Biomedical subjects

M Reincke

Publications and source records attributed to M Reincke.

At least 19 recordsLinked to original sources

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

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↗

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↗

PubMed1998

DAX-1 expression in human adrenocortical neoplasms: implications for steroidogenesis.

The DAX-1 gene encodes an orphan nuclear hormone receptor essential for normal fetal development of the adrenal cortex. Recently, DAX-1 has been shown to act as a transcriptional repressor of steroidogenic acute regulatory protein gene expression (StAR), suppressing steroidogenesis. We, therefore, investigated the expression of DAX-1 in a variety of adrenocortical tumors and compared the results with StAR mRNA expression. We found low or absent DAX-1 expression in aldosterone-producing adenomas (n = 11: 35 +/- 11%; normal adrenals: 100 +/- 17%) and in aldosterone-producing adrenocortical carcinomas (n = 2: 24 and 36%). Cortisol-producing adenomas showed intermediate DAX-1 expression (n = 8; 92 +/- 16), as did 3 non-aldosterone-producing carcinomas (72, 132 and 132%). High DAX-1 expression was present in nonfunctional adenomas (n = 3; 160 +/- 17%). In contrast to DAX-1, StAR mRNA expression did not show significant variations between groups. We did not detect the expected negative correlation between DAX-1 and StAR in adrenocortical tumors. These data suggest that high DAX-1 expression in adrenocortical tumors is associated with a non-functional phenotype whereas low DAX-1 expression favors mineralocorticoid secretion. These effects on steroidogenesis are mediated by mechanisms other than repression of StAR gene expression. Our results indicate that DAX-1 may be one of the factors influencing the steroid biosynthesis of adrenocortical neoplasms.

Adolescent↗

PubMed1998

Management of hypoparathyroidism during pregnancy--report of twelve cases.

There is no established therapeutic regimen for treatment of hypoparathyroidism during pregnancy. This is due particularly to uncertainty about the use of vitamin D or its analogues, as in animal experiments teratogenic side-effects have been reported. Nevertheless, vitamin D or its analogues are required to control tetany predisposing to abortion and preterm labour. We herein report the course of two pregnancies in a hypoparathyroid woman treated with calcitriol (1,25(OH)2D3). Additionally, we describe the outcome of pregnancy in ten women receiving calcitriol, reported to the Drug Safety Department (DSD), Hoffmann-La Roche AG. A 29-year-old hypoparathyroid woman receiving chronic treatment with calcitriol (0.25 microg/day) and calcium (1.5 g/day) was referred in the 6th week of her first pregnancy. Calcitriol was initially discontinued, but during the 20th week of pregnancy recurrent tetany occurred (serum calcium 1.74 mmol/l). Calcitriol (0.25 microg/day) was added, stabilizing serum calcium around 2.15 mmol/l with 1,25(OH)2D3 concentrations around 60 ng/l (normal range 35-80 ng/l). To maintain normocalcaemia the calcitriol dose was increased to 0.5 microg/day during the 33rd week and to 0.75 microg/day shortly before delivery of a healthy girl in the 3 7th week. During her second pregnancy calcitriol was given initially at a dose of 0.25 microg/day with further adaptation to 0.5 microg/day during the 20th and to 1.00 microg/day in the 31st week. Serum calcium and 1,25(OH)2D3 were continually within the lower normal range. She gave birth to another healthy girl during the 39th week. In eight of the ten pregnancies reported to the DSD no adverse effects of calcitriol (0.25-3.25 microg/day) were seen and healthy babies were delivered. In two retrospectively reported cases, serious adverse events were described: premature closure of the frontal fontanelle, and stillbirth in the 20th week due to complex fetal malformation respectively. However, in both cases the causative role of calcitriol administration remains highly questionable. We conclude that, during pregnancy, management of maternal hypoparathyroidism with calcitriol and calcium is feasible, if the 1,25(OH)2D3 concentrations are adapted to the physiological needs during pregnancy and serum calcium levels are kept in the lower normal range.

Adult↗

PubMed1998

Localization and expression of adrenocorticotropic hormone receptor mRNA in normal and neoplastic human adrenal cortex.

The recent cloning of the ACTH receptor (ACTH-R) gene allows investigation of the tissue localization and relative abundance of ACTH-R mRNA in normal and neoplastic adrenal cortex. Using in situ hybridization (ISH) we studied the expression of ACTH-R mRNA in four adult adrenals of brain-dead patients, two cortisol-producing adenomas (CPA), three aldosterone-producing adenomas (APA), one non-functional adenoma (NFA), and three carcinomas. The results were compared with the mRNA expression of key steroidogenic enzymes and of the glucocorticoid receptor (GR) mRNA using Northern blotting. In adult adrenals, messenger RNA encoding ACTH-R was localized in all three zones of the adrenal cortex, in accordance with the stimulatory role of ACTH on mineralocorticoid, glucocorticoid and adrenal androgen secretion. In comparison, expression of side-chain cleavage enzyme (P450scc) showed a similar tissue distribution with mRNA abundance in all three zones, whereas 17-hydroxylase/17-20 lyase (P450c17) mRNA expression was only detected in the zona fasciculata and zona reticularis. All CPAs and APAs expressed significant levels of ACTH-R mRNA whereas an NFA showed low expression of ACTH-R mRNA. Two of three adrenocortical carcinomas expressed ACTH-R mRNA. Northern analysis using dot blot was employed to quantify ACTH-R and GR mRNA expression and confirmed the ISH data: ACTH-R mRNA expression was high in CPAs (275 and 195% vs 100 +/- 25% in adult adrenals), APAs (127, 200 and 221%) and two carcinomas (99 and 132%), but low in the NFA (7%) and in an androgen secreting carcinoma (16%). GR mRNA expression was high in the NFA (195%) and in two of three carcinomas (93, 188, 227%). We conclude that ACTH-R mRNA is upregulated in functional adenomas by yet unidentified mechanisms. The tissue distribution of ACTH-R and P450 enzyme mRNA expression is highly variable in neoplastic adrenals and does not allow a clear differentiation between benign and malignant tumors.

Adenoma↗

PubMed1998

Aminoglutethimide suppresses adrenocorticotropin receptor expression in the NCI-h295 adrenocortical tumor cell line.

The adrenostatic compound aminoglutethimide (AG), a potent inhibitor of the P450 side chain cleavage enzyme, is used in the treatment of ACTH-dependent or adrenal Cushing's syndrome. Recently, AG has been shown to inhibit ACTH receptor (ACTH-R) mRNA expression in ovine adrenocortical cells in a time-dependent fashion. To investigate whether ACTH-R down-regulation will also be induced in tumor cells, we studied the effect of AG on ACTH-R expression in the human NCI-h295 adrenocortical carcinoma cell line, which expresses functional ACTH receptors and produces steroids of the glucocorticoid, mineralocorticoid and androgen pathway. The cells were incubated in triplicate with increasing doses of AG (3, 30, 300 microM) which suppressed steroid secretion dose-dependently. After 48 h, cells were harvested, and total RNA was extracted, electrophoresed, blotted and hybridized with a human ACTH-R cDNA probe. In parallel experiments, after preincubation with AG the cells were stimulated with ACTH (10 nM) for 10 min and the intracellular cAMP accumulation was determined by RIA. 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%). The reduced ACTH-R mRNA expression was paralleled by low ACTH-induced cAMP accumulation indicating reduced expression of the ACTH-R protein. The adrenostatic compound metyrapone, an inhibitor of 11beta-hydroxylase activity, also suppressed ACTH-R mRNA expression in a similar fashion. Stimulation of the protein kinase A pathway by simultaneous incubation of ACTH (10 nM) or forskolin (10 microM) together with AG was not able to overcome the steroid biosynthesis blockade, but reversed the inhibitory effects of AG on the ACTH-R mRNA expression. Also, cortisol (12 microM) reversed the AG-induced ACTH-R mRNA expression. We conclude that AG induces profound ACTH-R down-regulation in the NCI-h295 cell line either by affecting the gene expression or by decreasing transcript accumulation via an effect on RNA stability. This novel action of AG can be reversed by stimulation of the cAMP pathway and of the glucocorticoid-mediated signal transduction cascade. As the down-regulation occurs in vitro at concentrations which are reached during treatment with AG in humans it may contribute to its therapeutic activity in adrenal disease.

Adrenal Cortex Neoplasms↗

PubMed1997

Polymorphism of the glycogen synthase gene and non-insulin-dependent diabetes mellitus in the Russian population.

Recently, a polymorphism in the glycogen synthase gene was shown to be associated with the development of non-insulin-dependent diabetes mellitus (NIDDM) and identified patients with a strong family history of diabetes and hypertension in the Finnish population. However, no association was found in French and Japanese populations. We investigated the possible association between the XbaI polymorphism of the glycogen synthase gene and NIDDM in the Russian population. One hundred fifty NIDDM patients and 109 healthy controls were studied. In 16 of 150 Russian NIDDM patients (10.7%), the XbaI polymorphism was found, and 17 of 109 controls (15.6%) showed the XbaI polymorphism (P > .05). These results suggest that the XbaI polymorphism of the glycogen synthase gene cannot be used as a marker for NIDDM in the Russian population.

Adult↗

PubMed1997

Expression of adrenocorticotrophic hormone receptor mRNA in human adrenocortical neoplasms: correlation with P450scc expression.

OBJECTIVE: Adrenocorticotrophin (ACTH) is the main hormone-regulating steroid secretion from the adrenal cortex. The ACTH receptor (ACTH-R) has recently been cloned, allowing systematic evaluation of its expression and function in adrenal tumorigenesis. We investigated ACTH-R and P450 side-chain cleavage enzyme (P450scc) mRNA expression in a variety of neoplastic adrenocortical tissues by Northern blot and reverse-transcriptase-PCR (RT-PCR). PATIENTS AND MEASUREMENTS: We studied tissue from eight normal adrenals, six diffuse adrenocortical hyperplasias in patients with ACTH-dependent Cushing's syndrome, 22 adrenal adenomas, six carcinomas and two carcinoma cell lines. Poly A mRNA was electrophoresed, immobilized on a nylon membrane and hybridized using alpha 32P-CTP labelled human ACTH-R and P450scc cDNAs. RESULTS: Mean ACTH-R mRNA expression showed significant differences between groups (P = 0.0001), but appeared to be independent of plasma ACTH concentrations. Compared to normal adrenal (= 100 +/- 12%), expression was low in non-functional adenomas (23 +/- 11%) and carcinomas (19 +/- 12%), intermediate in adrenocortical hyperplasias (88 +/- 6%) and cortisol-producing adenomas (81 +/- 15%) and high in aldosteronomas (175 +/- 29%). In adenomas, ACTH-R mRNA expression correlated closely with the expression of P450scc mRNA(r = 0.8, P = 0.0001) suggesting regulation by similar factors. However, carcinomas and cancer cell lines did not show a positive correlation between these two parameters (r = -0.44, P = 0.3). CONCLUSIONS: We have demonstrated that plasma ACTH is not the major factor influencing ACTH-receptor mRNA expression in neoplastic adrenal tissue. In benign tumours of the adrenal cortex there was a close positive correlation between ACTH-receptor mRNA and P450scc mRNA which was missing in adrenocortical carcinomas, probably as a result of tumour dedifferentiation.

Adenoma↗

PubMed1997

Ectopic ACTH production by a bronchial carcinoid tumour responsive to desmopressin in vivo and in vitro.

A desmopressin-induced ACTH increase has been recently suggested to be specific for pituitary-dependent Cushing's disease. We present the case of a 47-year-old woman with Cushing's syndrome due to ectopic ACTH production by a bronchial carcinoid. While CRH failed to induce an ACTH or cortisol response, intravenous administration of desmopressin led to a 47% increase in serum ACTH and a 42% increase in serum cortisol concentration. After surgical removal of the tumour, the desmopressin response became negative. In vitro, ACTH production by tumour cells obtained at surgery was also stimulated by desmopressin but not by CRH. Additional receptor mRNA expression studies using RT-PCR revealed expression of both V2 and V3 vasopressin receptor subtypes in the carcinoid tumour at a level comparable to that recently described in pituitary corticotroph adenomas. This case illustrates that ACTH stimulation by desmopressin is not specific for pituitary-dependent Cushing's syndrome as vasopressin receptor subtypes known to interact with desmopressin may also be found in ectopic tumours producing ACTH.

ACTH Syndrome, Ectopic↗

PubMed1997

Polymorphism of the glucagon receptor gene and non-insulin-dependent diabetes mellitus in the Russian population.

Recently, a missense mutation in the glucagon receptor (GCG-R) gene causing a Gly to Ser change at codon 40 (Gly40Ser) has been associated and linked with non-insulin-dependent diabetes mellitus (NIDDM). We screened 150 unrelated NIDDM patients and 109 non-diabetic subjects for the presence of the Gly40Ser polymorphism by use of polymerase chain reaction-restriction fragment length polymorphism in the Russian population. None of the NIDDM patients showed this polymorphism. In contrast, two of the control subjects were heterozygous carriers of the polymorphism. Both were healthy females without a family history of diabetes. The body mass index, age, and 2-h blood glucose levels of the two subjects with the polymorphism were similar to those of the control subjects homozygous for the wild-type. Our results suggest that Gly40Ser polymorphism of the GCG-R gene is not associated with NIDDM in the Russian population and point to the genetic heterogeneity of NIDDM in different ethnic groups.

Adult↗

PubMed1997

Adrenocorticotropin receptor and adrenal disorders.

The ACTH receptor is the shortest G-protein-coupled receptor to date and consists of 297 residues with two putative glycosylation sites at the extracellular N terminus. In vitro studies have demonstrated upregulation of the ACTH receptor by its own ligand and by angiotensin II. Inactivating mutations of the ACTH receptor lead to the familial glucocorticoid deficiency (FGD) syndrome, a rare recessive autosomal disorder characterized by degeneration of the zona fasciculata/reticularis and unresponsiveness to exogenous ACTH. Interestingly, ACTH receptor mutations are not present in all patients with FGD and also not in the closely related "triple A' syndrome indicating that other mechanisms of ACTH resistance are still to be elucidated. Despite an extensive search, no activating ACTH receptor mutations have been found in adrenal tumors, excluding the ACTH receptor as a relevant oncogene for adrenal tumorigenesis. However, the ACTH receptor may play a role as a differentiation factor, as loss of heterozygosity for the ACTH receptor in adrenal tumors seems to be associated with an undifferentiated phenotype. ACTH receptor mRNA expression in benign adrenal tumors is strongly related to the expression of P-450 side chain cleavage enzyme mRNA indicating a close regulative relationship. However, this correlation is disrupted in adrenal carcinomas, an observation which may help in the difficult differential diagnosis between benign and malignant tumors. Surprisingly, the highest ACTH receptor mRNA expression was found in aldosteronomas, while it is low in non-functioning adenomas and carcinomas. No correlation between ACTH receptor mRNA expression and circulating ACTH levels has been found in patients with adrenal disorders casting doubts on the physiological significance of ACTH receptor upregulation by its own ligand in vivo.

Adrenal Gland Diseases↗

PubMed1997

Expression of glucocorticoid receptor gene isoforms in corticotropin-secreting tumors.

The molecular basis of Cushing's disease is not known. One of the most characteristic features of such tumors is their resistance to corticosteroid feedback at the pituitary level. We have hypothesized that abnormalities of the glucocorticoid receptor (GR) gene might play a role in the development of Cushing's disease via an increase in the relative production of the nonligand-binding splice variant of the GR, GR beta, known to exert dominant negative effects over the ligand-binding isoform, GR alpha. Alternatively, a change in overall GR expression, or mutations of some functional domains of the GR gene, might be involved in the pathogenesis of corticotroph tumors. We studied 22 tumors (17 pituitary ACTH-secreting tumors, 2 ectopic ACTH-producing tumors, 2 prolactinomas, and 1 nonfunctioning adenoma) and three normal pituitaries. RT-PCR was performed with primers specific to GR alpha and GR beta complementary DNA, followed by Southern blotting using an internal probe, and the ratio of the two bands quantitated by densitometry. We also assessed the overall expression of GR relative to the message of both the POMC gene and a housekeeping gene. Single-strand conformation polymorphism analysis of the DNA-binding domain and splice junction region of the gene was also performed. GR alpha messenger RNA was expressed at 37.3-fold +/- 5.7 (range, 32 to 46) excess, as compared with the GR beta subform. This pattern was observed both in the tumor samples and in the normal pituitaries used as controls. A majority of the ACTH-secreting tumors (16/19), including the ectopic secretors, showed variable but increased overall GR expression, whereas 3 tumors showed an expression approximately equivalent to the normal controls; however, no correlation was found between these two groups and the response to the high-dose dexamethasone test, nor was there any correlation with tumor histology. No mutations were found in any of the tumors by PCR-single-strand conformation polymorphism analysis. In conclusion, although both pituitary and ectopic ACTH-secreting tumors are at least partially glucocorticoid-resistant, no significant abnormalities in the relative expression of the two main GR subforms were observed in a series of such tumors. Additionally, mutations of regions critical to normal function of the receptor do not seem to be a frequent event in these tumors.

ACTH Syndrome, Ectopic↗

PubMed1997

Deletion of the adrenocorticotropin receptor gene in human adrenocortical tumors: implications for tumorigenesis.

Constitutive activating mutations of G protein-coupled receptors, such as that of TSH, have been implicated in the tumorigenesis of human endocrine neoplasms, such as thyroid adenomas. In a previous study we reported that constitutive activating point mutations of the ACTH receptor (ACTH-R) gene, a member of the G protein-coupled receptor superfamily, were not present in hormone-secreting and nonsecretory adrenocortical neoplasms. In this study, we investigated whether allelic loss of the ACTH-R gene is present in sporadic adrenal tumors. We identified a PstI polymorphism in the promoter region 3 kilobases upstream of the coding region of the ACTH-R gene. The rate of heterozygosity for this polymorphism in 99 unrelated Caucasian individuals was 53.5%. Using this polymorphism, we analyzed loss of heterozygosity (LOH) of the ACTH-R gene in 20 informative cases with benign and malignant adrenocortical tumors. Of 16 patients with benign lesions, LOH was present in 1 oncocytic nonfunctional adenoma, but not in 15 hyperfunctioning adenomas. Of 4 informative patients with adrenocortical carcinomas, LOH was present in 2 cases. Both patients had advanced tumor stages and showed a more rapid course than carcinoma patients without LOH. Analysis of the flanking region of the ACTH-R using the polymorphic microsatelite marker D18S37 and D18S40 showed that this deletion was confined to the ACTH-R gene. Northern blot experiments demonstrated reduced expression of ACTH-R messenger ribonucleic acid in the tumors with LOH of the ACTH-R gene, suggesting functional significance of this finding at the transcriptional level. We conclude that LOH of the ACTH-R gene is possibly involved in adrenal tumorigenesis, contributing to cellular dedifferentiation in adenomas and carcinomas.

Adenoma↗

PubMed1997

Frequent and frequently overlooked: treatment-induced endocrine dysfunction in adult long-term survivors of primary brain tumors.

New treatments for primary brain tumors have improved survival but quality of life may be impaired by neuroendocrine dysfunction. We performed a controlled, cross-sectional study to assess frequency and clinical impact of endocrine dysfunction in adult long-term survivors of primary brain tumors outside the hypothalamic-pituitary region. Thirty-one patients (19 males and 12 females; age, 25 to 66 years) and 31 sex- and age-matched controls were studied 1.5 to 11 years after radiotherapy with a mean total dose of 62.3 +/- 2.8 Gy (mean local doses pituitary, 51.1 +/- 12.1 Gy; hypothalamus, 57.0 +/- 7.8 Gy). Structured clinical assessment included a standardized questionnaire. Thyroid, adrenal, and gonadal hormones were measured at baseline and, in the patients, also after stimulation. Sixteen patients (52%) reported two or more symptoms suggestive of hypothyroidism; eight patients (26%) showed evidence of hypothalamic hypothyroidism. Patients had significantly lower serum baseline concentrations of cortisol and dehydroepiandrosterone sulfate than controls, but no manifest hypoadrenalism was noticed except in one patient with panhypopituitarism. Forty-seven percent of the male patients, but only six percent of the controls, suffered from erectile dysfunction; 42% of the male patients showed either evidence of hypothalamic hypogonadism (32%) or primary gonadal damage (10%). Nine patients (29%) presented with hyperprolactinemia and four women concurrently suffered from oligo-amenorrhea. In adult patients treated for primary brain tumors, endocrine dysfunction due to radiation-induced hypothalamic damage is common and has a significant impact on well being. Endocrinologic evaluation should be performed periodically in these patients.

Adrenal Glands↗

PubMed1997

Determinants of radial bone density as measured by PQCT in pre- and postmenopausal women: the role of bone size.

The aim of the present study was to examine the influence of anthropometric, hormonal, and geometric factors on the variability of radial bone mineral density (BMD) in women. In 583 healthy pre- and postmenopausal females (aged 40-60 years) radial total (BD) and trabecular BMD (TBD) was measured by peripheral quantitative computerized tomography at the nondominant distal forearm. In addition, 29 women who had suffered a Colles' fracture after minor trauma were also evaluated. There was no age-dependent change in radial BD and TBD before menopause. We found a negative correlation between BMD and age and years since menopause (YSM) in postmenopausal women (BD = 422.73 - 2.342 age - 6.308YSM; r = 0.36, p = 0.0001, n = 128). The variation of YSM, body mass index (BMI), and age accounted for 20% of the variability of BD in postmenopausal women. In contrast, in premenopausal women, only 3% of the variability could be explained by anthropometric variables. Bone mineral content (BMC) and bone area, but not BMD at the distal radius, were significantly correlated to grip strength (r = 0.25, p = 0.006 for BMC, r = 0.26, p = 0.003 for area). The cross-sectional bone area of the CT slice showed a significant increase with aging (y = 263.02 + 1.25x; r = 0.14, p = 0.0009). There was a strong negative correlation between bone area and BD and TBD (y = 516.04 - 0.668x; r = -0.57, p < 0.0001 for BD). If BMD is normalized for BA, variation is reduced by 32% (for BD) and 10% (for TBD), respectively. Women with Colles' fracture had a significantly lower TBD normalized for BA (fracture group [-0.71 +/- 0.88] vs. normals (0.03 +/- 0.99]; p = 0.00009). Our results show that YSM and BMI are predictors of postmenopausal BMD. However, radial BMD is influenced strongly by geometric variables such as cross-sectional bone area.

Absorptiometry, Photon↗