[Excision of pancreatic insulinoma under celioscopy].
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Female↗
Biomedical subjects
X Bertagna
Publications and source records attributed to X Bertagna.
Dosimetric and cytogenetic studies of multiple radiation-induced meningiomas for a single patient.
No criteria are currently available to determine the spontaneous or radiation-induced origin of a malignant tumor occurring in a previously irradiated area. This study presents the dosimetric and cytogenetic analysis of meningiomas diagnosed in irradiated brain areas from a single patient and a discussion of the karyotypes of spontaneous meningiomas and radiation-induced tumors published in the literature.
Adult↗
Pituitary-adrenal response to RU 486 in man.
New therapeutic indications of the antiprogesterone RU 486 are emerging which require long-term administration and raise the question of its safety because of the associated antiglucocorticoid action of the drug. A trial was designed to assess the antiglucocorticoid effect of RU 486, possible manifestations of peripheral cortisol deprivation, and the adrenocortical and corticotrophin reserves. Ten normal males were given RU 486 per os (200 mg/day) or placebo between 0800-0900 h for eight days in a randomized, double-blind, crossover design, with a 1-month interval between the two periods. RU 486 induced the overactivation of the pituitary-adrenal axis. Baseline values (mean +/- SEM) before and at end of treatment were, respectively: 0800 h plasma cortisol, 147.3 +/- 15.5 and 257.6 +/- 8.8 ng/ml; 0800 h salivary cortisol, 5.8 +/- 1.2 and 15.2 +/- 0.8 ng/ml; nocturnal (2200-0800 h) urinary cortisol, 8.4 +/- 1.5 and 33.7 +/- 11.1 micrograms; and 0800 h plasma ACTH, 29.2 +/- 3.7 and 60.2 +/- 8.4 pg/ml. All of these variations were different from those during placebo treatment (0.0001 < p < .03) and disappeared four days after the end of treatment. A daily record of subjective clinical symptoms, body weight and temperature, blood pressure, and heart rate showed no side effects, and no significant variation during treatment. Blood electrolyte and eosinophil counts were unchanged; fasting blood glucose was slightly higher at the end of treatment (5.0 +/- 0.2 vs. 4.7 +/- 0.1 mmol/L; p < .04). The adrenocortical response to Cortrosyn (0.25 mg IM) was exaggerated during RU 486 treatment (p < .006). Peak values before and at the end of treatment were, respectively: plasma cortisol, 272.5 +/- 15.2 and 347.1 +/- 20.6 ng/ml; and salivary cortisol, 17.0 +/- 2.2 and 31.1 +/- 3.1 ng/ml. Direct pituitary stimulation (100 micrograms ovine corticotrophin release hormone (CRH), followed by 1 IU LVP) also induced exaggerated corticotroph and adrenocortical responses (p < .005). Peak values before and at the end of treatment were, respectively: plasma ACTH, 147.7 +/- 24.6 and 254.0 +/- 41.3 pg/ml: and plasma cortisol, 231.6 +/- 7.3 and 319.2 +/- 12.3 ng/ml. These data show that 8-day treatment with 200 mg RU 486 daily induces a hormonally detectable antiglucocorticoid effect without clinical symptoms. This state results in a reversible cortisol overproduction and a preservation of adrenocortical and pituitary reserves.
Blood Pressure↗
V3 vasopressin receptor and corticotropic phenotype in pituitary and nonpituitary tumors.
Pituitary corticotropic cells express a specific vasopressin receptor, called V1b or V3, through which vasopressin stimulates corticotropin secretion. We recently cloned a cDNA coding for this receptor and showed that it belongs to the G protein-coupled receptor family. V3 mRNA is readily detected by RT-PCR in normal human pituitaries and corticotropic pituitary adenomas but not in PRL or GH-secreting adenomas, thus demonstrating that, like POMC itself and the CRH receptor, V3 is a marker of the corticotropic phenotype. Nuclease protection experiments suggest that V3 is overexpressed in some corticotropic adenomas, and thus may play a role in tumor development by activating the phospholipase C-signalling pathway. In addition analysis of its expression in nonpituitary neuroendocrine tumors showed a striking association with carcinoids of the lung responsible for the ectopic ACTH syndrome.
Adrenocorticotropic Hormone↗
High expression of the POU factor Brn3a in aggressive neuroendocrine tumors.
A new family of POU transcription factors called Brn plays a role in development of the brain and some neuroendocrine structure. Because a member of this family, Brn3a, is present in the ACTH-producing mouse pituitary tumor AtT-20, binds to POMC promoter, and stimulates its activity, we studied its human homolog in ACTH-secreting or nonsecreting tumors of pituitary and bronchial origins. A specific and quantitative reverse transcription-PCR assay was developed to assess Brn3a transcripts in tumor ribonucleic acid. Brn3a transcript levels were invariably low (< 5 x 10(-6) arbitrary units) in four GH-, two PRL-, three gonadotropin-, and seven of eight ACTH-producing pituitary adenomas. A single highly invasive ACTH-secreting pituitary adenoma in a patient who ultimately died with liver metastases, and the mouse corticotroph tumor cell line AtT-20 had high Brn3a transcripts levels at 3 x 10(-5) and 4 x 10(-4) arbitrary units, respectively. Five typical bronchial carcinoids had barely detectable levels (< 5 x 10(-6) arbitrary units), whereas seven of eight small cell carcinomas of the lung (SCCLs) had extremely high levels (between 10(-3)-10(-1) arbitrary units); six of seven atypical bronchial carcinoids had intermediate values, between 10(-6) and 5 x 10(-3) arbitrary units. Although nine bronchial tumors produced POMC, there was no association between Brn3a levels and POMC gene expression; the two tumors with the highest POMC messenger ribonucleic acid contents were two bronchial carcinoids with barely detectable Brn3a levels. A gel mobility shift assay was performed with a rat CRH promoter probe that binds Brn3a; extracts of the POMC-producing human SCCL line DMS-79, which contained high levels of Brn3a transcripts, generated the same specific complex as did AtT-20 cell extracts. These data show that Brn3a gene expression in neuroendocrine tumors is not correlated with POMC gene expression; rather, it is strikingly elevated in the highly aggressive tumors, independently of their POMC status and their pituitary or nonpituitary origin.
Adenoma↗
Structural and functional abnormalities at 11p15 are associated with the malignant phenotype in sporadic adrenocortical tumors: study on a series of 82 tumors.
Abnormalities of the 11p15 region with overexpression of the normally imprinted insulin-like growth factor II (IGF-II) gene have been implicated in the pathogenesis of adrenocortical tumors. We evaluated the frequency and distribution of 11p15 loss of heterozygosity (LOH) and IGF-II gene overexpression in a series of 82 sporadic adrenocortical tumors, screened for pathological functional imprinting of the 11p15 region in tumors not exhibiting LOH and evaluated the expression of H19 gene in these tumors. Abnormalities of the 11p15 region as LOH (loss of the maternal allele and duplication of the paternal allele) and/or IGF-II gene overexpression are frequent features of the malignant state and were found in 27 of 29 (93.1%) of the malignant tumors and in only 3 of 35 (8.6%) of the benign tumors. Tumors without abnormality of the 11p15 region (mainly benign tumors) did not exhibit pathological functional imprinting. In tumors with mosaicism for 11p15 LOH, biallelic expression of the IGF-II gene was constant in the tumor cell contingent not undergoing LOH. Abrogation of H19 expression correlated with the loss of the maternal allele (LOH or pathological imprinting), but did not always correlate with overexpression of the IGF-II gene. These data indicate the involvement of dysregulation of the 11p15 region in late steps of adrenocortical tumorigenesis and provide us with new molecular markers for a better diagnostic and prognostic evaluation of adrenocortical tumors.
Adolescent↗
Widespread transcription of the growth hormone-releasing peptide receptor gene in neuroendocrine human tumors.
GH-releasing peptides are a new class of potent GH secretagogs (GHS) in vivo and in vitro. In normal man GHS also elicit low but definite ACTH and prolactin secretion. Recently it was shown that patients with pituitary corticotrope adenomas respond to GHS with a dramatic rise in ACTH secretion, and it has been suggested that GHS may provide a diagnostic tool to differentiate Cushing's disease from the ectopic ACTH syndrome. GHS actions are mediated by a G protein-coupled receptor recently characterized and cloned in man and rat. In this study we analyzed GHS receptor (GHS-R) expression in various types of pituitary adenoma and in endocrine and non-endocrine lung tumors by RT-PCR. GHS-R transcription was detected in all normal pituitaries and GH-secreting adenomas as expected. The receptor was also transcribed in some prolactin-secreting adenomas and non-functioning adenomas, and, more strikingly, in all 18 ACTH-secreting pituitary adenomas studied. Furthermore, it was frequently expressed in endocrine bronchial tumors, especially carcinoids, whereas it was not found or barely detectable in non-endocrine bronchial tumors. Again ACTH-secreting carcinoids of the lung were all positive for GHS-R expression. These results show that GHS-R transcription is a common feature of endocrine tumors independent of their type and origin.
Adrenocorticotropic Hormone↗
[Pituitary adenoma: mechanisms of endocrine oncogenesis].
Molecular studies on pituitary adenomas support a major role of molecular alterations in the pathogenesis of pituitary adenomas. Nevertheless, alterations in the neuro-hormonal control of the pituitary could also be involved in pituitary tumors formation. The finding that most pituitary adenomas are monoclonal has stimulated a search for somatic mutations. For instance, activating mutations of the Gs protein, leading to constitutive stimulation of the cAMP pathway, have been found in a subset of GH-secreting adenomas. But GHRH (growth hormone-releasing hormone) tumoral hypersecretion also stimulates the cAMP pathway and causes acromegaly. Pituitary tumor formation might result from accumulation of several alterations that would determine the tumoral phenotype. The majority of these alterations remains to be found.
Adenoma↗
The pituitary V3 vasopressin receptor and the corticotroph phenotype in ectopic ACTH syndrome.
Ectopic ACTH secretion occurs in highly differentiated and rather indolent tumors like bronchial carcinoids or, in contrast, in various types of aggressive and poorly differentiated neuroendocrine tumors. We explored this phenomenon using the recently cloned human pituitary V3 vasopressin receptor as an alternate molecular marker of the corticotroph phenotype. Expression of V3 receptor, corticotrophin releasing hormone (CRH) receptor, and proopiomelanocortin (POMC) genes was examined in tumors of pituitary and nonpituitary origin. A comparative RT-PCR approach revealed signals for both V3 receptor and CHR receptor mRNAs in 17 of 18 ACTH-secreting pituitary adenomas, and 6 of 6 normal pituitaries; in six growth hormone- or prolactin-secreting adenomas, a very faint V3 receptor signal was observed in three cases, and CRH receptor signal was undetected in all. Six of eight bronchial carcinoids responsible for the ectopic ACTH syndrome had both POMC and V3 receptor signals as high as those in ACTH-secreting pituitary adenomas; in contrast, no POMC signal and only a very faint V3 receptor signal were detected in six of eight nonsecreting bronchial carcinoids. Northern blot analysis showed V3 receptor mRNA of identical size in ACTH-secreting bronchial carcinoids and pituitary tumors. Other types of nonpituitary tumors responsible for ectopic ACTH syndrome presented much lower levels of both POMC and V3 receptor gene expression than those found in ACTH-secreting bronchial carcinoids. In contrast with the V3 receptor, CRH receptor mRNA was detected in the majority of neuroendocrine tumors irrespective of their POMC status. These results show that expression of the V3 receptor gene participates in the corticotroph phenotype. Its striking association with ACTH-secreting bronchial carcinoids defines a subset of nonpituitary tumors in which ectopic POMC gene expression is but one aspect of a wider process of corticotroph cell differentiation, and opens new possibilities of pharmacological investigations and even manipulations of this peculiar ACTH hypersecretory syndrome.
ACTH Syndrome, Ectopic↗
High plasma proopiomelanocortin in aggressive adrenocorticotropin-secreting tumors.
A specific propiomelanocortin (POMC) immunoradiometric assay was developed using antibodies directed against ACTH and beta-endorphin (beta end). Partially purified standard POMC was prepared from the human small cell lung carcinoma cell line DMS-79 culture medium. Ten units (U) POMC had the same displacement ability as one pg beta end in a C-terminal beta end radioimmunoassay and thus were close if not equal to 10 pg POMC. This POMC assay was used to investigate patients with ACTH-dependent Cushing's syndrome. Plasma POMC was undetectable (< 60 U/mL) in 17 normal controls and in 4 patients with Addison's disease (concomitant ACTH plasma levels between 362 and 1058 pg/mL). Forty-two patients with Cushing's disease were studied, either before (n = 25) or after (n = 17) bilateral adrenalectomy: 7 patients with highly invasive macroadenomas had high POMC plasma levels, between 240 and 4200 U/ml (concomitant ACTH plasma levels between 77 and 5730 pg/mL); 35 patients, including one with an invasive macroadenoma, had undetectable POMC plasma levels (concomitant ACTH plasma levels between 31 and 2820 pg/mL). Among 20 patients with histologically proven ectopic ACTH syndrome, 16 had high POMC plasma levels, between 80 and 8000 U/mL (concomitant ACTH plasma levels between 45 and 9265 pg/mL); all those tumors were malignant, and the highest POMC/ACTH plasma levels ratios (taken as an index of altered POMC processing) were observed in the 3 patients with small cell carcinomas of the lung; in one of these patients, ACTH and POMC plasma levels both decreased during the course of chemotherapy, in parallel with the reduction of the tumoral mass. Four patients with ectopic ACTH syndrome had undetectable POMC plasma levels (concomitant ACTH plasma levels between 78 and 335 pg/mL): they were all typical bronchial carcinoids. These data show that high POMC plasma level is neither specific for nor constant in ectopic ACTH syndrome. Rather it should be considered as a marker of tumor aggressivity, in pituitary- and non-pituitary tumors. Its diagnostic help appears limited for the most frequent cause of occult ectopic ACTH syndrome, the typical bronchial carcinoids.
ACTH Syndrome, Ectopic↗
[Metastatic pulmonary carcinoma, revealed by Cushing syndrome, initially considered to have a pituitary origin. Course over 25 years].
It is often difficult to differentiate between Cushing's syndrome and ectopic ACTH hypersecretion which, in rare cases, may result from a carcinoid tumour. Several years may be required before development of patent Cushing's syndrome. We report the 25-year clinical course in a patient with a pulmonary carcinoid tumour. Initially, the hormone results led to the diagnosis of Cushing's syndrome and the patient was treated accordingly. Bilateral adrenectomy was performed in 1969 followed by radiotherapy of the pituitary gland in 1975 for suspected Nelson's syndrome. Actually, the carcinoid tumour, located retrocardially, had gone unnoticed until 1989. Diagnosis was suspected during a hospitalization in our unit and the patient underwent tumour exeresis and left inferior lobectomy. Despite tumour removal and demonstration of tumoural ACTH secretion, the levels of ACTH and beta-lipotrope hormone remained high suggesting lymph node and/or pulmonary metastasis. This observation emphasizes the long clinical course of carcinoid tumours despite their malignancy and the unusual response to the dexamethasone test.
Adrenocorticotropic Hormone↗
The RET protooncogene in sporadic pheochromocytomas: frequent MEN 2-like mutations and new molecular defects.
To assess the pathophysiological role of the RET protooncogene in sporadic pheochromocytomas, we examined the 2 regions of the gene in which molecular defects are specifically associated with the multiple endocrine neoplasias (MEN) type 2A (the cysteine-rich domain encoded by exons 10 and 11), and type 2B (the tyrosine kinase domain encoded by exon 16). The sequences of both regions were amplified by reverse transcriptase-polymerase chain reaction (PCR) or PCR from tumor RNA and/or leukocyte DNA. The amplified fragments were analyzed by denaturing gradient gel electrophoresis using chemical clamps. In 28 patients with unilateral sporadic tumors, 6 RET mutations were found, 3 in the MEN 2A region, 3 in the MEN 2B region. Five patients had missense mutations: 2 in the MEN 2A region (C634W and D631Y), and 3 in the MEN 2B region (M918T). Analysis of leukocyte DNA in 3 of these patients confirmed that RET mutations were only present in tumor DNA. The sixth patient had lost exon 10 in the tumor complementary DNA as a result of the deletion of the dinucleotide -AG- at the 3'splice acceptor site of intron 9; this molecular defect was only found in the tumor DNA. Thus RET mutations of the MEN 2A and 2B regions are also found in about 20% of sporadic pheochromocytomas. We describe new types of molecular defects of the RET protooncogene in the MEN 2A region that involve noncysteine residues and loss of exon 10. Further studies should be extended to analyze the entire RET protooncogene. These findings have a profound clinical impact for the management of patients with supposedly sporadic pheochromocytomas.
Adrenal Gland Neoplasms↗
Vasopressin-responsive adrenocortical tumor in a mild Cushing's syndrome: in vivo and in vitro studies.
We report a case of a Cushing's syndrome caused by an autonomously secreting unilateral adrenocortical tumor, characterized by a clinically and biologically mild hypercortisolemic state and an unusual response pattern to vasopressin. Laboratory tests showed normal early morning plasma cortisol and 24-h urinary cortisol excretion, but lack of nycthemeral variations and suppressed plasma ACTH. Urinary cortisol excretion was not suppressed by either the low dose or the high dose dexamethasone test. Injection of lysine vasopressin, (10 IU, im) induced a marked increase in plasma cortisol, without an elevation of plasma ACTH. Computed tomography scan revealed an adrenocortical mass of the left gland with a contralateral atrophic gland. Removal of the tumor led to complete remission of Cushing's symptoms. In vitro studies were then performed to investigate the effect of arginine vasopressin (AVP) on calcium mobilization in cultured tumor cells using a microfluorimetric technique. Application of AVP in the vicinity of the cells induced a rapid and marked increase in the intracellular calcium concentration. Preincubation of the cells with the V1 vasopressin receptor antagonist [d(CH2)5,Tyr(OMe)2]AVP totally suppressed the AVP-induced stimulation of intracellular calcium concentration. Reverse transcription followed by polymerase chain reaction of tumor ribonucleic acid with specific oligonucleotides amplified high levels of V1 receptor signal compared with normal adrenocortical ribonucleic acid. Specific oligonucleotides for the V2 or V3 receptors amplified only a faint signal. This is the first report describing a mild case of Cushing's syndrome caused by an AVP-sensitive cortisol-producing adenoma. The direct effect of AVP on cultured tumor cells was mediated through the V1 type of vasopressin receptor, similar to that previously characterized in normal human fasciculata cells, suggesting that the tumor expressed an eutopic V1 AVP receptor and exhibited overresponsiveness to AVP.
Adrenal Cortex Neoplasms↗
Recent advances in the pathogenesis of adrenocortical tumours.
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Adrenal Cortex Neoplasms↗
Oncogenic mutations of alpha-Gi2 protein are not determinant for human adrenocortical tumourigenesis.
Activating mutations of G proteins, which are membrane signal transducers, have been associated recently with the development of various endocrine neoplasms. Mutations of two highly conserved codons, Arg201 and Gln227, in the alpha-subunit of the Gs protein, the adenylyl cyclase-stimulating protein, were first described in growth hormone-producing pituitary tumours. They resulted in constitutive activation of the alpha s-subunit by decreasing intrinsic GTPase activity. A similar mutation, affecting codon Arg179 (exon 5) in the alpha-subunit of the Gi2 protein, the adenylyl cyclase-inhibiting protein, has been described by a single group in ovarian and adrenocortical tumours. We evaluated the frequency of activating mutations in the alpha-subunit of the Gi2 protein in 18 human adrenocortical tumours. We screened exons 5 (codon Arg179) and 6 (codon gln205) for mutations by denaturing gradient gel electrophoresis analysis of leucocyte and tumoural DNA. No abnormal migration pattern was found in either exon. The absence of mutation in exon 5, which includes the Arg179 codon, was confirmed in all tumoural DNA by direct sequencing. In conclusion, we did not find any oncogenic mutations in the GTPase domain of the alpha-subunit of the Gi2 protein in adrenocortical tumours. Thus, the previously oncogenic gip2 mutations do not appear to be determinant for adrenocortical tumourigenesis.
Adolescent↗
Long-distance and long-term follow-up of a patient with intermittent Cushing's disease by salivary cortisol measurements.
Salivary cortisol is an excellent indicator of the plasma free cortisol concentration in normal and pathological situations. We took advantage of its ease of sampling, allowing multiple collections at home, to follow the course of a patient with Cushing's disease living in North Africa. This 48-year-old woman presented with a clinically moderate hypercortisolism caused by a large basophilic pituitary adenoma. Bilateral extension to the cavernous sinuses precluded surgical therapy. She went into spontaneous remission based on clinical signs as well as biochemical findings. During the following 2 years she demonstrated intermittent relapses that were treated by radiotherapy (50 Gy), followed by ketoconazole and then o-paraprime-dichloro-diphenyl-dichloroethane (Op'DDD). After a prolonged clinical remission, Cushing's syndrome again became active. Bromocriptine was started without effect and a new treatment with Op'DDD was began. Evaluation and follow-up were performed during hospitalizations and mainly through the measurements of salivary cortisol in more than 100 samples sent from North Africa by air mail to our department in Paris. Thus we were able to demonstrate intermittent overproduction of cortisol before any treatment, with periods of normal and even low values, and to follow the efficacy of therapy and to detect the relapses. We conclude that measurement of salivary cortisol is a valuable tool in difficult clinical situations such as intermittent hypercortisolism and remoteness between the patient and hospital.
Africa, Northern↗
Functional analysis of the human pro-opiomelanocortin promoter in the small cell lung carcinoma cell line DMS-79.
DMS-79 is a human cell line derived from a small cell lung carcinoma (SCLC), which expresses the pro-opiomelanocortin (POMC) gene. We took it as a model in which to study the mechanism of POMC gene expression in these tumors: precursor processing is altered and gene expression is essentially unresponsive to glucocorticoids. POMC gene structure appeared normal by Southern blot analysis, indicating that gene rearrangement was not responsible for its expression in DMS-79. Indeed, using transient expression of human POMC-luciferase fusion genes in DMS-79, we showed that (1) the normal human POMC promoter was functional in DMS-79, and (2) the same proximal promoter region (-417; + 21) produced the full transcriptional activity in DMS-79 and in the mouse pituitary cell line AtT-20. Progressive 5' deletion analysis revealed differences between AtT-20 and DMS-79: region (-611; -376) was active in AtT-20 and not in DMS-79, whereas region (-95; -161) was active in both cell lines and (-376; -417) was only active in DMS-79. The latter partially overlaps a motif homologous to the DE-2 rat element which confers the tissue-specific expression of POMC in AtT-20 cells; however, this motif had no effect in DMS-79. These data suggest that POMC gene transcription is achieved through a different set of transacting factors in DMS-79 and AtT-20. Altogether, our results provide evidence that DMS-79 is a valid model of tumors responsible for the ectopic ACTH syndrome and that the mechanism of POMC gene expression in these SCLC cells is different from that in pituitary cells.
Animals↗
Cloning and characterization of the human V3 pituitary vasopressin receptor.
Arginine-vasopressin (AVP) plays a determinant role in the normal ACTH response to stress in mammals. We cloned a human cDNA coding a 424 amino acid G-protein coupled receptor structurally related to the vasopressin/oxytocin receptor family. When expressed in COS cells, this receptor binds AVP with a high affinity (Kd = 0.55 +/- 0.13 nM) and is functionally coupled to phospholipase C. Competition studies with peptidic or non peptidic AVP analogues reveal that it is pharmacologically distinct from V1a and V2 AVP receptors and therefore it is designated V3. RT-PCR analysis shows that the human V3 receptor is expressed in normal pituitary and also in kidney, but is undetectable in liver, myometrium and adrenal gland. Northern blot analysis reveals a approximately 4.8 kb messenger in human corticotropic pituitary adenomas.
Adenoma↗