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M Reincke

Publications and source records attributed to M Reincke.

At least 55 records · Page 3Linked to original sources
PubMed2000

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

BACKGROUND: Adrenostatic compounds are frequently used in the treatment of patients with Cushing's 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. MATERIALS AND METHODS: Cells were incubated with increasing doses of the adrenostatic compounds. Steroid hormone secretion (cortisol, 17-OH-progesterone, DHEA-S) and cAMP synthesis were determined and Northern blot analysis and cell proliferation experiments were performed. RESULTS: ETO was the most potent adrenostatic compound inhibiting P450c11 hydroxylase at low concentrations (IC50 15 nM), and also blocking P450 side-chain cleavage (scc) enzyme (IC50 400 nM) at higher concentrations. The pattern of enzyme inhibition was similar for MTP with an IC50 of 3-5 microM for P450c11 and 17 microM for P450scc, while AG blocked P450scc with an IC50 of 10 microM. AG significantly suppressed the baseline ACTH-R mRNA expression in a dose-dependent fashion (300 microM AG: 5% +/- 1%; 30 microM AG: 64% +/- 1%; 3 microM AG: 108% +/- 19% compared with control cells: 100% +/- 11%) but increased glucocorticoid receptor mRNA. The reduced ACTH-R mRNA was paralleled by low ACTH-induced cAMP accumulation indicating reduced expression of ACTH-R protein. The simultaneous incubation of hydrocortisone together with AG reversed the inhibitory effect of AG on the ACTH-R expression. AG and ETO inhibited cell proliferation in the NCI-h295 cells, but ETO was much more potent and showed antiproliferative effects at concentrations of 6 microM. The growth inhibition was not reversed by administration of hydrocortisone. CONCLUSIONS: Our data demonstrate that adrenostatic compounds not only act by suppression of steroidogenic enzymes but can also influence both ACTH-R expression and cell proliferation in adrenal cells. As these effects occur in vitro at concentrations that are reached during treatment with these drugs in patients, they are probably also of clinical relevance. Particularly the antiproliferative activity of ETO may be useful in Cushing's syndrome due to adrenocortical cancer. The interaction of steroidogenesis, ACTH-R and glucocorticoid receptor expression as well as cell proliferation provides a new concept of the intra-adrenal response to stress in humans.

Adrenal Cortex Neoplasms↗
PubMed2000

Metabolism of glucocorticoids and mineralocorticoids in patients with adrenal incidentalomas.

BACKGROUND: Adrenal incidentalomas are mostly nonfunctioning adrenocortical adenomas (NFI). However, in 5%-12% of the patients a preclinical Cushing's 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. DESIGN: (1) Tetrahydrocortisol, tetrahydrocortisone, urinary free cortisone together with urinary free cortisol were measured in 35 patients with adrenal incidentalomas (29 NFI and six PCS) and in 35 healthy controls. (2) Since little is known about daily aldosterone production, aldosterone metabolite excretions were measured. (3) As recently reported, ACTH stimulation revealed an increased response of precursors of the glucocorticoid and mineralocorticoid pathway. To find out which steroidogenic enzymes have altered activities, a 1-24ACTH stimulation test (250 microg i.v.) was carried out in 25 patients and 18 healthy controls with determination of multiple steroids. (4) Finally, since it was assumed that 21-hydroxylase deficiency or even 11b-hydroxylase deficiency may be involved in adrenal tumourigenesis, the prevalence of germline CYP21B and CYP11B1 mutations were studied in the same patients, who had underwent the ACTH stimulation test. RESULTS: (1) Glucocorticoid metabolites were within the normal range in all but three patients with NFI. As a group, the patients had subtle alterations in cortisol metabolism. Tetrahydrocortisol excretion was elevated in NFI and PCS compared with normal subjects (2.1 +/- 0.2 and 2.5 +/- 0.5 vs. 1.5 +/- 0.1 mg 24 h(-1); P < 0.05). Accordingly, the twofold elevation of the tetrahydrocortisol/free cortisol ratio indicates an increased 5beta-reduction of cortisol in the liver. (2) Tetrahydroaldosterone and aldosterone-18-glucuronide excretions were not different to controls. (3) In patients with incidentalomas an increased response to ACTH was seen for 17-hydroxyprogesterone (595 +/- 133 vs. 160 +/- 25 ng dL(-1)), 21-desoxycortisol (105 +/- 25 vs. 29 +/- 9 ng dL(-1)) and 11-desoxycortisol (401 +/- 40 vs. 293 +/- 17 ng dL(-1)). (4) In only one of 25 patients, a heterozygous deletion in exon 3 of the CYP21B gene was detected. CONCLUSIONS: (1) In conclusion, even the excretion of the main glucocorticoid metabolites is not a marker sensitive enough to distinguish between NFI and PCS. However, it is also possible that alterations in cortisol secretion are qualitative rather than quantitative. (2) Zona glomerulosa function is not influenced. (3) The elevation of 21-desoxycortisol argues against an impairment of 11beta-hydroxylase and favours a decreased activity of 21-hydroxylase. All others had wild-type sequences of both genes. (4) In conclusion, neither 21-hydroxylase deficiency nor 11beta-hydroxylase deficiency are predisposing factors for adrenal tumourigenesis.

Adenoma↗
PubMed2000

Steroidogenic acute regulatory protein mRNA expression in adrenal tumours.

The rate limiting step in steroidogenesis is cholesterol transport through the outer to the inner mitochondrial membrane and the cytochrome P450 side chain cleavage (P450scc) complex. The protein factor responsible for this transport, and as such necessary for regulating the acute production of steroids, has been identified and named the steroidogenic acute regulatory protein (StAR). We investigated the expression of StAR in functional and non-functional adrenal neoplasms and compared the expression with that of P450scc. Poly A RNA was extracted from normal adrenal glands (NAG, n=5), aldosterone producing adenomas (APA, n=4), cortisol producing adenomas (CPA, n=5), adrenocortical carcinomas (ACC, n=6) and non-functional adenomas (NFA, n=3), electrophoresed through a 1% agarose gel, blotted and hybridised with a PCR-generated cDNA labelled with [(32)P]CTP. The blots were stripped and re-hybridised with a P450scc cDNA and a mouse beta-actin probe. Compared with P450scc, StAR mRNA expression showed little variability in the magnitude of expression and did not correlate with the endocrine profiles (NAG: StAR 100+/-16%, P450scc 100+/-14%; APA: StAR 80+/-3%, P450scc 94+/-13%; CPA: StAR 71+/-10%, P450scc 109+/-15%; NFA: StAR 64+/-9.5%, P450scc 18+/-5%; means+/-s.e.m.). ACC expressed low levels of both genes probably as a result of dedifferentiation (StAR 29+/-9%, P450scc 46+/-18%). Incubation of the NCI-h295 tumour cell line with 10nmol ACTH and 10micromol forskolin induced an increase in the abundance of StAR and P450scc mRNA, demonstrating gene regulation by the cAMP protein kinase A pathway. Furthermore, we incubated the NCI-h295 tumour cell line with the adrenostatic compounds, aminoglutethimide and metyrapone. We could not detect an effect on the expression of StAR mRNA, whereas the expression of P450scc mRNA was significantly reduced. We conclude that, in contrast to P450scc, StAR seems to be evenly expressed in adrenocortical adenomas. Therefore, the endocrine activity of a given tumour cannot be explained by the abundance of StAR expression. In ACC, both StAR and P450scc expression is low, explaining the relatively inefficient steroid production of these tumours.

Adenoma↗
PubMed2000

Multiple endocrine neoplasia type 1 gene expression is normal in sporadic adrenocortical tumors.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder with neoplasia of the anterior pituitary, the parathyroid, the endocrine pancreas and other endocrine tissues including the adrenal cortex. The tumor-suppressor gene causing this disease was identified at the gene locus 11q13. We recently reported that adrenocortical carcinomas frequently show loss of heterozygosity (LOH) of 11q13, but do not contain point mutations within the MEN1-coding region. To investigate whether reduced gene expression (for example by mutations within the MEN1 promoter) may contribute to the tumorigenesis of sporadic adrenocortical tumors, 24 adrenocortical specimen were studied by Northern blot analysis. This series included six adrenocortical carcinomas, four cortisol-producing adenomas, six aldosterone-producing adenomas, three endocrine-inactive adenomas and six normal adrenal glands. The presence of LOH of 11q13 was investigated using five polymorphic microsatellite markers (D11S956, PYGM, D11S4939, D11S4946 and D11S987) close to the MEN1 gene. Poly-A mRNA was hybridized with a PCR-generated cDNA probe of the MEN1 gene, a cDNA of the former MEN1 candidate gene phospholipase (PLC) beta3 and a mouse beta-actin cDNA for normalization. LOH of 11q13 was detected in five out of six carcinomas and two inactive adenomas, but in none of the hormone-producing adenomas. Compared with normal adrenals (100+/-6. 5%, mean+/-s.e.m.) MEN1 mRNA in adrenocortical tumors was expressed in similar amounts (carcinomas 109+/-11%, cortisol-producing adenomas 131+/-10%, aldosterone-producing adenomas 113+/-13%, endocrine-inactive adenomas 111+/-2%) with the exception of one adrenocortical carcinoma with low MEN1 mRNA expression (66%). PLCbeta3 mRNA expression showed a variable pattern without reaching significant differences between the groups. We conclude that since mRNA levels were unaltered in the majority of tumors, mutations of the MEN1 gene causing altered gene transcription is unlikely to be a major pathogenic factor of sporadic adrenocortical tumors.

Adenoma↗
PubMed2000

Adrenocortical function in patients with macrometastases of the adrenal gland.

OBJECTIVE: Metastases of the adrenal gland are a frequent finding in patients with malignant tumors like bronchogenic carcinoma or breast cancer. Only limited and conflicting data on adrenocortical function in these patients are available. DESIGN: Cross-sectional study. METHODS: We investigated the impact of adrenal macrometastases on adrenocortical function in a series of 28 tumor patients using the ACTH(1-24) stimulation test and dexamethasone suppression test. Seven normal controls (Con), eleven patients without adrenal metastases (No Met), eight patients with unilateral (Uni Met) and nine patients with bilateral adrenal metastases (Bil Met) were investigated. RESULTS: The prevalence of adrenal insufficiency was low in our study population, with only two of nine patients with bilateral metastases having subclinical adrenocortical insufficiency. In the remaining patients with uni- or bilateral metastases, baseline and stimulated cortisol concentrations were higher than in controls and cancer patients without metastases (baseline cortisol (in nmol/l): Con: 307+/-33.2 vs Uni Met: 440+/-53.5, and Bil Met: 637.6+/-92.1, P=0.04 by ANOVA; cortisol 60 min after ACTH(1-24): Con: 794.6+/-41.2 vs Uni Met: 990.8+/-92.9, and Bil Met: 1151.4+/-155.5, P=0.03 by ANOVA). Simultaneously, baseline and stimulated serum aldosterone concentrations were significantly blunted in the tumor groups. CONCLUSIONS: Adrenal insufficiency is infrequent and develops only in patients with bilateral metastases. However, the majority of patients have activation of the hypothalamic-pituitary-adrenal axis despite adrenal metastases with strongly elevated cortisol concentrations.

Adrenal Cortex↗
PubMed2000

Cortisol producing adrenal adenoma--a new manifestation of Gardner's syndrome.

INTRODUCTION: Familial adenomatous polyposis (FAP) is an autosomal dominant disorder which typically presents with colorectal cancer in early adult life secondary to extensive adenomatous polyps of the colon. Gardner's syndrome is a variant of FAP in which desmoid tumors, osteomas and pigmented retinal lesions occur together with intestinal manifestations. The APC gene (adenomatous polyposis coli) at 5q21 is a tumor suppressor gene which is mutant in FAP. PATIENT: A 36 year old woman presented with a history of polyposis ventriculi, ovarian desmoid cysts, and disseminated desmoid tumors. Her familial history was unremarkable. On admission she complained weight gain, secondary amenorrhea, and episodes of hypertension followed by paroxysmal headache. RESULTS: Elevated urinary free cortisol (878 microg/24h), suppressed basal ACTH (< 5 pg/ml) and insuppressible serum cortisol after low dose dexamethasone (189 ng/ml) revealed adrenal Cushing's syndrome. Abdominal NMR showed an adrenal mass two centimeter in diameter with inhomogeneous contrast enhancement. Unilateral adrenalectomy was performed and an adrenal adenoma was diagnosed by histological criteria. For mutational detection DNA from peripheral blood leucocytes was extracted. A protein truncation test was performed, which revealed a termination mutation between codon 1099 and 1623 of the APC gene. Direct sequencing showed a point mutation in exon 15 of the APC gene at position 1542 (CAG --> TAG). This region is known to be altered in patients with extraintestinal manifestation of FAP. CONCLUSION: In patients with Gardner's syndrome adrenal tumors leading to hormonal excess should be considered. Whether mutations in the APC gene have implications in sporadic adrenal tumorigenesis needs to be proven.

Adenoma↗
PubMed2000

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.

Adolescent↗
PubMed1999

Evidence against a role of physiological concentrations of estrogen in post-myocardial infarction remodeling.

OBJECTIVES: The purpose of this study was to examine whether endogenous estrogen deficiency induced by ovariectomy affects chronic left ventricular dysfunction post-myocardial infarction (MI). BACKGROUND: Epidemiologic findings suggest that mortality of postmenopausal women is increased after MI, but the underlying mechanisms are unknown. METHODS: Rats were either not ovariectomized (non-OVX), ovariectomized (OVX) or ovariectomized and treated with subcutaneous 17-beta-estradiol (E2) pellets (OVX + E2). Two weeks later, animals were sham-operated (Sham) or left coronary artery ligated (MI). Eight weeks later, in vivo echocardiographic and hemodynamic measurements were performed. Thereafter, hearts were isolated and perfused isovolumically. RESULTS: Mean infarct size was similar among the three MI groups. Ovariectomy decreased serum E2 levels (11 +/- 4 vs. 49 +/- 11 pg/ml in non-OVX, p < 0.01) and increased body weight. These changes were reversed by E2 replacement. The degree of cardiac hypertrophy was similar for all groups post-MI. Left ventricular diameters were increased post-MI (8.9 +/- 0.4 in non-OVX + MI vs. 6.7 +/- 0.2 mm in non-OVX + Sham hearts, p < 0.0001), but OVX or OVX + E2 replacement did not alter left ventricular diameters in post-MI and Sham hearts. Left ventricular fractional shortening was severely impaired post-MI (19 +/- 2% vs. 50 +/- 3 in non-OVX + Sham hearts, p < 0.0001) with no influence of hormonal status. Left ventricular end-diastolic pressure, measured in vivo, was increased in all MI groups without significant differences between groups. Pressure-volume curves, obtained in perfused hearts, demonstrated a right and downward shift with reduced maximum left ventricular developed pressure post-MI (75 +/- 6 vs. 108 +/- 3 mm Hg in non-OVX + Sham hearts, p < 0.001) and were also unaffected by either OVX or E2 replacement. CONCLUSIONS: Chronic endogenous estrogen deficiency does not have major effects on the development of cardiac hypertrophy, dysfunction and dilation post-MI.

Animals↗
PubMed1999

Dehydroepiandrosterone replacement in women with adrenal insufficiency.

BACKGROUND: The physiologic role of dehydroepiandrosterone in humans is still unclear. Adrenal insufficiency leads to a deficiency of dehydroepiandrosterone; we therefore, investigated the effects of dehydroepiandrosterone replacement, in patients with adrenal insufficiency. METHODS: In a double-blind study, 24 women with adrenal insufficiency received in random order 50 mg of dehydroepiandrosterone orally each morning for four months and placebo daily for four months, with a one-month washout period. We measured serum steroid hormones, insulin-like growth factor I, lipids, and sex hormone-binding globulin, and we evaluated well-being and sexuality with the use of validated psychological questionnaires and visual-analogue scales, respectively. The women were assessed before treatment, after one and four months of treatment with dehydroepiandrosterone, after one and four months of placebo, and one month after the end of the second treatment period. RESULTS: Treatment with dehydroepiandrosterone raised the initially low serum concentrations of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, and testosterone into the normal range; serum concentrations of sex hormone-binding globulin, total cholesterol, and high-density lipoprotein cholesterol decreased significantly. Dehydroepiandrosterone significantly improved overall well-being as well as scores for depression and anxiety. For the global severity index, the mean (+/-SD) change from base line was -0.18+/-0.29 after four months of dehydroepiandrosterone therapy, as compared with 0.03+/-0.29 after four months of placebo (P=0.02). As compared with placebo, dehydroepiandrosterone significantly increased the frequency of sexual thoughts (P=0.006), sexual interest (P=0.002), and satisfaction with both mental and physical aspects of sexuality (P=0.009 and P=0.02, respectively). CONCLUSIONS: Dehydroepiandrosterone improves well-being and sexuality in women with adrenal insufficiency.

Adrenal Insufficiency↗
PubMed1999

Adrenal-sparing surgery for phaeochromocytoma.

BACKGROUND: Adrenalectomy is the current treatment for phaeochromocytoma. Consequently, patients with bilateral adrenal phaeochromocytoma become steroid dependent. An adrenal-sparing surgical technique was introduced in 1985. The results of this treatment have been reviewed. METHODS: Since 1985, 39 patients with adrenal phaeochromocytoma (16 men and 23 women, aged 10-76 years) have been treated. Thirty-three patients had unilateral and six had bilateral phaeochromocytomas. Seven of the former 33 had a contralateral adrenal tumour resected previously. All 39 patients were re-evaluated biochemically and clinically for ipsilateral recurrence. RESULTS: Adrenal-sparing surgery was performed successfully in 37 of the 39 patients. In one, adrenal-sparing resection was impossible anatomically and total adrenalectomy was necessary. Another patient with bilateral tumours had retroperitoneal haemorrhage and became steroid dependent. None of the remaining 12 patients who had bilateral adrenal surgery required steroid replacement. Adrenocortical function was normal in eight and mildly impaired in two of the ten patients who had evaluation by adrenocorticotrophic hormone stimulation. After a mean follow-up of 73 months, one patient with von Hippel-Lindau disease developed a recurrence in the ipsilateral adrenal gland. Genetic testing revealed that 26 of the 39 patients, including half of those with a unilateral tumour, had hereditary phaeochromocytoma. CONCLUSION: Adrenal-sparing surgery is safe and effective, and may become the treatment of choice in patients with hereditary phaeochromocytoma.

Adolescent↗
PubMed1999

Multiple mechanisms are involved in the acute vasodilatory effect of 17beta-estradiol in the isolated perfused rat heart.

The purpose of this study was to define the dose-dependent effects of 17beta-estradiol on coronary flow and cardiac function in isolated rat hearts and to identify the mechanisms involved in its vasodilator action. Hearts from female and male Wistar rats were perfused at constant pressure (100 mm Hg). Stereoisomer specificity and the mechanism of vasodilation by 17beta-estradiol were examined in female rat hearts. Function was measured by a left ventricular (LV) balloon and coronary flow (CF) with an ultrasonic flowmeter. 17Beta-estradiol at 10(-6), 5 x 10(-6), and 10(-5) M increased CF in female hearts by 5 +/- 2, 27 +/- 4 (p < 0.05 vs. baseline), and 40 +/- 4% (p < 0.05 vs. baseline), respectively. The effect of 17beta-estradiol in hearts from male rats was similar but less pronounced compared with females [deltaCF 8 +/- 3, 19 +/- 3 (p < 0.05 vs. baseline)] and 25 +/- 7% (p < 0.05 vs. baseline; p < 0.05 vs. female 17beta-estradiol). Maximum vasodilation by the stereoisomer 17alpha-estradiol was significantly smaller [deltaCF 5 +/- 3, 4 +/- 3 (p < 0.05 vs. female 17beta-estradiol) and 14 +/- 1% (p < 0.05 vs. baseline; p < 0.05 vs. female 17beta-estradiol)] for 10(-6), 5 x 10(-6), and 10(-5) M. Pretreatment with the NO-synthesis inhibitor Nomega-methyl-L-arginine (10(-4) M) had no effect on the maximal vasodilator response to 17beta-estradiol (10(-5) M) [deltaCF 36 +/- 6% (p < 0.05 vs. baseline)]. When hearts were pretreated with the prostaglandin-synthesis inhibitor diclofenac (10(-6) M), the maximal vasodilator effect of 17beta-estradiol was partially attenuated [deltaCF 12 +/- 7% (p < 0.05 vs. female 17beta-estradiol)]. Similarly, pretreatment with the K+ATP-blocker glibenclamide (10(-6) M) partially inhibited the maximal vasodilator effect of 17beta-estradiol [deltaCF 22 +/- 6% (p < 0.05 vs. baseline; p < 0.05 vs. female 17beta-estradiol)]. Pretreatment with the Ca2+ channel antagonist nifedipine (7.2 x 10(-8) M) completely blocked the vasodilator effect. In isolated perfused rat hearts, 17beta-estradiol induced marked acute coronary vasodilation; this effect is in part gender specific, and in female hearts, largely stereoisomer specific. The dilator effect is mediated predominantly by calcium channel blockade, but prostaglandin release and K+ATP channel activation also are involved. In the isolated perfused rat heart, NO production does not contribute to the acute vasodilator effect of 17beta-estradiol.

Animals↗
PubMed1999

MEN1 gene analysis in sporadic adrenocortical neoplasms.

Adrenocortical tumors occur as sporadic tumors, as part of the multiple endocrine neoplasia type 1 (MEN1) syndrome or as part of other hereditary disorders. We recently cloned the MEN1 gene, a tumor-suppressor gene located on chromosome 11q13. Subsequently, we showed that sequential somatic inactivation of both alleles of the MEN1 gene contributes to the development of some sporadic endocrine neoplasms (parathyroid, enteropancreatic neuroendocrine, bronchial carcinoid, and pituitary tumors). We now studied whether somatic inactivation of the MEN1 gene contributes to the pathogenesis of sporadic adrenocortical neoplasms. Seven adrenocortical carcinomas, 2 adrenocortical carcinoma cell lines, and 11 aldosterone-secreting, 8 cortisol-secreting, and 5 nonsecreting benign adrenocortical tumors were studied. Seven tumors (5 of 5 carcinomas, 2 of 21 nonsecreting benign adenomas; P < 0.001) exhibited loss of heterozygosity on 11q13. All 33 tumors and cell lines were screened for mutation throughout the MEN1 open-reading frame and adjacent splice junctions. None exhibited a mutation within the MEN1-coding region. We conclude that somatic MEN1 mutation within the MEN1-coding region does not occur commonly in sporadic adrenocortical tumors, although the majority of adrenocortical carcinomas exhibit 11q13 loss of heterozygosity.

Adrenal Cortex Neoplasms↗
PubMed1999

Biotransformation of oral dehydroepiandrosterone in elderly men: significant increase in circulating estrogens.

The most abundant human steroids, dehydroepiandrosterone (DHEA) and its sulfate ester DHEAS, may have a multitude of beneficial effects, but decline with age. DHEA possibly prevents immunosenescence, and as a neuroactive steroid it may influence processes of cognition and memory. Epidemiological studies revealed an inverse correlation between DHEAS levels and the incidence of cardiovascular disease in men, but not in women. To define a suitable dose for DHEA substitution in elderly men we studied pharmacokinetics and biotransformation of orally administered DHEA in 14 healthy male volunteers (mean age, 58.8 +/- 5.1 yr; mean body mass index, 25.5 +/- 1.5 kg/m2) with serum DHEAS concentrations below 4.1 micromol/L (1500 ng/mL). Diurnal blood sampling was performed on 3 occasions in a single dose, randomized, cross-over design (oral administration of placebo, 50 mg DHEA, or 100 mg DHEA). The intake of 50 mg DHEA led to an increase in serum DHEAS to mean levels of young adult men, whereas 100 mg DHEA induced supraphysiological concentrations [placebo vs. 50 mg DHEA vs. 100 mg DHEA; area under the curve (AUC) 0-12 h (mean +/- SD) for DHEA, 108 +/- 22 vs. 252 +/- 45 vs. 349 +/- 72 nmol/L x h; AUC 0-12 h for DHEAS, 33 +/- 9 vs. 114 +/- 19 vs. 164 +/- 36 micromol/L x h]. Serum testosterone and dihydrotestosterone remained unchanged after DHEA administration. In contrast, 17beta-estradiol and estrone significantly increased in a dose-dependent manner to concentrations still within the upper normal range for men [placebo vs. 50 mg DHEA vs. 100 mg DHEA; AUC 0-12 h for 17beta-estradiol, 510 +/- 198 vs. 635 +/- 156 vs. 700 +/- 209 pmol/L x h (P < 0.0001); AUC 0-12 h for estrone, 1443 +/- 269 vs. 2537 +/- 434 vs. 3254 +/- 671 pmol/L x h (P < 0.0001)]. In conclusion, 50 mg DHEA seems to be a suitable substitution dose in elderly men, as it leads to serum DHEAS concentrations usually measured in young healthy adults. The DHEA-induced increase in circulating estrogens may contribute to beneficial effects of DHEA in men.

Aged↗
PubMed1999

Preserved adrenocortical function after laparoscopic bilateral adrenal sparing surgery for hereditary pheochromocytoma.

BACKGROUND: Familial pheochromocytoma, increasingly diagnosed in asymptomatic subjects with inherited syndromes such as multiple endocrine neoplasia type 2 and Von Hippel-Lindau disease, is frequently bilateral and multifocal, but very rarely malignant. Therefore, bilateral adrenalectomy and subsequent lifelong steroid replacement, with its attendant side effects, is not desirable. Minimally invasive adrenal sparing surgery by means of laparoscopy was explored for the treatment of bilateral pheochromocytoma. We report on the cure rate and adrenocortical function in a series of patients treated accordingly. PATIENTS AND METHODS: Four patients (three male, one female, ages 9-60 yr) with hereditary bilateral adrenal pheochromocytoma were treated by laparoscopic surgery in an organ sparing fashion. Postoperatively, all patients were reevaluated for complete tumor removal and for adrenocortical function. RESULTS: Two to 24 months after surgery, all patients were normotensive, had normal sodium potassium, glucose, aldosterone, renin, and cortisol serum concentrations, 24-h excretion of norepinephrine, epinephrine, and vanillylmandelic acid. Abdominal magnetic resonance imaging (n = 3) and computed tomographic scan (n = 1) disclosed no remnant or relapsing tumor tissue. ACTH stimulation testing resulted in normal cortisol responses. CONCLUSION: By adrenal sparing laparoscopic surgery not only bilateral pheochromocytoma can be successfully removed, but also adrenocortical function preserved. This may become the treatment of choice for familial pheochromocytoma.

Adrenal Cortex↗
PubMed1998

Neuroendocrine dysfunction in African trypanosomiasis. The role of cytokines.

Sleeping sickness (SS; African trypanosomiasis) is an anthropozoonosis transmitted by the tsetse fly. Infection with Trypanosoma brucei in humans is associated with adynamia, lethargy, anorexia, and more specifically amenorrhea/infertility in women and loss of libido/impotence in men. Recent evidence suggests that experimental infection in animals with Trypanosoma brucei species causes polyglandular endocrine failure by local inflammation of the pituitary, thyroid, adrenal, and gonadal glands. In a cross-sectional study we investigated the prevalence and significance of neuroendocrine abnormalities in 137 Ugandan patients with SS. In the untreated stage of the disease, there was a high prevalence of adrenal insufficiency (27%), hypothyroidism (50%) and hypogonadism (85%). Pituitary function tests suggested an unusual combined central (hypothalamic/pituitary) and peripheral defect in hormone secretion. Specific therapy resulted in a rapid recovery of adrenal/thyroid function, whereas hypogonadism persisted for years in a substantial portion of patients. We did not detect pituitary, thyroid, adrenal, and gonadal autoantibodies in patients with endocrine dysfunction, ruling out an autoimmune origin of the endocrine abnormalities. However, the presence of hypopituitarism correlated with high cytokine concentrations (TNF-alpha, IL-6) which--together with direct parasitic infiltration of the endocrine glands--are involved in the pathogenesis of SS-associated endocrine dysfunction.

Animals↗
PubMed1998

Oral dehydroepiandrosterone for adrenal androgen replacement: pharmacokinetics and peripheral conversion to androgens and estrogens in young healthy females after dexamethasone suppression.

Women with adrenal insufficiency suffer from chronic dehydroepiandrosterone (sulfate) [DHEA(S)] deficiency. To define a suitable dose for DHEA replacement, we studied the pharmacokinetics and biotransformation of orally administered DHEA in nine healthy female volunteers (mean age 23.3 +/- 4.1 yr, mean body mass index 22.5 +/- 1.8 kg/m2) with transient suppression of adrenal androgen secretion because of dexamethasone (dex) administration (4 x 0.5 mg/day for 4 days). Diurnal blood sampling was performed during the early follicular phase of four subsequent menstrual cycles (study period 1: baseline; study periods 2-4: dex + placebo, dex + 50 mg DHEA or dex + 100 mg DHEA in a randomized cross-over design). Dex induced not only a significant suppression of serum cortisol (to 8% of baseline) but also of DHEA (18%), DHEA(S) (16%), and androstenedione (26%), as well as of testosterone (28%), dihydrotestosterone (43%), and estrone (54%). Oral administration of 50 mg DHEA led to restoration of DHEA(S) baseline levels, whereas 100 mg induced supraphysiological concentrations [baseline vs. 50 mg DHEA vs. 100 mg DHEA: area under the concentration-time curve (AUC) 0-12 h DHEA: 280 +/- 85 vs. 241 +/- 73 vs. 383 +/- 106 nmol/L x h; AUC 0-12 h DHEA(S): 89.1 +/- 48.4 vs. 139.6 +/- 43.5 vs. 213.3 +/- 21.6 mumol/L x h). Serum concentrations of dihydrotestosterone and estrone were restored to baseline after 50 mg DHEA, whereas baseline testosterone and androstenedione levels were only achieved by administration of 100 mg DHEA. In conclusion, 50 mg DHEA seems to be a suitable replacement dose in females with adrenal insufficiency. Furthermore, the rapid and lasting conversion to potent androgens demonstrates a potential role of DHEA for androgen replacement in females in general.

Administration, Oral↗
PubMed1998

Steroid 21-hydroxylase mutations and 21-hydroxylase messenger ribonucleic acid expression in human adrenocortical tumors.

Twenty-one hydroxylase (P450c21) is a key enzyme essential for normal zona glomerulosa and fasciculata function. Recently, 21-hydroxylase deficiency has been implicated in the pathogenesis of adrenocortical tumors. Therefore, we investigated the mutational spectrum of the CYP21B gene and the messenger RNA expression of P450c21 in six aldosterone-producing adenomas, seven cortisol-producing adenomas, two nonfunctional incidentally detected adenomas, and four adrenal carcinomas. DNA from leukocytes and tumors was amplified by PCR using primers specific for the CYP21B gene. The 10 exons, intron 2, intron 7, all other exon/intron junctions, and 380 bp of the promoter region of CYP21B were automatically sequenced. Poly(A) RNA was extracted from tumor tissue, dot blotted on a nylon membrane, and hybridized with 32P-labeled P450 side-chain cleavage, P450 17-alpha-hydroxylase, and P450c21 complementary DNA probes. We detected heterozygous germline mutations (exon 7, Val 281Leu) in two patients, one with a cortisol-producing adenoma and the other with an androgen-secreting adrenocortical carcinoma. A somatic, heterozygous microdeletion was found in exon 3 of one aldosterone-producing adenoma. The P450c21 gene expression correlated with the clinical phenotype of the tumor, with low P450c21 messenger RNA expression in nonfunctional adenomas (18.8%, 1.5%) compared with high P450c21 expression in aldosterone- and cortisol-producing adenomas (84 +/- 8% and 101 +/- 4%, respectively, vs. normal adrenals, 100 +/- 10%). In conclusion, the prevalence of heterozygous germline mutations in the CYP21B gene was higher in patients with adrenocortical tumors (11%; 95% confidence interval, 1-34%) than in the general European population (2%; 95% confidence interval, 1.93-2.06%), but this difference is questionable because of the low number of subjects in our series. The pathophysiological significance of this finding in the presence of one normal CYP21B gene seems to be low, suggesting that 21-hydroxylase deficiency is not a major predisposing factor for adrenal tumor formation.

Adrenal Cortex Neoplasms↗