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Context Pheochromocytomas and paragangliomas (PPGLs) with pathogenic mutations in the succinate dehydrogenase subunit B (SDHB) are associated with a high metastatic risk. Somatostatin receptor 2 (SSTR2)–dependent imaging is the most sensitive imaging modality for SDHB-related PPGLs, suggesting that SSTR2 expression is a significant cell surface therapeutic biomarker of such tumors. Objective Exploration of the relationship between SSTR2 immunoreactivity and SDHB immunoreactivity, mutational status, and clinical behavior of PPGLs. Evaluation of SSTR-based therapies in metastatic PPGLs. Methods Retrospective analysis of a multicenter cohort of PPGLs at 6 specialized Endocrine Tumor Centers in Germany, The Netherlands, and Switzerland. Patients with PPGLs participating in the ENSAT registry were included. Clinical data were extracted from medical records, and immunohistochemistry (IHC) for SDHB and SSTR2 was performed in patients with available tumor tissue. Immunoreactivity of SSTR2 was investigated using Volante scores. The main outcome measure was the association of SSTR2 IHC positivity with genetic and clinical–pathological features of PPGLs. Results Of 202 patients with PPGLs, 50% were SSTR2 positive. SSTR2 positivity was significantly associated with SDHB- and SDHx-related PPGLs, with the strongest SSTR2 staining intensity in SDHB-related PPGLs (P = .01). Moreover, SSTR2 expression was significantly associated with metastatic disease independent of SDHB/SDHx mutation status (P < .001). In metastatic PPGLs, the disease control rate with first-line SSTR-based radionuclide therapy was 67% (n = 22, n = 11 SDHx), and with first-line “cold” somatostatin analogs 100% (n = 6, n = 3 SDHx). Conclusion SSTR2 expression was independently associated with SDHB/SDHx mutations and metastatic disease. We confirm a high disease control rate of somatostatin receptor–based therapies in metastatic PPGLs.

Context:Somatic mutations have been found causative for endocrine autonomy in aldosterone-producing adenomas (APAs). Whereas mutations of PRKACA (catalytic subunit of protein kinase A) have been identified in cortisol-producing adenomas, the presence of PRKACA variants in APAs is unknown, especially in those that display cosecretion of cortisol.Objective:The objective of the study was to investigate PRKACA somatic variants identified in APA cases.Design:Identification of PRKACA somatic variants in APAs by whole-exome sequencing followed by in vitro analysis of the enzymatic activity of PRKACA variants and functional characterization by double immunofluorescence of CYP11B2 and CYP11B1 expression in the corresponding tumor tissues.Setting and Patients:APA tissues were collected from 122 patients who underwent unilateral adrenalectomy for primary aldosteronism between 2005 and 2015 at a single institution.Results:PRKACA somatic mutations were identified in two APA cases (1.6%). One APA carried a newly identified p.His88Asp variant, whereas in a second case, a p.Leu206Arg mutation was found, previously described only in cortisol-producing adenomas with overt Cushing's syndrome. Functional analysis showed that the p.His88Asp variant was not associated with gain of function. Although CYP11B2 was strongly expressed in the p.His88Asp-mutated APA, the p.Leu206Arg carrying APA predominantly expressed CYP11B1. Accordingly, biochemical Cushing's syndrome was present only in the patient with the p.Leu206Arg mutation. After adrenalectomy, both patients improved with a reduced number of antihypertensive medications and normalized serum potassium levels.Conclusions:We describe for the first time PRKACA mutations as rare findings associated with unilateral primary aldosteronism. As cortisol cosecretion occurs in a subgroup of APAs, other molecular mechanisms are likely to exist.

About 35% of patients with pheochromocytoma/paraganglioma carry a germline mutation in one of the 10 main susceptibility genes. The recent introduction of next-generation sequencing will allow the analysis of all these genes in one run. When positive, the analysis is generally unequivocal due to the association between a germline mutation and a concordant clinical presentation or positive family history. When genetic analysis reveals a novel mutation with no clinical correlates, particularly in the presence of a missense variant, the question arises whether the mutation is pathogenic or a rare polymorphism.We report the case of a 35-year-old patient operated for a pheochromocytoma who turned out to be a carrier of a novel SDHD (succinate dehydrogenase subunit D) missense mutation. With no positive family history or clinical correlates, we decided to perform additional analyses to test the clinical significance of the mutation.We performed in silico analysis, tissue loss of heterozygosity analysis, immunohistochemistry, Western blot analysis, SDH enzymatic assay, and measurement of the succinate/fumarate concentration ratio in the tumor tissue by tandem mass spectrometry.Although the in silico analysis gave contradictory results according to the different methods, all the other tests demonstrated that the SDH complex was conserved and normally active. We therefore came to the conclusion that the variant was a nonpathogenic polymorphism.Advancements in technology facilitate genetic analysis of patients with pheochromocytoma but also offer new challenges to the clinician who, in some cases, needs clinical correlates and/or functional tests to give significance to the results of the genetic assay.

Item does not contain fulltext Objective: The aim was to formulate clinical practice guidelines for pheochromocytoma and paraganglioma (PPGL). Participants: The Task Force included a chair selected by the Endocrine Society Clinical Guidelines Subcommittee (CGS), seven experts in the field, and a methodologist. The authors received no corporate funding or remuneration. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. The Task Force reviewed primary evidence and commissioned two additional systematic reviews. Consensus Process: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, European Society of Endocrinology, and Americal Association for Clinical Chemistry reviewed drafts of the guidelines. Conclusions: The Task Force recommends that initial biochemical testing for PPGLs should include measurements of plasma free or urinary fractionated metanephrines. Consideration should be given to preanalytical factors leading to false-positive or false-negative results. All positive results require follow-up. Computed tomography is suggested for initial imaging, but magnetic resonance is a better option in patients with metastatic disease or when radiation exposure must be limited. (123)I-metaiodobenzylguanidine scintigraphy is a useful imaging modality for metastatic PPGLs. We recommend consideration of genetic testing in all patients, with testing by accredited laboratories. Patients with paraganglioma should be tested for SDHx mutations, and those with metastatic disease for SDHB mutations. All patients with functional PPGLs should undergo preoperative blockade to prevent perioperative complications. Preparation should include a high-sodium diet and fluid intake to prevent postoperative hypotension. We recommend minimally invasive adrenalectomy for most pheochromocytomas with open resection for most paragangliomas. Partial adrenalectomy is an option for selected patients. Lifelong follow-up is suggested to detect recurrent or metastatic disease. We suggest personalized management with evaluation and treatment by multidisciplinary teams with appropriate expertise to ensure favorable outcomes.

Item does not contain fulltext CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) are diagnosed earlier in patients with hereditary than sporadic disease. Whether other factors influence age at diagnosis is unclear. OBJECTIVE: We examined ages at which PPGLs were diagnosed according to different catecholamine phenotypes and locations of tumors. DESIGN & SETTING: Retrospective multicenter study. PATIENTS: Patients with PPGLs included 172 with and 183 without identified germline mutations or hereditary syndromes. BIOCHEMICAL MEASUREMENTS: Differences in plasma concentrations of metanephrine, a metabolite of epinephrine, were used to distinguish epinephrine-producing tumors from those lacking epinephrine production. RESULTS: Patients with epinephrine-producing tumors were diagnosed 11 yr later (P < 0.001) than those with tumors lacking appreciable epinephrine production. Among patients without evidence of a hereditary condition, those with and without epinephrine-producing tumors had respective mean +/- se ages of 50 +/- 2 and 42 +/- 2 yr (P < 0.001) at diagnosis. Patients with multiple endocrine neoplasia type 2 and neurofibromatosis type 1, all with epinephrine-producing tumors, were similarly diagnosed with disease at a later age than patients with tumors that lacked appreciable epinephrine production secondary to mutations of von Hippel-Lindau and succinate dehydrogenase genes (40 +/- 2 vs. 31 +/- 1 yr, P < 0.001). Among the latter patients, those with multifocal tumors were diagnosed earlier than those with solitary tumors (19 +/- 3 vs. 34 +/- 2 yr, P < 0.001). CONCLUSIONS: The variations in ages at diagnosis associated with different tumor catecholamine phenotypes and locations suggest origins of PPGLs from different chromaffin progenitor cells with variable susceptibility to disease causing mutations. Different optimal age cut-offs for mutation testing are indicated for patients with and without epinephrine-producing tumors (44-49 vs. 30-35 yr, respectively).

Contains fulltext : 70145timmers.pdf (Publisher’s version ) (Open Access) CONTEXT: Patients with adrenal and extra-adrenal abdominal paraganglioma (PGL) almost invariably have increased plasma and urine concentrations of metanephrines, the O-methylated metabolites of catecholamines. We report four cases of biochemically silent abdominal PGL, in which metanephrines were normal despite extensive disease. OBJECTIVE: Our objective was to identify the mechanism underlying the lack of catecholamine hypersecretion and metabolism to metanephrines in biochemically silent PGL. DESIGN: This is a descriptive study. SETTING: The study was performed at a referral center. PATIENTS: One index case and three additional patients with large abdominal PGL and metastases but with the lack of evidence of catecholamine production, six patients with metastatic catecholamine-producing PGL and a mutation of the succinate dehydrogenase subunit B (SDHB) gene, and 136 random patients with catecholamine-producing PGL were included in the study. MAIN OUTCOME MEASURES: Plasma, urine, and tumor tissue concentrations of catecholamines and metabolites were calculated with electron microscopy and tyrosine hydroxylase immunohistochemistry. RESULTS: All four patients with biochemically silent PGL had an underlying SDHB mutation. In the index case, the tumor tissue concentration of catecholamines (1.8 nmol/g) was less than 0.01% that of the median (20,410 nmol/g) for the 136 patients with catecholamine-producing tumors. Electron microscopy showed the presence of normal secretory granules in all four biochemically silent PGLs. Tyrosine hydroxylase immunoreactivity was negligible in the four biochemically silent PGLs but abundant in catecholamine-producing PGLs. CONCLUSIONS: Patients with SDHB mutations may present with biochemically silent abdominal PGLs due to defective catecholamine synthesis resulting from the absence of tyrosine hydroxylase. Screening for tumors in patients with SDHB mutations should not be limited to biochemical tests of catecholamine excess.

Context: Patients with classic congenital adrenal hyperplasia (CAH) have adrenomedullary dysplasia and hypofunction, and their lack of adrenomedullary reserve has been associated with a defective glucose response to brief high-intensity exercise. Objective: Our objective was to assess hormonal, metabolic, and cardiovascular response to prolonged moderate-intensity exercise comparable to brisk walking in adolescents with classic CAH. Subjects and Methods: We compared six adolescents with classic CAH (16–20 yr old) with seven age-, sex-, and body mass index group-matched controls (16–23 yr old) using a 90-min standardized ergometer test. Metabolic, hormonal, and cardiovascular parameters were studied during exercise and recovery. Results: Glucose did not change throughout exercise and recovery for controls, whereas CAH patients showed a steady decline in glucose during exercise with an increase in glucose in the postexercise period. Glucose levels were significantly lower in CAH patients at 60 (P = 0.04), 75 (P = 0.01), and 90 (P = 0.03) min of exercise and 15 (P = 0.02) min post exercise, whereas glucose levels were comparable between the two groups early in exercise and at 30 min (P = 0.19) post exercise. As compared with controls, CAH patients had significantly lower epinephrine (P = 0.002) and cortisol (P ≤ 0.001) levels throughout the study and similar norepinephrine, glucagon, and GH levels. Patients with CAH and controls had comparable cardiovascular parameters and perceived level of exertion. Despite having lower glucose levels, insulin levels were slightly higher in CAH patients during the testing period (P = 0.17), suggesting insulin insensitivity. Conclusion: CAH patients have defective glycemic control and altered metabolic and hormonal responses during prolonged moderate-intensity exercise comparable to brisk walking.

Context: Pheochromocytomas are rare tumors of predominantly adrenal origin that often produce and secrete catecholamines. Malignancy occursinavariablepercentageofcasesdependingongeneticbackground andtumorlocation.Definitivediagnosisreliesonthedetectionofdistant metastases. Treatments for malignant pheochromocytoma include surgical debulking, pharmacological control of hormone-mediated symptoms, targeted methods such as external irradiation, and systemic antineoplastic therapy. Different agents and protocols for this purpose are reviewed, and their therapeutic potential is discussed. Evidence Acquisition: Literature on antineoplastic therapies for malignant pheochromocytoma was identified by searching the PubMed database with restriction to articles published in English during the past 30 yr. Evidence Synthesis: Because of the rarity of the condition, no randomized clinical trials concerning the treatment of malignant pheochromocytoma have been performed. The strategy established best is [ 131 I]meta-iodobenzylguanidine (MIBG) therapy, which is well tolerated. Similar to cytotoxic chemotherapy with cyclophosphamide, vincristine, and dacarbazine, MIBG can induce remission for a limited period in a significant proportion of patients. Octreotide as a single agent seems to be largely ineffective. Conclusions: MIBG radiotherapy and cyclophosphamide, vincristine, and dacarbazine chemotherapy are comparable with respect to response rate and toxicity. It is unclear whether combining both can improve the outcome. Future developments may include new multimodal concepts with focus on inhibition of angiogenetic factors and heat shock protein 90. Any present or new therapeutic approach must take into account the highly variable natural course of the disease. (J Clin Endocrinol Metab 92: 1217–1225, 2007)

Classic congenital adrenal hyperplasia (CAH) is associated with impaired function of the adrenal cortex and medulla leading to decreased production of cortisol and epinephrine. As a result, the normal exercise-induced rise in blood glucose is markedly blunted in such individuals. We examined whether an extra dose of hydrocortisone, similar to that given during other forms of physical stress such as intercurrent illness, would normalize blood glucose levels during exercise in patients with CAH. We studied hormonal, metabolic, and cardiorespiratory parameters in response to a standardized high-intensity exercise protocol in nine adolescent patients with classic CAH. Patients were assigned to receive either an additional morning dose of hydrocortisone or placebo, in addition to their usual glucocorticoid and mineralocorticoid replacement in a randomized, double-blind, crossover design 1 h before exercising. Although plasma cortisol levels approximately doubled after administration of the additional hydrocortisone dose compared with the usual single dose, fasting and exercise-induced blood glucose levels did not differ. In addition, no differences were observed in the serum concentrations of the glucose-modulating hormones epinephrine, insulin, glucagon, and GH and of the metabolic parameters lactate and free fatty acids. Although maximal heart rate was slightly higher after stress dosing (193 +/- 3 vs. 191 +/- 3 beats/min, mean +/- sem, P < 0.05), this did not affect exercise performance or perceived exertion. We conclude that patients with classic CAH do not benefit from additional hydrocortisone during short-term, high-intensity exercise. Although this has not been tested with long-term exercise, a high degree of caution should be used when considering the frequent use of additional hydrocortisone administration with exercise, given the adverse side effects of glucocorticoid excess.

Classic congenital hyperplasia (CAH) is characterized by impaired adrenocortical function with a decrease in cortisol and aldosterone secretion and an increase in androgen secretion. Adrenomedullary function is also compromised due to developmental defects in the formation of the adrenal medulla, leading to decreased production of epinephrine. To examine the response to a natural stressful stimulus in patients with classic CAH, we studied hormonal, metabolic, and cardiorespiratory parameters in response to a standardized high-intensity exercise protocol in nine adolescent patients with CAH and nine healthy controls matched for gender, age, and percent body fat. The same relative workload was applied, based on individual maximal aerobic capacity, and all patients received their usual glucocorticoid and mineralocorticoid replacement. When compared with their normal counterparts, patients with CAH had significantly lower epinephrine levels both at baseline and at peak exercise (P < 0.01), whereas norepinephrine levels did not differ. Blood glucose concentrations were similar at baseline, but the normal exercise-induced rise observed in the healthy controls was significantly blunted in the CAH patients (P < 0.01). Peak heart rate was also lower in CAH patients than healthy controls (P < 0.05). As expected, the normal exercise-induced increase in cortisol was not observed in patients with CAH. No significant differences were found in serum levels of insulin, glucagon, GH, lactate and free fatty acids, blood pressure, or ability to sustain exercise between the two groups. Patients with CAH replaced with glucocorticoids have decreased adrenomedullary reserve and impaired exercise-induced changes in glucose but normal short-term high-intensity exercise performance. Whether the combination of epinephrine and cortisol deficiency poses a risk for hypoglycemia and/or decreased endurance during long-term physical stress has to be determined.

The purpose of the study was to assess the diagnostic utility of 6-[(18)F]-fluorodopamine ([(18)F]-DA) positron emission tomography scanning (PET) vs. [(131)I]-metaiodobenzylguanidine (MIBG) scintigraphy in patients with metastatic pheochromocytoma (PHEO). We studied 10 men and six women (mean age 38.2 +/- 11.5 yr) referred to our institution for metastatic PHEO; two patients were studied twice within a 2-yr interval. Imaging modalities included computed tomography (CT), magnetic resonance imaging (MRI), [(131)I]-MIBG scintigraphy, and [(18)F]-DA PET. Fifteen of 16 patients had positive findings on CT and/or MRI consistent with the presence of pheochromocytoma. [(18)F]-DA PET was positive in all patients, but seven patients had negative [(131)I]-MIBG scans. Thirty-eight foci of uptake were shown by both [(18)F]-DA PET and [(131)I]-MIBG scintigraphy, 90 only by [(18)F]-DA PET, and 10 only by [(131)I]-MIBG; most lesions were also visible on CT/MRI. In this initial series of patients with metastatic pheochromocytoma, [(18)F]-DA PET localized PHEO in all patients and showed a large number of foci that were not imaged with [(131)I]-MIBG scintigraphy. Thus, [(18)F]-DA PET was found to be a superior imaging method in patients with metastatic PHEO, in which correct detection of disease extension often determines the most appropriate therapeutic plan and future follow-up.

Adipose tissue lipolysis is at least in part stimulated by the sympathetic nervous system (SNS). Although there is a generalized decrease in SNS activity with fasting, the rate of lipolysis during fasting increases. The aim of this study was to determine whether there is an association between activation of sympathetic nerves innervating adipose tissue and the increase in lipolysis seen during fasting in humans. We used the isotope dilution technique to measure regional norepinephrine spillover from abdominal sc adipose tissue from seven healthy subjects before and after a 72-h fast. Our results showed a significant increase in adipose tissue spillover of norepinephrine (mean ± sem, 0.40 ± 0.09 vs. 1.08 ± 0.18 pmol·100 g−1·min−1, P < 0.05) and arterial norepinephrine concentrations (0.92 ± 0.10 vs. 1.23 ± 0.08 nmol·liter−1, P < 0.05) after the fast with no significant change in total body norepinephrine spillover, forearm norepinephrine spillover, epinephrine concentrations, or energy expenditure. We show for the first time, in humans, a selective regional increase in adipose tissue norepinephrine spillover in response to a 72-h fast and suggest that the SNS may play a greater role in the regulation of lipid metabolism during fasting than previously thought.

Leptin is secreted by the white adipose tissue and modulates energy homeostasis. Nutritional, neural, neuroendocrine, paracrine, and autocrine factors, including the sympathetic nervous system and the adrenal medulla, have been implicated in the regulation of leptin secretion. Classic congenital adrenal hyperplasia (CAH) is characterized by a defect in cortisol and aldosterone secretion, impaired development and function of the adrenal medulla, and adrenal hyperandrogenism. To examine leptin secretion in patients with classic CAH in relation to their adrenomedullary function and insulin and androgen secretion, we studied 18 children with classic CAH (12 boys and 6 girls; age range 2-12 yr) and 28 normal children (16 boys and 12 girls; age range 5-12 yr) matched for body mass index (BMI). Serum leptin concentrations were significantly higher in patients with CAH than in control subjects (8.1 +/- 2.0 vs. 2.5 +/- 0.6 ng/ml, P = 0.01), and this difference persisted when leptin values were corrected for BMI. When compared with their normal counterparts, children with CAH had significantly lower plasma epinephrine (7.1 +/- 1.3 vs. 50.0 +/- 4.2, P < 0.001) and free metanephrine concentrations (18.4 +/- 2.4 vs. 46.5 +/- 4.0, P < 0.001) and higher fasting serum insulin (10.6 +/- 1.4 vs. 3.2 +/- 0.2 microU/ml, P < 0.001) and testosterone (23.7 +/- 5.3 vs. 4.6 +/- 0.5 ng/dl, P = 0.003) concentrations. Insulin resistance determined by the homeostasis model assessment method was significantly greater in children with classic CAH than in normal children (2.2 +/- 0.3 vs. 0.7 +/- 0.04, P < 0.001). Leptin concentrations were significantly and negatively correlated with epinephrine (r = -0.50, P = 0.001) and free metanephrine (r = -0.48, P = 0.002) concentrations. Stepwise multiple linear regression analysis indicated that serum leptin concentrations were best predicted by BMI in both patients and controls. Gender predicted serum leptin concentrations in controls but not in patients with classic CAH. No association was found between the dose of hydrocortisone and serum leptin (r = -0.17, P = 0.5) or insulin (r = 0.24, P = 0.3) concentrations in children with CAH. Our findings indicate that children with classic CAH have elevated fasting serum leptin and insulin concentrations, and insulin resistance. These most likely reflect differences in long-term adrenomedullary hypofunction and glucocorticoid therapy. Elevated leptin and insulin concentrations in patients with CAH may further enhance adrenal and ovarian androgen production, decrease the therapeutic efficacy of glucocorticoids, and contribute to later development of polycystic ovary syndrome and/or the metabolic syndrome and their complications.

Glucocorticoids are required for the normal functioning of chromaffin cells and their capacity to produce epinephrine. This was modeled in a unique clinical syndrome of isolated glucocorticoid deficiency due to unresponsiveness to ACTH. The working hypotheses were that in patients with isolated glucocorticoid deficiency, adrenomedullary epinephrine would be suppressed despite replacement therapy; that norepinephrine might show a compensatory response; and that the physiological response to stress would reflect these changes. Toward these hypotheses, patients with ACTH unresponsiveness on glucocorticoid replacement were subjected to three levels of acute stress: assumption of upright posture, cold pressor, and exercise. Their catecholamine and physiological response were monitored. Patients with isolated glucocorticoid deficiency of this study had severe adrenomedullary dysfunction, characterized by a minimal resting production of epinephrine (6 ± 2 pg/ml compared with 64 ± 22 pg/ml of the controls) and a minimal response to stress. A slight compensatory increase of norepinephrine was found in response to cold pressor test (754 ± 200 pg/ml compared with 431 ± 73 pg/ml of the control). The physiological response is characterized by low systolic blood pressure and high pulse rate in rest and mild stress and in a pressor response to exercise (diastolic 87 ± 5 mm Hg, compared with 73 ± 2 mm Hg of the control). It is concluded that intra-adrenal glucocorticoids are essential for epinephrine secretion, that norepinephrine may be compensatory, and that these result in a distinct physiological response. The implications of the pressor response to exercise, the declining pulse pressure, and the increased pulse response insinuate a lower physical fitness in patients with adrenal insufficiency.

This study examined the mechanisms linking different biochemical and clinical phenotypes of pheochromocytoma in multiple endocrine neoplasia type 2 (MEN 2) and von Hippel-Lindau (VHL) syndrome to underlying differences in the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis, and of phenylethanolamine N-methyltransferase (PNMT), the enzyme that converts norepinephrine to epinephrine. Signs and symptoms of pheochromocytoma, plasma catecholamines and metanephrines, and tumor cell neurochemistry and expression of TH and PNMT were examined in 19 MEN 2 patients and 30 VHL patients with adrenal pheochromocytomas. MEN 2 patients were more symptomatic and had a higher incidence of hypertension (mainly paroxysmal) and higher plasma concentrations of metanephrines, but paradoxically lower total plasma concentrations of catecholamines, than VHL patients. MEN 2 patients all had elevated plasma concentrations of the epinephrine metabolite, metanephrine, whereas VHL patients showed specific increases in the norepinephrine metabolite, normetanephrine. The above differences in clinical presentation were largely explained by lower total tissue contents of catecholamines and expression of TH and negligible stores of epinephrine and expression of PNMT in pheochromocytomas from VHL than from MEN 2 patients. Thus, mutation-dependent differences in the expression of genes controlling catecholamine synthesis represent molecular mechanisms linking the underlying mutation to differences in clinical presentation of pheochromocytoma in patients with MEN 2 and the VHL syndrome.

The sympathetic nervous system regulates lipolysis. There are regional differences in the sensitivity of lipolysis to adrenergic regulation. Little is known about regional sympathetic activity in response to eating in humans. We studied the effect of feeding on systemic and local sympathetic nervous system activity and lipolysis in lean healthy subjects (three women and five men; age, 27.0 ± 2.0; body mass index, 23.4 ± 1.2 kg/m−2) using isotope dilution methodology and arterio-venous sampling. Feeding increased arterial norepinephrine (NE) concentration (mean premeal, 0.96 ± 0.12 nmol/L·L; mean postmeal, 1.28 ± 0.14 nmol/L·L; P < 0.02) and total body NE spillover (mean premeal, 2.11 ± 0.30 nmol/min·L; mean postmeal, 2.76 ± 0.31 nmol/min·L; P < 0.02), whereas the arterial epinephrine concentration decreased (mean premeal, 289 ± 61 pmol/L; mean postmeal, 170 ± 5 pmol/L; P < 0.02). Palmitate concentration and total body systemic rate of appearance of palmitate declined postprandially (mean premeal, 117± 15 ...

Dopamine in the circulation occurs mainly as dopamine sulfate, the sources and physiological significance of which have been obscure. In this study, plasma concentrations of dopamine sulfate were measured after a meal, after fasting for 4 days, and during i.v. L-DOPA, nitroprusside, or trimethaphan infusion in volunteers; after dopamine infusion in patients with L-aromatic-amino-acid decarboxylase deficiency; in arterial and portal venous plasma of gastrointestinal surgery patients; and in patients with sympathetic neurocirculatory failure. Meal ingestion increased plasma dopamine sulfate by more than 50-fold; however, prolonged fasting decreased plasma dopamine sulfate only slightly. L-DOPA infusion produced much larger increments in dopamine sulfate than in dopamine; the other drugs were without effect. Patients with L-aromatic amino acid decarboxylase deficiency had decreased dopamine sulfate levels, and patients with sympathetic neurocirculatory failure had normal levels. Decarboxylase-deficient patients undergoing dopamine infusion had a dopamine sulfate/dopamine ratio about 25 times less than that at baseline in volunteers. Surgery patients had large arterial-portal venous increments in plasma concentrations of dopamine sulfate, so that mesenteric dopamine sulfate production accounted for most of urinary dopamine sulfate excretion, a finding consistent with the localization of the dopamine sulfoconjugating enzyme to gastrointestinal tissues. The results indicate that plasma dopamine sulfate derives mainly from sulfoconjugation of dopamine synthesized from L-DOPA in the gastrointestinal tract. Both dietary and endogenous determinants affect plasma dopamine sulfate. The findings suggest an enzymatic gut-blood barrier for detoxifying exogenous dopamine and delimiting autocrine/paracrine effects of endogenous dopamine generated in a "third catecholamine system."

Division of Endocrinology, Department of Medicine III (R.D., G.E., V.K., S.R.B., L.C.H.), Department of Nuclear Medicine (K.Z.), Institute of Clinical Chemistry and Laboratory Medicine (G.E.), Institute for Diagnostic Radiology (N.A.), Department of Surgery (J.G.), and Institute of Pathology (K.W.), Dresden Technical University Medical Center, 01307 Dresden, Germany; and Department of Internal Medicine (V.J.), Dobeln General Hospital, 04720 Dobeln, Germany

Context Catecholamines and adrenocortical steroids are important regulators of blood pressure. Bidirectional relationships between adrenal steroids and catecholamines have been established but whether this is relevant to patients with pheochromocytoma is unclear. Objective This study addresses the hypothesis that patients with pheochromocytoma and paraganglioma (PPGL) have altered steroid production compared with patients with primary hypertension. Design Multicenter cross-sectional study. Setting Twelve European referral centers. Patients Subjects included 182 patients with pheochromocytoma, 36 with paraganglioma and 270 patients with primary hypertension. Patients with primary aldosteronism (n = 461) and Cushing syndrome (n = 124) were included for additional comparisons. Intervention In patients with PPGLs, surgical resection of tumors. Outcome measures Differences in mass spectrometry–based profiles of 15 adrenal steroids between groups and after surgical resection of PPGLs. Relationships of steroids to plasma and urinary metanephrines and urinary catecholamines. Results Patients with pheochromocytoma had higher (P < .05) circulating concentrations of cortisol, 11-deoxycortisol, 11-deoxycorticosterone, and corticosterone than patients with primary hypertension. Concentrations of cortisol, 11-deoxycortisol, and corticosterone were also higher (P < .05) in patients with pheochromocytoma than with paraganglioma. These steroids correlated positively with plasma and urinary metanephrines and catecholamines in patients with pheochromocytoma, but not paraganglioma. After adrenalectomy, there were significant decreases in cortisol, 11-deoxycortisol, corticosterone, 11-deoxycorticosterone, aldosterone, and 18-oxocortisol. Conclusions This is the first large study in patients with PPGLs that supports in a clinical setting the concept of adrenal cortical–medullary interactions involving an influence of catecholamines on adrenal steroids. These findings could have implications for the cardiovascular complications of PPGLs and the clinical management of patients with the tumors.