The ectopic adrenocorticotropin syndrome: clinical features, diagnosis, management, and long-term follow-up.

CONTEXT: There are few large series of patients with ectopic, nonpituitary, corticotropin (ACTH) secretion (EAS). OBJECTIVE: The objective of this study was to analyze the clinical, biochemical, and radiological features, management, and treatment outcome of patients with EAS. DESIGN: This was a retrospective case-record study. SETTING: The setting for this study was a tertiary referral hospital center. PATIENTS: Forty patients with EAS were studied. MAIN OUTCOME MEASURES: Clinical, biochemical, and radiological features and response to therapy and survival were measured. RESULTS: The median follow-up was 5 yr (range, 2-30 yr). None of the dynamic tests achieved 100% accuracy, but bilateral inferior petrosal sinus sampling showed an absent central gradient in all but one case (one of 12). Imaging correctly identified the lesion at first investigation in 65% of cases. Bronchial carcinoid tumors were the most common cause of EAS (n = 12; 30%), followed by other neuroendocrine tumors (n = 13, 32.5%). In 12.5% of patients, the source of EAS was never found. Octreotide scintigraphy and whole-body venous sampling were of limited value. Surgical attempt at curative resection was successful in 83% (10 of 12) of patients with bronchial carcinoid tumors; others responded generally well to adrenolytic therapy or bilateral adrenalectomy. Tumor histology and the presence of distant metastases were the main predictors of overall survival (P < 0.05). CONCLUSIONS: A variety of tests and imaging studies are necessary for the correct diagnosis of the EAS, but even then, up to 20% of cases present a covert or occult EAS syndrome. These cases require a prolonged follow-up, review, and repetition of diagnostic tests and scans.

ACTH and alpha-MSH inhibit leptin expression and secretion in 3T3-L1 adipocytes: model for a central-peripheral melanocortin-leptin pathway.

Leptin is the 167 amino-acid protein product of the Lep (obese) gene that is released predominantly from adipose tissue and circulates at levels related to the amount of fat. Leptin expression is hormonally regulated: insulin and glucocorticoids are stimulators, while inhibitors include beta-adrenergic agonists and testosterone. Recently, adenylate cyclase-coupled melanocortin receptors have been identified in murine adipose tissue, the 3T3-L1 adipocyte cell line, and in human fat tissue. These studies prompted us to evaluate the effects of pro-opiomelanocortin (POMC)-derived peptides on leptin production and expression in 3T3-L1 adipocytes in culture. 3T3-L1 pre-adipocytes differentiated by the insulin/indomethacin (I/I) method produced leptin at levels that were two times higher than those obtained in cells differentiated by the more traditional insulin/dexamethasone/isobutylmethylxanthine (I/D/M) method. By RT-PCR studies, 3T3-L1 cells expressed both the melanocortin 2 receptors (MC2-R) and melanocortin 5 receptors (MC5-R) isoforms of the melanocortin receptor at an early stage of differentiation. When I/I differentiated 3T3-L1 adipocytes were incubated with different concentrations of dibutyryl cAMP (db-cAMP) or POMC-derived peptides (ACTH and alpha-MSH), ACTH and alpha-MSH stimulated cAMP production after 30 min (2-fold increase) associated with a dose-dependent inhibition of leptin secretion (ACTHz.Gt;alpha-MSH; IC(50)=3.2+/-0.4 SE and 36+/-5 nM, respectively), maximal after 3 h of incubation (30% inhibition). In addition, 100 nM ACTH and alpha-MSH induced a 60% reduction in leptin expression by RT-PCR. Incubation of cells with 0.5 mM db-cAMP led to a more prominent inhibition of leptin expression and secretion (up to 80% at 1 and 24 h, respectively). The ACTH and alpha-MSH inhibitory effects on leptin secretion were mediated by activation of the MC2-R and MC5-R and were reversed by the MC-R antagonists ACTH(11-24) and ACTH(7-38). In summary, we have shown that POMC-peptides are potent inhibitors of leptin expression and production in 3T3-L1 adipocytes. The finding of ACTH/alpha-MSH receptor-induced inhibition of leptin production and expression in adipocytes support the possibility that there is a control mechanism for modulation of adipose tissue function via a melanocortin-leptin axis.

Penile pharmacotesting in diagnosing male erectile dysfunction: evidence for lack of accuracy and specificity.

Penile pharmacotesting (PPT) with alprostadil (PGE1) represents the most common diagnostic approach to male erectile dysfunction (ED). A positive response - i.e. normal erectile rigidity of sustained duration - is presumed to exclude venous or arterial pathology with enough accuracy. To test this assumption we compared PPT vs. flowmetric results obtained by colour-duplex Doppler ultrasound (CDDU) in patients (pts) undergoing diagnostic evaluation for ED under conditions of maximal cavernous relaxation. A total of 195 non-consecutive impotent pts were diagnosed after dynamic CDDU as non-vasculogenic (NOR), or having arteriogenic (AR), veno-occlusive (VO) or mixed (MX) ED. Maximal erection obtained after PPT was scored as: type-1 (full tumescence - no sustained rigidity, angle on the abdominal plane >90 degrees), type-2 (sustained partial erection, valid for intromission, angle=90 degrees) and type-3 (sustained full erection, angle <90 degrees). Comparing PPT with flowmetric results, we found that a type-3 response had 20% false negative diagnosis of NOR (17% of AR- and 3% of VO- and MX-ED, respectively), while a type-2 response had 63% false negative diagnosis (20% of AR, 37% of VO- and 6% MX-ED, respectively). Type-1 response was associated with the presence of VO dysfunction in 99% of cases. These data suggest that a positive response to PPT (type-2 and type-3) assessed by the visual rating of erection is associated with both arterial (up to 20%) and/or VO (up to 43%) ED, as detected by CDDU. We conclude that PPT alone is a misleading diagnostic test to exclude vascular ED and that dynamic CDDU should be offered to pts investigated for male ED.