximately 90%-100%), whereas patients with values from 10 to 100 pg/mL (normal values: <8.5 pg/mL for men, <5.0 pg/mL for women; immunochemiluminometric assay) have a <25% risk for medullary thyroid carcinoma.In multiple endocrine neoplasia type 2 (MEN2), RET mutation analysis is the gold-standard for the recommendation of total preventive thyroidectomy to relatives at risk of harboring a germline RET mutation (50%). False-positive calcitonin results within MEN2 families have led to incorrect indications of preventive total thyroidectomy to RET mutation negative relatives. In this review, we focus on the differential diagnosis of hypercalcitoninemia, underlining its importance for the avoidance of misdiagnosis of medullary thyroid carcinoma and consequent incorrect recommendation for thyroid surgery.

Hypercalcitoninemia is not pathognomonic of medullary thyroid carcinoma: [revision]

Hypercalcitoninemia has frequently been reported as a marker for medullary thyroid carcinoma. Currently, calcitonin measurements are mostly useful in the evaluation of tumor size and progression, and as an index of biochemical improvement of medullary thyroid carcinomas. Although measurement of calcitonin is a highly sensitive method for the detection of medullary thyroid carcinoma, it presents a low specificity for this tumor. Several physiologic and pathologic conditions other than medullary thyroid carcinoma have been associated with increased levels of calcitonin. Several cases of thyroid nodules associated with increased values of calcitonin are not medullary thyroid carcinomas, but rather are related to other conditions, such as hypercalcemias, hypergastrinemias, neuroendocrine tumors, renal insufficiency, papillary and follicular thyroid carcinomas, and goiter. Furthermore, prolonged treatment with omeprazole (> 2-4 months), beta-blockers, glucocorticoids and potential secretagogues, have been associated with hypercalcitoninemia. An association between calcitonin levels and chronic auto-immune thyroiditis remains controversial. Patients with calcitonin levels >100 pg/mL have a high risk for medullary thyroid carcinoma (~90%-100%), whereas patients with values from 10 to 100 pg/mL (normal values: <8.5 pg/mL for men, < 5.0 pg/mL for women; immunochemiluminometric assay) have a <25% risk for medullary thyroid carcinoma. In multiple endocrine neoplasia type 2 (MEN2), RET mutation analysis is the gold-standard for the recommendation of total preventivethyroidectomy to relatives at risk of harboring a germline RET mutation (50%). False-positive calcitonin results within MEN2 families have led to incorrect indications of preventive total thyroidectomy to RET mutation negative relatives. In this review, we focus on the differential diagnosis of hypercalcitoninemia, underlining its importance for the avoidance of misdiagnosis...

Protective effects of Peganum harmala extracts on thiourea-induced diseases in adult male rat.

Cancers and hepatoprotective prevention using traditional medicines have attracted increasing interest. The aim of our study was to characterize the putative protective effects of ethanol and chloroform extracts of Peganum harmala on thiourea-induced diseases in adult male rat. We seek to determine the effects of these plant extracts on body weight, thyroid and endocrine cancer parameters. In addition the putative hepatoprotective effect was checked by the determination of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and the bilirubin level in the blood. Our data show that ethanol and chloroform extracts of Peganum harmala protected the animal against the carcinogenic effects induced by thiourea since neuron-specific enolase (NSE) and thyroglobulin (TG) levels were back to the normal range. In addition, the observed-hepatocytotoxicity after thiourea treatment was greatly reduced (AST and ALT activities were respectively 270 IU/l and 60 IU/l and in the same order of magnitude as in the untreated rats) as well as the bilirubin levels (6 micromol/l) especially for animals receiving the choroform preparation. Therefore we may suggest that extracts of Peganum harmala are efficient to reduce the toxicity induced by thiourea in male rat as far as the above parameters are concerned.

Chromogranin A, a member of neuroendocrine secretory proteins as a selective marker for laboratory diagnosis of pheochromocytoma.

The function of chromogranin A (CGA) is reviewed, and the radioimmunometric determination of plasma CGA was evaluated as a marker of pheochromocytoma using a comparison of pheochromocytoma patients immediately before surgery (group P, n=25, 635+/-451 ng/ml) with other groups of patients, i.e. pheochromocytoma patients approximately 1 year after removal of tumor (group PP, n=13, 69+/-33 ng/ml), medullary thyroid carcinoma patients (group M, n= 22, 106+/-59 ng/ml), congenital adrenal hyperplasy patients (n=33, 65+/-40 ng/ml), and controls (n=31, 66+/-29 ng/ml). A CGA level above cut off value 130 ng/ml was found in 24 of 25 patients in group P, 1 (relapse) of 13 patients in group PP, and 4 of 22 patients in group M. In the group P we found a significant association between the size of the tumors removed and plasma CGA concentrations (p=0.0016), and also a significant (p=0.0016) relationship between plasma CGA concentrations and PASS score rating the malignity of pheochromocytoma. We can conclude that plasma CGA concentration as determined by radioimmunometric assay (which is simple without the necessity of special laboratory equipment) is an effective marker of pheochromocytoma with association to malignity and tumor mass.

Interpretation of intra-operative PTH changes in patients with multi-glandular primary hyperparathyroidism (pHPT).

BACKGROUND: The correct interpretation of intraoperative parathyroid hormone (IOPTH) levels in patients with primary hyperparathyroid patients (pHPT) with multiglandular disease (MGD) can impact the success rate of initial parathyroid exploration, but it remains an understudied topic. METHODS: In all, 592 of 823 patients were explored by a single surgeon with biochemical evidence of pHPT (1997-2007) and underwent parathyroidectomy using IOPTH. We investigated the incidence of MGD in patients with an appreciable (>50%) decrease in IOPTH levels and in patients whose levels failed to normalize after single gland excision. RESULTS: The mean age of patients was 56.7 years, and 74% of patients were women. Thirty-one patients had PTH levels that decreased by greater than 50% from baseline 10-15 min after single gland excision, but the levels failed to normalize. Of these, 9 patients (29%) had MGD (8 double adenomas, 1 hyperplasia). The incidence of MGD in the remainder of IOPTH patients was 13.9% (78 of 561 patients). Within the subgroup of 31 patients, those with single adenomas did not differ from patients with MGD in baseline IOPTH levels and weights of first adenoma excised, although they demonstrated greater serum creatinine concentrations and a decrease in mean IOPTH. CONCLUSION: Commonly accepted decreases in IOPTH levels (>50%) for patients who undergo minimally invasive parathyroidectomy may lead to an appreciable number of missed parathyroid adenomas or hyperplastic disease.

Evaluation of IGF-I levels during long-term somatostatin analogs treatment in patients with gastroenteropancreatic endocrine tumors.

Previous experiments reported desensitization to SS action in rat anterior pituitary cells and cell lines. The aim of the study was to verify whether the lack of desensitization to SS analogs (SSa) observed in acromegalic patients was also present in subjects with normal hypothalamic-pituitary function. The effect of chronic treatment with octreotide long-acting release (o-LAR, 10-30 mg/28 days) on IGF-I levels was then evaluated in 23 patients with gastroenteropancreatic (GEP) endocrine tumors (8 gastrinomas, 6 carcinoids, and 9 functioning pancreatic tumors). Serum IGF-I, clinical symptoms, plasma chromogranin-A (CgA) and markers of hepatic synthesis were evaluated before and after a short-term period in all the patients (median 4.5 months), after a medium-term period in 12 (median 18 months) and after a long-term follow-up period in 9 of them (median 48 months). Mean IGF-I levels decreased from 17.3+/-7.0 to 12.8+/-6.2 nmol/l in the short-term (p<0.005) being reduced from baseline concentrations in 87% and under the normal range for age in 35% of patients. Afterwards, they always remained stable both in the medium- and long-term periods, still being low in 3/12 and 2/9 patients, respectively. No alterations in biochemical markers of liver function were found either before or during therapy. No correlation between IGF-I levels, CgA concentrations and/or clinical definitive outcome was observed. In conclusion, the study demonstrated that: a) similarly to that observed in acromegalic patients, chronic o-LAR treatment did not induce desensitization of pituitary SS receptors (SSR) in humans with intact hypothalamic-pituitary axis, and b) in patients with GEP endocrine tumors, GH/IGF-I inhibition did not contribute to SSa efficacy.

Current applications of the intraoperative parathyroid hormone assay in parathyroid surgery.

Parathyroid hormone measurement using a two-site immunochemiluminometric assay has allowed for a rapid and accurate technique that has found its way into the operative armamentarium of some parathyroid surgeons. It can be used to assess the completeness of parathyroid gland resection and allow for a minimally invasive parathyroidectomy. This operative approach has become a popular marketing tool, providing patients with confidence in their surgical outcome. The purpose of this review is to provide the surgeon with the practical points and pitfalls of the use of intraoperative parathyroid hormone in the treatment of parathyroid disease.

Carney complex: pathology and molecular genetics.

Carney complex (CNC) is a unique multiple endocrine neoplasia syndrome (MIM 160980) which is characterized by unusual biochemical features (chronic hypersomatotropinemia and paradoxical responses of cortisol production to glucocorticoids) and multi-tissue involvement. The gene coding for the protein kinase A (PKA) type 1alpha regulatory subunit, PRKAR1A, had been mapped to 17q22-24, one of the genetic loci involved in CNC, and allelic analysis using probes from this chromosomal region revealed consistent changes in CNC tumors. Sequencing of the PRKAR1A gene in over 100 kindreds showed a number of mutations; in almost all cases, the sequence change was predicted to lead to a premature stop codon, and mutant mRNAs were subject to nonsense-mediated mRNA decay. In CNC cells, PKA activity assays showed increased stimulation by cAMP. Few mutations that did not lead to a premature stop codon have been described; they are also associated with increased PKA activity. PRKAR1A has been investigated in sporadic endocrine tumors; it does not appear to be mutated in pituitary adenomas, but both thyroid and adrenal neoplasms have been found to harbor somatic mutations of this gene. Animal models of the disease have been developed. CNC is the first human disease caused by mutations of one of the subunits of the PKA holoenzyme, a critical component of numerous cellular signaling systems. This has wide implications for cAMP involvement in endocrine tumorigenesis.

Parathyroid surgical failures with sufficient decline of intraoperative parathyroid hormone levels: unobserved multiple endocrine neoplasia as an explanation.

HYPOTHESIS: A sufficient decline in levels of parathyroid hormone measured intraoperatively (ioPTH) precludes early and late surgical failures. DESIGN: A case series of consecutive patients undergoing parathyroidectomy with ioPTH measurement. SETTING: A university hospital. PATIENTS AND INTERVENTION: Two hundred sixty-nine consecutive patients with sporadic primary hyperparathyroidism who underwent first-time parathyroid surgery with ioPTH measurement were followed up for as long as 10 years after surgery. Data on all patients have been collected in a prospective database. MAIN OUTCOME MEASURES: Surgical failures up to 10 years after parathyroid surgery. RESULTS: With an average follow-up of 3.6 years (range, 6-120 months), the overall cure rate was 96%. The ioPTH level correctly predicted long-term outcome in 248 (92%) of 269 patients. Six patients had a false-positive ioPTH finding. Five of these patients were found to have germline mutations in the gene for multiple endocrine neoplasia. The remaining patient has not undergone genetic testing. The mutations have rarely (n = 1) or never (n = 4) been described before, to our knowledge. CONCLUSIONS: Intraoperative measurement of PTH level has a high overall accuracy with a mean follow-up of 3.6 years. However, among the late surgical failures with false-positive ioPTH findings, overlooked mutations in the multiple endocrine neoplasia gene should be suspected, and therefore genetic analyses in these patients are of great importance.

A six month mitotane course induced sustained correction of hypercortisolism in a young woman with PPNAD and Carney complex.

A low-dose mitotane (MT) regimen was evaluated as a pharmacological approach for correcting the severe hypercortisolism in a young woman affected by Carney complex (CNC) and primary pigmented nodular adrenocortical disease (PPNAD). In the first 12 week period, the MT daily dose was progressively increased from 0.5 to 4.0 g/day. This dosage was maintained for an additional 16 weeks (cumulative dose 602 g, plasma MT maximum level 12 microg/ml), and then stopped because of sustained signs of hypoadrenalism requiring prednisone replacement. Complete regression of seborrhea, acne, and plethora was observed after 8 weeks of treatment (cumulative dose 95 g). Regular menses returned after 13 weeks (cumulative dose 197 g, plasma MT 8 microg/ml). Profound decrease of both serum cortisol (from 615 to 220 nmol/l) and urinary free cortisol (UFC) values (from 1498 to 477 nmol/day) was noted after 16 weeks of treatment (cumulative dose 314 g, plasma MT 8 microg/ml). MT treatment was associated with mild gastric discomfort and reversible increase of cholesterol plasma levels. Low serum cortisol and UFC were still observed 41 weeks after MT was discontinued (plasma MT 0.2 microg/ml). Our report demonstrates that low dose MT treatment may be a safe and effective modality for a sustained correction of hypercortisolism by PPNAD in subjects with CNC waiting for surgery.

Parathyroid surgery in familial hyperparathyroid disorders.

The management of hyperparathyroidism (HPT) in the setting of familial HPT differs between the specific syndromes and is generally complex because of the underlying disease, which predisposes patients to persistent and recurrent HPT. The basic principles of surgery include achieving and maintaining normocalcaemia for the longest time possible, avoiding both iatrogenic hypocalcaemia and operative complications, and facilitating future surgery for recurrent disease. Multiple endocrine neoplasia type 1 (MEN1) is treated with either subtotal parathyroidectomy or total parathyroidectomy with immediate heterotopic autotransplantation of parathyroid tissue. MEN2A, familial isolated HPT and HPT-associated with the hyperparathyroidism-jaw tumour (HPT-JT) syndrome typically can be treated with parathyroidectomy, i.e. subtotal or less. The increased risk of parathyroid cancer in HPT-JT requires special attention. Parathyroid surgery in familial HPT syndromes in the setting of underlying mutations in the calcium receptor (CASR) gene involves radical subtotal parathyroidectomy. Intraoperative parathyroid hormone (PTH) measurements may help guide the extent of parathyroid resection, particularly in the case of multigland HPT. The vast majority of patients with familial HPT who require surgery are best served with bilateral cervical explorations. However, minimally invasive parathyroidectomy (MIP) techniques that have become routine for sporadic HPT at selected institutions may be extrapolated to a subset of cases of familial HPT.

Increased plasma atrial natriuretic factor in catecholamine-producing tumor patients.

The aim of this study was to evaluate plasma levels of ANF in patients with catecholamine-secreting tumors with and without hypertension and to relate ANF secretion to levels of plasma and urinary catecholamines and blood pressure. Twenty-one pheochromocytoma (15 with sustained, 6 with paroxysmal hypertension), 6 neuroblastoma (1 hypertensive) patients and 28 aged-matched controls were studied in basal conditions. Plasma and urinary norepinephrine (NE),epinephrine (E), dopamine (DA) and DOPA were determined by HPLC-ED and plasma ANF by RIA. Both neuroblastoma and pheochromocytoma patients had significantly higher plasma ANF levels than controls. Neuroblastomas showed higher ANF concentration than pheochromocytomas. No differences were found in plasma ANF between hypertensive and normotensive patients. Pheochromocytomas with ANF levels within the normal range had plasma and urinary NE and urinary DA and DOPA levels significantly higher than patients with high ANF. Plasma ANF levels were unrelated to systolic or diastolic blood pressure or heart rate. A negative correlation between plasma ANF and urinary DA was found only in the patients groups. In conclusion, plasma ANF was increased in pheochromocytoma and neuroblastoma patients. Our data suggest that the excessive catecholamine secretion is not responsible for the increased ANF secretion in these patients. The significance of the relationships among plasma ANF and urinary and plasma catecholamines requires further investigation.

Clinical spectrum of hyperglucagonemia associated with malignant neuroendocrine tumors.

OBJECTIVE: To review the clinical features associated with hyperglucagonemia in malignant neuroendocrine tumors. MATERIAL AND METHODS: We retrospectively reviewed the medical records of patients with hyperglucagonemia encountered at our institution from Oct. 17, 1988, through February 1993 who had a fasting serum glucagon level of at least 120 pg/mL (twice the normal value). The 71 study patients also had no evidence of a secondary cause of hyperglucagonemia and had pathologic confirmation of a neuroendocrine tumor. RESULTS: The study group consisted of 46 men and 25 women with a median age of 57 years. Two patients had multiple endocrine neoplasia. Forty-nine patients had biochemically polyfunctional tumors, and 22 had hyperglucagonemia only. The most common initial symptoms were weight loss, abdominal pain, diarrhea, nausea, peptic ulcer disease, diabetes, and necrolytic migratory erythema (NME). Diabetes eventually developed in 25 patients and was associated with NME in 11. The highest median serum glucagon values occurred in patients with the glucagonoma syndrome or insulinomas, and the lowest median values were in those with carcinoid syndrome, Zollinger-Ellison syndrome, or diabetes without NME. Fasting glucagon and glucose measurements were not correlated. The most common hormonal syndromes were the Zollinger-Ellison syndrome and the glucagonoma syndrome. All the neuroendocrine tumors were malignant. Several methods of treatment, including surgical debulking, chemotherapy, somatostatin, and hepatic artery embolization, were used. Death occurred in 29 patients at a median of 2.79 years after diagnosis; 42 patients were alive at a median of 2.86 years after diagnosis. CONCLUSION: A mild degree of hyperglucagonemia can commonly be associated with multifunctional neuroendocrine tumors. The glucagonoma syndrome occurs in a few patients with malignant neuroendocrine tumors and hyperglucagonemia and is associated with very high serum glucagon levels. The correlation between serum glucagon levels and the development of diabetes is limited, and other factors such as insulin may be more important than hyperglucagonemia in the development of diabetes.

The genetic aspects of medullary thyroid carcinoma: recognition and management.

OBJECTIVE: To examine the extent to which clinicians recognize the genetic aspects of medullary thyroid carcinoma (MTC) and undertake appropriate investigation and management of patients and their at-risk relatives. DESIGN: retrospective review of case notes. SUBJECTS: all individuals aged 70 or under with a 'raised' calcitonin level during 1990-91. Information was obtained from a questionnaire. Forty-one cases were diagnosed in 1990-91: 10 (24%) multiple endocrine neoplasia (MEN) type 2A, four (10%) MEN type 2B, and 27 (66%) sporadic MTC. Between 1980 and 1989, 87 cases were diagnosed: 20 (23%) MEN type 2A, six (7%) MEN type 2B, four (5%) familial MTC, 53 (61%) sporadic MTC, and four (5%) of uncertain diagnosis. MAIN RESULTS: a pedigree was drawn in only 7/37 (19%) and 26/83 (31%) of cases diagnosed in 1990-91 and 1980-89, respectively, where a family history had been taken. All known hereditary cases were investigated for phaeochromocytoma. In 9/27 (33%) and 14/52 (27%) apparently sporadic cases diagnosed in the two periods respectively, no investigations were performed. Genetic counselling was offered to all known hereditary cases except one, but no offer was made in 11/25 (44%) and 16/52 (31%) apparently sporadic cases. There was no record that screening should be offered to the family in 15/35 (43%) and 25/68 (37%) cases identified from clinical investigations; in the majority it could be argued that it should have been. CONCLUSIONS: this study has shown that clinicians do not always have the necessary training or experience to undertake family studies and screening in this rare disorder.

Prolactinoma in 53 men: clinical characteristics and modes of treatment (male prolactinoma).

The data of 53 men treated for hyperprolactinemia were reviewed retrospectively to determine the efficacy of the medical and surgical treatment. The clinical assessment, radiological and neuro-ophthalmological investigations and hormonal measurements were performed before treatment as well as during the follow-up period. Imaging evaluation included computed tomography and/or nuclear magnetic resonance of the pituitary. The hormonal profile examined was PRL, FSH, LH and testosterone, as well as TSH, T4, T3 and cortisol. Thirty patients were treated solely by dopamine agonists (DA), twenty-two men had pituitary surgery in addition to DA treatment, and one patient was operated with no need for medical treatment. Decreased sexual function was the most frequent presenting symptom (85% of the men). Most of the patients had large invasive macroadenomas, with suprasellar extension. More than 40% had visual field defects. Baseline PRL (mean +/- SE) was 51,842 +/- 9,292 mU/L and decreased to a level below 575 mU/L in 70% of the patients after DA therapy. Mean testosterone, FSH, and LH levels increased slightly but significantly from the low baseline values. Complete clinical response to DA was achieved in 49% of the men and the tumor mass disappeared entirely in 21%, and incompletely in 42%. The surgical success rate (transsphenoidal or trans-cranial operation) was low--only one of the 23 patients operated recovered completely, and most of the patients were left with hormonal deficits and hyperprolactinemia. These findings indicate that continuous medical treatment with DA should be the preferred mode of treatment for male prolactinomas. Removal of these large tumors is recommended only when the tumors are life-threatening or if drug resistance or severe adverse reactions to DA develop.

Localization and identification of the multiple endocrine neoplasia type 1 disease gene.

The familial and genetic nature of multiple endocrine neoplasia type 1 (MEN 1) syndrome was first pointed out by Wermer in 1954, who suggested that an autosomal dominant gene with high penetrance controls the trait. The clinical picture is variable, depending mainly on which glands are involved and whether the tumors hypersecrete symptom-causing hormones. The most frequent endocrinopathies are hyperparathyroidism, pancreatic-duodenal, and pituitary tumors. Other tumors are also seen more frequently than in the general population, e.g., adrenocortical and thyroid tumors, carcinoids, lipomas, and pinealomas.

Urinary and plasma catecholamines and urinary catecholamine metabolites in pheochromocytoma: diagnostic value in 19 cases.

We review our data on the measurement of catecholamines and their metabolites in 19 patients with pheochromocytoma. All the assays were specific high-performance liquid chromatographic procedures with electrochemical detection. The assay of fractionated metanephrines was 100% sensitive. Normal values for both urinary norepinephrine and epinephrine were found in two asymptomatic patients with pheochromocytoma. Normal values for 3-methoxy-4-hydroxymandelic acid (VMA) were found in two patients with pure epinephrine-secreting tumors and in one patient with multiple endocrine neoplasia type II. Plasma catecholamines were usually less increased than their urinary counterparts. We recommend the specific measurement of norepinephrine and epinephrine as the initial test for patients with suggestive symptoms, and specific measurement of normetanephrine and metanephrine for patients in whom an adrenal mass is incidentally found. We argue against the use of total metanephrines, total catecholamines, and VMA because of their lack of diagnostic sensitivity.