Martin Reincke

Adrenocortical carcinoma is characterized by a high frequency of chromosomal gains and high‐level amplifications

Distinction of adrenocortical carcinoma from benign adrenocortical lesions by standard criteria is often difficult. In order to search for additional diagnostic parameters, a series of 25 adrenocortical tumors, 8 adenomas, 14 primary carcinomas, 1 metastasis, and the 2 adrenocortical carcinoma cell lines SW13 and NCI‐H295 were analyzed by the approach of comparative genomic hybridization (CGH). Except for the two smallest adenomas, all tumors showed chromosomal imbalances with a high incidence of chromosomal gains, most frequently involving chromosomes or chromosome arms 5, 7, 8, 9q, 11q, 12q, 14q, 16, 17q, 19, 20, and 22q. The only significant loss of material concerned the distal part of 9p. Furthermore, 21 high‐level amplifications were identified in 15 different regions of the genome. The consensus regions of recurrent gains and the focal high‐level amplifications allowed identification of a series of chromosomal subregions containing candidate proto‐oncogenes of potential pathogenic function in adrenocortical tumors: 1p34.3–pter, 1q22–q25, 3p24–pter, 3q29, 7p11.2–p14, 9q34, 11q12–11q13, 12q13, 12q24.3, 13q34, 14q11.2–q12, 14q32, 16p, 17q24–q25, 19p13.3, 19q13.4, and 22q11.2–q12. A subset of the CGH data was independently confirmed by interphase cytogenetics. Interestingly, the adenomas larger than 4 cm contained gained material of regions also overrepresented in carcinomas. In addition, several chromosomal gains, in particular the high‐level amplifications, were exclusive for the malignant status of the tumors. These data indicate that the larger adrenal lesions need to be carefully considered in the diagnosis of adrenocortical tumors, and that genetic aberrations might provide useful markers for a better diagnostic differentiation. Genes Chromosomes Cancer 28:145–152, 2000.

Effects of the Neuropeptide Substance P on Sleep, Mood, and Neuroendocrine Measures in Healthy Young Men☆

The neuropeptide substance P (SP) has been supposed to be involved in the etiopathology of affective disorders, mainly because of the finding of increased levels of SP in the cerebrospinal fluid of depressed patients and the preliminary evidence of antidepressant effects of SP-receptor antagonists in depressed patients. We investigated whether SP may induce changes of sleep, mood and neuroendocrine measures that are similar to those in depressed patients. In a double-blind, randomized cross-over design, 12 healthy young men were investigated in two blocks of three consecutive nights, in which SP or NaCl was intravenously infused during the third night. Polysomnographic recordings were obtained during all nights and blood samples were drawn every 30 min during the third night. Infusion of SP caused a significant worsening of the mood of the subjects, led to an increase of REM latency and time awake during the SP-infusion intervals, caused increased stage 1 sleep in the first part of the night, and led to increased cortisol and thyroid stimulating hormone levels and a trend for decreased growth hormone levels. These effects can be interpreted as evidence for a central arousing effect of SP. Further studies should focus on the effects of substance P in patients with depressive or other psychiatric disorders.

Angiotensin II type 1 receptor and ACTH receptor expression in human adrenocortical neoplasms

OBJECTIVE Type 1 angiotensin II (Ang II) receptors transduce most of the known actions of Ang II, including steroidogenesis and trophic actions on the adrenal cortex. We investigated the type 1 Ang II receptor expression in adrenocortical tissues to define its regulation in adrenocortical neoplasms and to compare its expression with that of the ACTH receptor (ACTH‐R).

New mechanisms of adrenostatic compounds in a human adrenocortical cancer cell line

Adrenostatic compounds are frequently used in the treatment of patients with Cushings syndrome and act via direct inhibition of steroidogenic enzymes. However, additional mechanisms may be involved in the blockade of adrenal steroid secretion. We therefore investigated the effects of aminoglutethimide (AG), metyrapone (MTP) and etomidate (ETO) in the human NCI‐h295 adrenocortical carcinoma cell line.

Transient total sleep loss in cerebral Whipple's disease: a longitudinal study

A case with transient, almost complete sleep loss caused by cerebral manifestation of Whipples disease (WD) is presented. Cerebral WD is rare and in most cases occurs after gastrointestinal infection. In our case, a progressive and finally almost complete sleep loss was the initial and predominant symptom. Polysomnographic studies in several consecutive nights and over 24 h showed a total abolition of the sleep–wake cycle with nocturnal sleep duration of less than 15 min. Endocrine tests revealed hypothalamic dysfunction with flattening of circadian rhythmicity of cortisol, TSH, growth hormone and melatonin. Cerebrospinal fluid (CSF) hypocretin was reduced. [18F]Deoxyglucose positron emission tomography (FDG‐PET) revealed hypermetabolic areas in cortical and subcortical areas including the brainstem, which might explain sleep pathology and vertical gaze palsy. In the course of treatment with antibiotics and additional carbamazepine for 1 year, insomnia slowly and gradually improved. Endocrine investigations at 1‐year follow‐up showed persistent flattening of circadian rhythmicity. The FDG‐PET indicated normalized metabolism in distinct regions of the brain stem which paralleled restoration of sleep length. The extent of sleep disruption in this case of organic insomnia was similar to cases of familial fatal insomnia, but was at least partially reversible with treatment.

Molecular adrenocortical tumourigenesis

Adrenocortical neoplasms are the most frequent abnormality of the adrenal cortex. Most of these lesions are clinically silent and are detected incidentally by ultrasound or computed tomography. The prevalence of these so‐called ‘incidentalomas’ in the general population is around 1%, increasing with age and reaching 6% among those in the age range 60–70 years. In contrast, primary adrenocortical carcinoma, a highly malignant tumour, is rare, having an incidence of one case per million per year. Recent progress has been achieved in the understanding of adrenocortical tumourigenesis by mapping and identification of genes responsible for hereditary tumours that involve the adrenal gland. Investigation of the clonal composition of adrenal tumours demonstrates that adrenal carcinomas are monoclonal, whereas adrenal adenoma may be polyclonal in approximately 25–40% of cases. Oncogenes and tumour‐suppressor genes involved in adrenal carcinomas include mutations in the p53 tumour‐suppressor gene and rearrangements of the chromosomal locus 11p15.5 associated with IGF II hyperexpression. Constitutive activation of the ACTH receptor‐G protein‐cAMP signal cascade does not play a role in adrenal tumour formation. Conversely, deletions of the ACTH receptor gene have recently been found in undifferentiated adenomas and in aggressive adrenocortical carcinomas, and, more recently, confirmed in a larger series of tumours. The available literature indicates that the signalling pathways of adrenocortical tumours are different from those of other endocrine neoplasms, such as pituitary and thyroid adenomas.

Metabolism of glucocorticoids and mineralocorticoids in patients with adrenal incidentalomas

Adrenal incidentalomas are mostly nonfunctioning adrenocortical adenomas (NFI). However, in 5%–12% of the patients a preclinical Cushings syndrome (PCS) with autonomous cortisol production by the tumour is present. Since urinary free cortisol excretion is not sensitive enough to determine subclinical hypercortisolism, in the present study more sensitive indicators of daily cortisol production were measured.

Oral administration of the growth hormone secretagogue NN703 in adult patients with growth hormone deficiency.

objective Little is known of the usefulness of GH secretagogues (GHSs) in GH‐deficient (GHD) adults. The objective of this study was to determine the number of responders to treatment with NN703 in GHD adults.

Der Aldosteron-Renin-Quotient bei sekundärer Hypertonie

Leitsymptome und Screening:Der primäre Hyperaldosteronismus (PHA)—Leitsymptome: Hypertonie und hypokaliämische Alkalose—wurde 1954 erstmals von J. Conn beschrieben. In seiner klassischen Ausprägung ist der PHA selten. Die Prävalenz liegt bei unter 0,5% aller Hypertoniker. Neuere Untersuchungen zeigen, dass eine normokaliämische Variante des PHA wesentlich häufiger ist (Prävalenz bis 11% aller Hypertoniker). Der beste Screeningtest für das normokaliämische Conn-Syndrom ist der Aldosteron-Renin-Quotient. Ein begründeter Verdacht besteht bei einem erhöhten Quotienten bei gleichzeitig hohem absoluten Serumaldosteron (ca. 90%ige Sensitivität und Spezifität). Zur Diagnosesicherung wird ein unabhängiger Bestätigungstest durchgeführt. Hierzu stehen NaCl-Suppressionsstest, Bestimmung der Aldosteronmetaboliten im Sammelurin, Fludrocortisonbelastungstest und Captopril-Belastungstest zur Verfügung. Die weitere differentialdiagnostische Abklärung zur Unterscheidung zwischen Aldosteron produzierendem Adenom und bilateraler idiopathischer Nebennierenhyperplasie erfolgt mittels sich ergänzender biochemischer und bildgebender Verfahren. Da es sich beim PHA um eine potentiell heilbare Erkrankung handelt, wird ein Screening von Patienten mit akzelerierter, schlecht einstellbarer Hypertonie empfohlen.Classical Features and Screening:The classical features of primary aldosteronism—hypertension, hypokalemia and metabolic alkalosis—were first described by J. Conn in the midfifties of the last century. The classical form of primary aldosteronism is a rare disease with prevalence rates of 0.1–0.5% within the hypertensive population. The normokalemic variant of primary aldosteronism seems to be much more frequent (5–13%). Although a validated and standardized diagnostic protocol for this entity is still missing recent studies established the aldosterone to renin ratio as a useful screening test. To increase diagnostic sensitivity and specificity of the ratio aldosterone should be added as second screening criterion (sensitivity and specificity about 90%). Dynamic confirmatory testing proving autonomous aldosterone secretion is required to verify the diagnosis in case of a positive screening test. A simple confirmatory test is the salt loading test. Alternatively, the fludrocortisone-suppression-test, the Captopril-challenge- test or the daily exretion rate of aldosterone-18-glucuronide and tetrahydroaldosterone in urine can be used. In case of proven primary aldosteronism further diagnostic evaluation (e. g. CT scanning, postural-test and in case of discrepancy adrenal vein catheterization) is mandatory to differentiate the most common forms of primary aldosteronism, aldosterone producing adenoma and idiopathic hyperaldosteronism. Since many patients with primary aldosteronism can be cured by surgery and missing the diagnosis often leads to significant end-organ damage it is important to evaluate hypertensive patients with therapy-resistant hypertension for primary aldosteronism.

Expression of HER-2/neu receptor protein in adrenal tumors

The HER-2/neu protein is overexpressed in many human carcinomas obtained from different tissues and may represent a useful target for therapy with the commercially available monoclonal antibody trastuzumab (herceptin). Novel therapeutic options are needed for metastasized adrenocortical cancer. Therefore, we studied expression of the HER-2/neu cell surface receptor protein using three different antibodies in 12 adrenal adenomas, 17 adrenocortical carcinomas and 5 pheochromocytomas. Normal adrenals (n = 5) served as controls. One adenoma showed very weak membranous immunostaining with the Dako antibody, two others showed a nonspecific cytoplasmic staining pattern. A nonspecific reaction in the cytoplasm was demonstrable in seven carcinomas with the Novocastra antibody. In all pheochromocytomas, a granular intracytoplasmic and, rarely, slightly membranous immunostaining with the Dako antibody was found. From our data we conclude that specific and significant membranous immunostaining indicating strong overexpression (grade 3) of HER-2/neu protein is not present in adrenocortical tumors. The granular cytoplasmic immunostaining of the medulla may be helpful for differentiation of adrenocortical tumors from pheochromocytomas.