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M Reincke

Publications and source records attributed to M Reincke.

At least 91 records · Page 5Linked to original sources
PubMed1996

Comparison of the pharmacodynamic effects of deflazacort and prednisolone in healthy subjects.

OBJECTIVE: Deflazacort, a synthetic oxazoline derivative of prednisolone, has been suggested as having major advantages over other glucocorticoids, as it is claimed to cause fewer adverse effects at equivalent antiinflammatory potency. The assumed equipotency ratio of deflazacort versus other glucocorticoids is critical for this assumption. METHODS: In a randomized cross-over study we compared the acute effects of deflazacort and prednisolone on serum cortisol, osteocalcin, insulin and blood cells (eosinophils and lymphocytes) in normal subjects. On seven occasions separated by a wash out period > or = 1 week all participants received placebo, prednisolone (8 mg, 20 mg, 40 mg) and deflazacort (12 mg, 30 mg, 60 mg). The medication was given orally at 20.00 h as a single dose. Blood was collected at 8.00 h before and after each medication. Log (dose) response relationships were calculated and were used to compare the drugs. RESULTS: The following equipotent dose ratios (mg deflazacort: mg prednisolone) were found: osteocalcin suppression 1.54, cortisol suppression 2.27, suppression of eosinophils 1.14 and lymphocytes 2.77. As parallelism between regression curves was rejected, equipotency could not be calculated for insulin. In 3 subjects even the highest dose of deflazacort failed to suppress serum cortisol. CONCLUSION: Our study highlights the difficulties of establishing equipotency ratios for glucocorticoids. It casts doubts on the generally assumed equipotency dose ratio of deflazacort vs prednisolone, as both for cortisol and lymphocytes the 95% CI was > 1.2. Thus, reduced adverse effects during deflazacort therapy may be a consequence of lower effective glucocorticoid dosage.

Adult↗
PubMed1996

Hypogonadism in Rhodesian sleeping sickness: evidence for acute and chronic dysfunction of the hypothalamic-pituitary-gonadal axis.

OBJECTIVE: To investigate acute and long-term effects of Rhodesian sleeping sickness on the function of the hypothalamic-pituitary-gonadal (HPG) axis in men. DESIGN: An observational, cross-sectional study. SETTING: Primary health care centers under care of the National Sleeping Sickness Control Program in southeast Uganda. PARTICIPANTS: Fifty-two male patients with sleeping sickness at different stages of treatment and 11 clinically healthy male volunteers recruited from health care personnel. INTERVENTIONS: Patients and controls were questioned about loss of libido and impotence. All received 100 micrograms GnRH i.v. Blood was drawn before and 30 minutes after GnRH administration. MAIN OUTCOME MEASURES: Frequency of loss of libido and impotence. Baseline T and sex hormone-binding globulin baseline and GnRH- stimulated serum LH and FSH concentrations. RESULTS: Loss of libido and/or impotence were present in 39% of men with active disease before therapy, whereas 84% were biochemically hypogonadal. After cure, 45% of men still were symptomatic and 45% were biochemically hypogonadal. Compared with controls (806 +/- 59 pg/mL [conversion factor to SI unit, 0.03467]; mean +/- SEM), T concentrations were decreased substantially in patients before (249 +/- 48 ng/dL), during treatment (429 +/- 56 ng/dL), and after cure (431 +/- 58 ng/dL). Corresponding baseline LH concentrations were inappropriately low and the relative LH response to GnRH was reduced both before and during treatment (794% +/- 131% versus 322% +/- 68%). Follicle-stimulating hormone concentrations increased gradually up to 8.0 +/- 1.3 mIU/mL (conversion factor to SI unit, 1.00) at the end of treatment, returning to 4.2 +/- 0.6 mIU/mL after cure. CONCLUSIONS: Rhodesian sleeping sickness causes acute and chronic HPG axis dysfunction. The clinical and biochemical picture suggest a combined central and peripheral hypogonadism. This is only in part reversible after cure and most likely due to direct parasitic infiltration and/or secondary inflammation causing necrosis and/or fibrosis at the pituitary and gonadal levels.

Adult↗
PubMed1996

Adrenal incidentalomas: a manifestation of the metabolic syndrome?

Recent evidence suggests that insulin is mitogenic on the adrenal cortex and stimulates adrenocortical tumor formation. We, investigated whether hyperinsulinemia is present in 13 patients with incidentally detected adrenal tumors. Patients with adrenal incidentalomas were obese (mean BMI 29.7 +/- 1.2 kg/m2, normal < 25; % body fat 35 +/- 1.5%, normal < 30%) with increased abdominal fat deposition (waist to hip ratio 0.92 +/- 0.02, normal < 0.85). All 13 patients were insulin resistant. Five had NIDDM, of the remaining patients 5 had fasting insulin concentrations above 15 microE/ml, and all 8 patients had elevated insulin concentrations after 75 g of glucose orally. To further investigate the potential role of insulin we examined its effects on the NCI-h295 cell line. Insulin (1-100 micrograms/ml) stimulated cell proliferation in a time and dose-dependent matter without affecting cortisol synthesis. At this concentrations insulin was equally potent to IGF I (10-80 ng/ml) or IGF II (10-100 ng/ml). We conclude that the majority of patients with adrenal incidentalomas are insulin-resistant/hyperinsulinemic. Insulin stimulates adrenal cancer cell lines in vitro. We propose that adrenal incidentalomas are a newly recognized manifestation of the metabolic syndrome comparable to insulin-mediated stimulation of the ovary in the polycystic ovary syndrome.

Adrenal Cortex Neoplasms↗
PubMed1996

Nelson's syndrome associated with a somatic frame shift mutation in the glucocorticoid receptor gene.

Nelson's syndrome is the appearance and/or progression of ACTH-secreting pituitary macroadenomas in patients who had previously undergone bilateral adrenalectomy for Cushing's disease. Extremely high plasma ACTH levels and aggressive neoplastic growth might be explained by the lack of appropriate glucocorticoid negative feedback due to defective glucocorticoid signal transduction. To study the glucocorticoid receptor (GR) gene in Nelson's syndrome, DNA was extracted from pituitary adenomas and leukocytes of four patients with this condition and amplified by PCR for direct sequence analysis. In one of the tumors, a heterozygous mutation, consisting of an insertion of a thymine between complementary DNA nucleotides 1188 and 1189, was found in exon 2. This frame-shift mutation led to premature termination at amino acid residue 366 of the wild-type coding sequence, excluding the expression of a functioning receptor protein from the defective allele. The mutation was not detected in the sequence of the GR gene in the patient's leukocyte DNA, indicating a somatic origin. By lowering the receptor number in tumorous cells, this defect might have caused local resistance to negative glucocorticoid feedback similar to that caused by the presence of a null allele in a kindred with the generalized glucocorticoid resistance syndrome. P53 protein accumulation, previously reported in 60% of corticotropinomas, could not be detected in any of the four pituitary tumors examined by immunohistochemistry. We suggest that a somatic GR defect might have played a pathophysiological role in the tumorigenesis of the corticotropinoma bearing this mutation.

Adrenocorticotropic Hormone↗
PubMed1996

p53 mutations in adrenal tumors: Caucasian patients do not show the exon 4 "hot spot" found in Taiwan.

Mutations in the p53 tumor suppressor gene are frequently present in human cancers but have rarely been described in benign tumors. We previously reported mutations in the "hot spots" between exons 5-8 of the p53 gene in adrenocortical carcinomas but not in adenomas. Recently, a previously unknown hot spot in exon 4 of the p53 gene was described in adrenal adenomas and pheochromocytomas of Taiwanese patients. We, therefore, investigated whether these mutations are also present in Caucasian patients from the U.S. and Europe. We analyzed tumor tissue of 12 aldosterone-producing adenomas, 7 cortisol-producing adenomas, and 6 pheochromocytomas. Overexpression of the p53 protein was investigated by immunohistochemistry. Point mutations within exon 4 were identified by polymerase chain reaction (PCR) amplification and direct sequencing of the PCR product. The pYNZ22 microsatellite located on chromosome 17p, close to the p53 gene, was used to screen for allelic loss (LOH) of the p53 gene. Overexpression of p53 was not identified in any of the adenomas and pheochromocytomas. Point mutations within exon 4 were found in 0/25 tumors. LOH was present in 1/13 informative adenomas and 0/2 informative pheochromocytomas. We conclude that p53 mutations do not play a major role in the tumorigenesis of adrenal adenomas and pheochromocytomas of Caucasian patients. Thus, ethnic and environmental factors may be responsible for the mutational spectrum found in Taiwanese patients.

Adenoma↗
PubMed1995

Dual-energy X-ray absorptiometry at the lumbar spine in German men and women: a cross-sectional study.

A cross-sectional, population-based study of 238 randomly selected females and 224 males with German ethnic background (aged 20-80 years) was carried out to establish lumbar spine bone mineral density (BMD) values, using dual X-ray absorptiometry (DXA), for a German population. Comparison was made to the reference range provided by the manufacturer of the DXA equipment. No sex difference in peak spine BMD was found in our study (1.091 +/- 0.114 g/cm2 for males versus 1.070 +/- 0.113 g/cm2 for females, n.s.). Different patterns of bone loss could be detected in both sexes. In premenopausal women there was no significant correlation between age and BMD (y = 1.044 + 0.00047x, r = 0.03, P = 0.73) whereas reduction of female BMD at the spine was demonstrated in postmenopausal women (y = 1.189-0.0041x, r = -0.28, P = 0.01), underscoring the important role of the menopause for later manifestation of spinal osteoporosis in women. In contrast, in males we found no significant change of BMD with aging (y = 1.071-0.0007x, r = -0.08, P = 0.25). Employing commonly used exclusion criteria, BMD values of the study subjects were found mostly within the normal range of BMD. The major finding of our study was good concordance between female data of our study population and the reference data provided by the manufacturer. Clinically significant discrepancies between our data and the Hologic reference range for males could be detected. Our data on males (30-39 years of age) were up to 7% lower than those provided by the manufacturer, probably due to differences in sampling procedures.

Absorptiometry, Photon↗
PubMed1995

No evidence for oncogenic mutations in the adrenocorticotropin receptor gene in human adrenocortical neoplasms.

The mechanism(s) of tumorigenesis for the majority of adrenocortical neoplasms remain unknown. G-Protein-coupled receptors were recently proposed as candidate protooncogenes. That activating mutations of this class of receptors might be important for tumor induction or progression of endocrine neoplasms was strengthened by the recent identification of such mutations in hyperfunctioning thyroid adenomas. To examine whether the ACTH receptor (ACTH-R) gene could be an oncogene in human adrenocortical tumors, we amplified by the polymerase chain reaction and directly sequenced the entire exon of the ACTH-R gene in 25 adrenocortical tumors (17 adenomas and 8 carcinomas) and 2 adrenocortical cancer cell lines. We found no missense point mutations or even silent polymorphisms in any of the tumors and cell lines studied. We conclude that activating mutations of the ACTH-R gene do not represent a frequent mechanism of human adrenocortical tumorigenesis.

Adolescent↗
PubMed1995

High-dose progesterone infusion in healthy males: evidence against antiglucocorticoid activity of progesterone.

High concentrations of unbound cortisol in late pregnancy have been explained by the antiglucocorticoid activity of high progesterone levels. To further test this hypothesis we studied the effect of high-dose progesterone on baseline and corticotrophin-releasing hormone (CRH)-induced hormone secretion in humans. In a double-blind crossover study eight healthy male volunteers received either progesterone (0.714 mg.kg-1.h-1 for 60 min followed by a dose of 0.45 mg.kg-1.h-1 over a total infusion time of 315 min) or vehicle as a continuous intravenous infusion. At 210 min a CRH test (0.1 microgram/kg body weight as bolus iv) was performed. Within 30 min after the start of progesterone administration the serum progesterone level increased to 454 +/- 31 nmol/l and remained in the range of third trimester pregnancy concentrations throughout the infusion period. During vehicle infusion the progesterone level remained in the normal range for healthy males and demonstrated a small but significant increase after CRH (1.52 +/- 0.23 vs 0.74 +/- 0.14 mmol/l; p < 0.01). However, baseline and CRH-stimulated serum cortisol and plasma adrenocorticotrophic hormone remained unaffected by high-dose progesterone. Moreover, unbound salivary cortisol also was not affected by progesterone, suggesting that there is no significant competition for transcortin binding sites. In conclusion, no antiglucorticoid activity was found after short-term administration of progesterone in males. These findings cast doubts on the concept that the alterations of the pituitary-adrenal axis in late pregnancy are induced by the antiglucocorticoid activity of high progesterone concentrations.

Adrenocorticotropic Hormone↗
PubMed1994

[The Gitelman syndrome--a differential diagnosis of Bartter syndrome].

BACKGROUND: Hypokalemia due to renal potassium wasting in the absence of hypertension, moderate metabolic alkalosis, hyperreninism and hyperaldosteronism suggest the presence of Bartter's syndrome. The underlying cause is an inherited defect of sodium chloride reabsorption in the thick ascending limb of Henle. A differential diagnosis of Bartter's syndrome is Gitelman's syndrome, another hypokalemia-hypomagnesemia syndrome, which is thought to be caused by a transport defect in the distal tube. PATIENTS AND METHODS: We report 3 patients presenting with signs primarily suggestive of Bartter's syndrome, who turned out to have Gitelman's syndrome after determining the excretion of calcium in the urine. RESULTS: Two women, 36- and 55-year old, suffered from paresthesias in the hands and feet and from tetanic convulsions. The brother of the 36-year old woman presented in our hospital because of an accidentally discovered hypokalemia without any clinical symptoms. In all patients the outstanding biochemical features were hypokalemia, hypomagnesemia and moderate metabolic alcalosis. The renin and aldosterone values were inappropriately high. The most characteristic finding in the urine, besides the presence of hyperkaliuria was the diminution of calcium excretion, despite normocalcemia. CONCLUSION: The association between sodium and calcium reabsorption in the loop of Henle predicts hypercalciuria in patients with a defect in salt reabsorption in this segment, as in Bartter's syndrome. In Gitelman's syndrome the laboratory features resemble the findings in Bartter's syndrome, except for the presence of hypocalciuria. Since hypocalciuria follows also the administration of thiazide diuretics, which act in the early part of distal tube, a transport defect in this part of the tube is thought to be responsible for the electrolyte disturbances in Gitelman's syndrome. The measurement of the urinary calcium excretion in patients with an unclear hypokalemia-hypomagnesemia-syndrome allows easily the differentiation between Bartter's and Gitelman's syndrome.

Adult↗
PubMed1994

Clonal composition of human adrenocortical neoplasms.

The mechanisms of tumorigenesis of adrenocortical neoplasms are still not understood. Tumor formation may be the result of spontaneous transformation of adrenocortical cells by somatic mutations. Another factor stimulating adrenocortical cell growth and potentially associated with formation of adrenal adenomas and, less frequently, carcinomas is the chronic elevation of proopiomelanocortin-derived peptides in diseases like ACTH-dependent Cushing's syndrome and congenital adrenal hyperplasia. To further investigate the pathogenesis of adrenocortical neoplasms, we studied the clonal composition of such tumors using X-chromosome inactivation analysis of the highly polymorphic region Xcen-Xp11.4 with the hybridization probe M27 beta, which maps to a variable number of tandem repeats on the X-chromosome. In addition, polymerase chain reaction amplification of a phosphoglycerokinase gene polymorphism was performed. After DNA extraction from tumorous adrenal tissue and normal leukocytes in parallel, the active X-chromosome of each sample was digested with the methylation-sensitive restriction enzyme HpaII. A second digestion with an appropriate restriction enzyme revealed the polymorphism of the region Xcen-Xp11.4 and the phosphoglycerokinase locus. Whereas in normal polyclonal tissue both the paternal and maternal alleles are detected, a monoclonal tumor shows only one of the parental alleles. A total of 21 female patients with adrenal lesions were analyzed; 17 turned out to be heterozygous for at least one of the loci. Our results were as follows: diffuse (n = 4) and nodular (n = 1) adrenal hyperplasia in patients with ACTH-dependent Cushing's syndrome, polyclonal pattern; adrenocortical adenomas (n = 8), monoclonal (n = 7), as well as polyclonal (n = 1); adrenal carcinomas (n = 3), monoclonal pattern. One metastasis of an adrenocortical carcinoma showed a pattern most likely due to tumor-associated loss of methylation. In the special case of a patient with bilateral ACTH-independent macronodular hyperplasia, diffuse hyperplastic areas and a small nodule showed a polyclonal pattern, whereas a large nodule was monoclonal. We conclude that most adrenal adenomas and carcinomas are monoclonal, whereas diffuse and nodular adrenal hyperplasias are polyclonal. The clonal composition of ACTH-independent massive macronodular hyperplasia seems to be heterogeneous, consisting of polyclonal and monoclonal areas.

Adenoma↗
PubMed1994

[Bilateral massive macronodular adrenal gland hyperplasia. A rare cause of Cushing's syndrome].

A 46-year-old man with known arterial hypertension for 10 years had, over the last two years, developed increasing obesity, particularly of the trunk, with other symptoms typical of Cushing's syndrome. Hormone analysis demonstrated hypercortisolism and decreased plasma ACTH concentration. The dexamethasone inhibition test failed to show any significant suppression of serum cortisol. Plasma ACTH was not increased in the corticotrophin-releasing hormone and the metyrapone tests. In the short ACTH test there was an excessive cortisol increase. Abdominal computed tomography revealed both adrenals to be enlarged (6 x 4 cm) and coarsely nodular. Adrenolytic treatment with ketoconazole (400 mg daily) caused symptoms of adrenal insufficiency, but a reduced dosage of 200 mg daily lowered the cortisol level to between 5 and 11 micrograms/dl and normalized the blood pressure and clinical signs of Cushing's syndrome disappeared. Subsequent bilateral adrenalectomy confirmed the diagnosis of massive macronodular adrenal hyperplasia. Substitution treatment with twice daily 25 mg cortisone acetate and 0.05 mg fludrocortisone was started postoperatively.

Adrenal Gland Diseases↗
PubMed1994

Suramin in adrenocortical cancer: limited efficacy and serious toxicity.

OBJECTIVE: No satisfactory treatment for adrenocortical carcinoma (ACC) is available. We investigated the efficacy and toxicity of suramin in the treatment of metastatic ACC since suramin has been recently reported to be active as a single agent therapy for patients with ACC and prostatic carcinoma. DESIGN: We collected data on 9 patients with metastatic ACC treated with suramin in four centres in Germany between 1987 and 1992. PATIENTS: Nine patients (5 women, 4 men; age range 32-67 years) were included. Biochemical evidence of steroid excess was found in 6/9, in three leading to clinical symptoms (hypertension, hyperglycaemia, hirsutism, gynaecomastia). MEASUREMENTS: Tumour responses were assessed by radiological and biochemical evaluation. Other investigations included regular measurements of blood cell counts, coagulation, hepatic and renal function parameters, and serum suramin concentrations. RESULTS: The patients received cumulative doses ranging from 8.2 to 30.2 g suramin over periods of 1-15 months. 3/9 achieved a partial response, 2/9 disease stabilization and 4/9 experienced progressive disease. Tumour responses were transient. Suramin treatment was without direct influence on steroid excess. Serious side-effects included coagulopathy (6/9), thrombocytopenia (6/9), polyneuropathy (2/9) and allergic skin reactions (4/9); the death of two patients was possibly related to suramin therapy. Both toxicity and tumour response were strongly associated with serum level or cumulative dose of suramin. CONCLUSIONS: (1) Suramin is of antineoplastic efficacy in the treatment of metastatic adrenocortical carcinoma. (2) The clinical use of suramin is limited by a narrow therapeutic window with the risk of serious and possibly lethal toxicity at one extreme, and loss of efficacy at the other. Strict monitoring of suramin serum levels is mandatory aiming at levels between 200 and 250 mg/l. Suramin should not be considered as first-line treatment for metastatic adrenocortical carcinoma. (3) To improve treatment options in adrenocortical carcinoma as well as for further investigation on the usefulness of suramin, controlled prospective trials are urgently needed.

Adrenal Cortex Neoplasms↗
PubMed1994

Impairment of adrenocortical function associated with increased plasma tumor necrosis factor-alpha and interleukin-6 concentrations in African trypanosomiasis.

African sleeping sickness (SS) is a severe, potentially lethal parasitic disease. The treatments of choice are the antiparasitic agents suramin, which is adrenotoxic, and/or melarsoprol. We evaluated the functional integrity of the hypothalamic-pituitary-adrenal (HPA) axis of patients with SS before, during, and after therapy with suramin and/or melarsoprol, in two sequential stages. First, we employed the standard adrenocorticotropic hormone (ACTH) 1-24 stimulation test (250 micrograms i.v.) to assess the maximal adrenocortical responsiveness of 69 patients with SS and 38 normal controls. We demonstrated paradoxically subnormal cortisol responses before suramin therapy [net cortisol response 60 min after stimulation: 10.5 +/- 2.9 (mean +/- SE) vs. 17.5 +/- 1.0 micrograms/dl for controls, p = 0.004], with 27% of the patients falling within the adrenal insufficiency range (stimulated cortisol concentration < 20 micrograms/dl). These responses subsequently and unexpectedly improved with suramin and/or melarsoprol therapy. Second, we performed a human corticotropin-releasing hormone (hCRH) test (100 micrograms i.v.) in 68 additional patients with SS and 14 control subjects to examine whether the glucocorticoid deficiency observed was primary and/or secondary. Compared to controls, the ACTH and cortisol responses to hCRH were blunted (ACTH after 60 min: 29 +/- 7 vs. 58 +/- 8 pg/ml in controls, p = 0.014; cortisol: 15.2 +/- 1.5 vs. 19.6 +/- 0.7 micrograms/dl, p = 0.018), suggesting the presence of secondary adrenal insufficiency. There was improvement of both ACTH and cortisol responsiveness to hCRH with therapy, with cortisol recovery occurring before ACTH, suggesting an additional primary component of adrenal dysfunction in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

p53 mutations in human adrenocortical neoplasms: immunohistochemical and molecular studies.

The mechanisms of tumorigenesis of adrenocortical neoplasms have not been elucidated as yet. However, loss of heterozygosity at chromosomal locus 17p has been consistently observed in adrenocortical cancer. p53 is a recessive tumor suppressor gene located on chromosome 17p. Mutations in the p53 gene play an important role in the tumorigenesis of diverse types of human neoplasms including breast and colon cancers. More than 90% of all mutations discovered in such tumors have been detected in 4 hot spot areas that lie between exons 5 and 8. In contrast to wild-type p53, mutant p53 accumulates intracellularly and can be easily detected by immunohistochemistry. We therefore investigated the frequency of p53 mutations in human adrenocortical neoplasms using molecular biology and immunohistochemistry techniques. Five patients with adrenocortical adenomas (5 female; ages 39-72 yr), 11 patients with adrenocortical carcinomas (8 female, 3 male; ages 15-50 yr), and two adrenocortical tumor cell lines were studied. After DNA extraction from frozen tumor tissue or paraffin-embedded material, exons 5 through 8 were amplified using the polymerase chain reaction and directly sequenced by the dideoxy termination method. Immunohistochemistry was performed on paraffin-embedded tumor specimens obtained during adrenalectomy using a monoclonal antibody reacting with both wild-type and mutant p53. Prevalence of mutations was adenomas, 0/5, carcinomas, 3/11, and adrenocortical cell lines, 2/2. Single point mutations were detected in 3 cases (exons 5, 6, and 7, respectively), and rearrangements of exon 7/8 and 8 were found in 2 cases. Immunohistochemistry detected strong nuclear and/or cytoplasmic p53 immunoreactivity in all adrenocortical carcinomas with point mutations of the p53 gene but not in adenomas and carcinomas with the wild-type sequence or with deletion/rearrangement of the p53 gene. We conclude that p53 plays a role in the tumorigenesis of adrenocortical carcinomas but is of less importance to benign adenomas.

Adolescent↗