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T Brue

Publications and source records attributed to T Brue.

At least 19 recordsLinked to original sources
PubMed2001

Combined pituitary hormone deficiency due to the F135C human Pit-1 (pituitary-specific factor 1) gene mutation: functional and structural correlates.

The pituitary-specific transcription factor Pit-1 (pituitary-specific factor 1) is known to play a key role in the differentiation of PRL-, GH-, and TSH-secreting cells, and in the regulation of expression of the corresponding genes. In recent years, 12 distinct mutations of the Pit-1 gene have been shown to be responsible for a phenotype of multiple congenital pituitary hormone deficiency involving PRL, GH, and TSH. We had previously identified, in four siblings with GH, PRL, and TSH deficiencies, a mutation (F135C) resulting in a single amino acid change within the POU-specific binding domain of the Pit-1 molecule. In the present report, we have explored the functional effect of the F135C mutation. In vitro activity tests performed by transfection in human HeLa cells showed decreased transactivation capacity on the PRL, GH, and Pit-1 genes. The DNA binding experiments performed by gel shift showed that the F135C mutation generated a protein capable of binding to DNA response elements. To analyze how the F135C mutation might affect functionality of the transcription factor despite a normal DNA binding, we used a structure modelization approach and also analyzed two other Pit-1 mutant proteins (F135A and F135Y). The loss of functionality in these two mutants was similar to that of F135C. This finding was in keeping with our molecular modeling studies. According to structural data derived from the crystallographic analysis of the DNA/Pit-1 POU domain complex, the conformation of the first helix of the F135C-mutated POU-specific domain could be perturbed to such an extent that any interaction with other transcription cofactors might be definitively prevented.

Amino Acid Sequence↗
PubMed2000

Markers of tumor invasion are major predictive factors for the long-term outcome of corticotroph microadenomas treated by transsphenoidal adenomectomy.

OBJECTIVE: To assess the postsurgical outcome of patients with corticotroph microadenomas and to define predictors of the long-term outcome, with special emphasis on markers of tumor extension. DESIGN: Prospective study of 53 corticotroph microadenomas treated by enlarged adenomectomy. Patients followed for at least 2 years were classified into two groups: those in long-term remission and uncured patients (immediate failures and recurrences). Pre-, per- and postoperative parameters were analyzed as predictors of the long-term outcome. METHODS: Baseline hormone assessments were performed preoperatively, 8 days after surgery and every 6-12 months thereafter. Pituitary magnetic resonance imaging (MRI) allowed analysis of possible tumor extension to adjacent structures. Apparent completeness of the surgical removal was determined, and fragments labeled either 'tumor' or 'surrounding pituitary tissue' were submitted to serial sectioning. RESULTS: Immediate control of hypercortisolism was achieved in 43/53 patients (81%). However, later recurrences were observed in five patients (9%). Preoperative MRI showed tumor extension into adjacent structures with good specificity (91%) for prediction of surgical failure. Evidence of local invasion at surgery was also significantly predictive of the long-term outcome. A corticotroph adenoma was found at histological examination in 96% of the patients, and 26% had irregular limits, a feature significantly correlated with a poor outcome. Immediate postoperative plasma cortisol did not allow discrimination between long-term remissions and recurrences. CONCLUSION: Surgical failure was best predicted by signs of tumor 'invasiveness' at MRI, confirmed by peroperative examination and histology.

Adenoma↗
PubMed2000

[Pituitary development and pathology of transcription factors].

Over the last 10 years, important data on pituitary development have been reported using spontaneous or experimental models of gene inactivation. The development pathways of the anterior pituitary lobe include organogenesis resulting in Rathke pouch formation and cell differentiation. Pituitary development is controlled by sequential series of specific signaling molecules and specific transcription factors. In humans, inactivation of Pit-1, Prop-1, Rpx and Ptx2 genes is responsible for pituitary combined deficiency. In this paper, updated data on the embryology of the pituitary gland and the clinical phenotypes of inactivation of pituitary transcription factors are reported.

Animals↗
PubMed1999

Defective retinoic acid regulation of the Pit-1 gene enhancer: a novel mechanism of combined pituitary hormone deficiency.

Pit-1 is a pituitary-specific transcription factor responsible for pituitary development and hormone expression in mammals. Pit-1 contains two protein domains, termed POU-specific and POU-homeo, which are both necessary for DNA binding and activation of the GH and PRL genes and regulation of the PRL, TSH-beta subunit (TSH-beta), and Pit-1 genes. Pit-1 is also necessary for retinoic acid induction of its own gene during development through a Pit-1-dependent enhancer. Combined pituitary hormone deficiency is caused by defective transactivation of target genes in the anterior pituitary. In the present report, we provide in vivo evidence that retinoic acid induction of the Pit-1 gene can be impaired by a Pit-1 gene mutation, suggesting a new molecular mechanism for combined pituitary hormone deficiency in man.

Animals↗
PubMed1999

An ultrarapid prognostic index in microprolactinoma surgery.

OBJECT: Prolactinomas account for approximately 40% of pituitary tumors. If the tumor does not exceed 10 mm at its largest diameter (microprolactinoma), the chances of definitive cure as a result of surgery alone vary from 62 to 89% depending on the series. Until now, however, there was no mechanism to predict whether total excision of a tumor had been accomplished. To improve the chances of total excision, we compared the peri- and postoperative kinetics of circulating prolactin (PRL) in patients judged to be cured and those not cured. METHODS: The pre-, peri-, and postoperative variations in blood PRL concentrations were determined using assays conducted at 10-minute intervals. Of the 36 patients included in the study, 27 were considered cured (resumption of a normal menstrual cycle within 6 months, PRL concentration at 9 days [mean +/- standard deviation 2.5+/-2.1 ng/ml] and 12 months [4.5+/-2.2 ng/ml] after the operation < 10 ng/ml and normally stimulated by metoclopramide and thyrotropin-releasing hormone [TRH]). Nine patients were not cured (PRL 20+/-15.7 ng/ml at 9 days after surgery, with no response to metoclopramide and TRH). The kinetics of PRL decrease in definitively cured patients were characterized by the following: 1) the initial slope of the curve decreased by at least 11% within the first 10 minutes after resection, and 2) immediate postoperative PRL concentrations were 20 ng/ml or less. CONCLUSIONS: The measurement of the kinetics of PRL decrease during surgery allows the chance of gross-total resection to be successfully predicted less than 25 minutes after excision of the adenoma. Provided an ultrarapid assay is available (the test used in the present study took < 15 minutes), this prognostic index would be useful to make a decision to continue the surgical procedure when the initial PRL slope is judged to be insufficient. Its use may also be extended to other pituitary tumors such as somatotropic adenoma and basophilic adenoma (Cushing's disease).

Adolescent↗
PubMed1999

[Transcription factors of the anterior pituitary and combined hypopituitarism].

In the recent years, spontaneous and experimental models of hypopituitarism have underlined the involvement of a number of homeodomain transcription factors in different forms of congenital anterior pituitary hormone deficiencies. Indeed, abnormalities of the transcription factor Pit-1 are responsible for combined deficiencies affecting thyrotroph, somatotroph and lactotroph cell lineages both in dwarf mouse strains (Snell, Jackson) and in human patients. More recently, alterations of the Prop-1 gene have been shown to induce a similar phenotype in the Ames mice, and alterations of the human homolog gene have been evidenced in patients with anterior pituitary deficiencies involving the same three lineages together with the gonadotrophs. Gene knock-out experiments have demonstrated the importance of other transcription factors such as Lhx3 and Lhx4 in the development of the normal pituitary gland. These findings illustrate the potential involvement of anomalies of these and many other factors in the various forms of multiple hypopituitarism.

Animals↗
PubMed1999

[An immunologic etiology for hyperprolactinemia: macroprolactinemia].

Besides classical etiologies of hyperprolactinaemia (pregnancy, pharmacological treatments, pituitary or hypothalamic perturbations), another less known cause may explain a spectacular idiopathic elevation of plasma concentrations of prolactin hormone. Macroprolactinaemia is characterized by the presence of a circulating high molecular weight complex of prolactin with an immunoglobulin G. In this article, we report the cases of 3 female patients for whom size exclusion chromatography technique permitted to give a precise biological diagnosis and to avoid heavy, expensive, time consuming and unnecessary clinical investigations or therapeutic actions. Patients with macroprolactinaemia do not exhibit clinical features of classical hyperprolactinaemia, notably as regard to menstrual and fertility disturbances.

Adult↗
PubMed1998

The hormonal response to stress is not modified by the dramatic decrease in prolactin plasma concentration during surgery for microprolactinoma.

OBJECTIVES: To determine the endocrine response to surgical stress in a homogeneous population of 36 women with microprolactinomas, particularly to evaluate the effect of the sharp decrease in plasma prolactin on stress induced hormonal secretion. In addition, the effects of exogenous opiates on prolactin secretion were studied. METHODS: The plasma kinetics of cortisol, prolactin, ACTH, GH, and beta-endorphin like immunoreactivity (beta-ELI) were analysed by including patients operated on with strict anaesthetic and surgical protocols, and by sampling blood every 10 minutes, starting at premedication up to 3 hours after induction. RESULTS AND CONCLUSIONS: (a) Surgical stress or opiate administration did not induce prolactin release in patients with microprolactinoma. (b) The dramatic decrease in prolactin concentrations have apparently no effect on the release of other hormones involved in stress. (c) The existence of an early GH peak, independently of any surgical procedure, strongly suggests that GH is released by surgical stress whereas beta-endorphin is secreted in response to pain. Thus GH may be a useful marker of surgical stress.

Adolescent↗
PubMed1997

[Cushing syndrome disclosing bronchial neuroendocrine carcinoma: value of scintigraphy with octreotide].

A 44-year-old man presenting with atypical maniac behavior and hypokaliemia was diagnosed with Cushing's syndrome and treated in emergency by bilateral adrenalectomy. Endocrine investigations were suggestive of an ectopic adrenocorticotropic (ACTH) secretion, both at baseline (mean ACTH levels = 215 pg/mL, beta-lipotropic hormone = 2329 pg/mL; molar ratio > 5) and after pharmacodynamic testing (lack of inhibition of ACTH by dexamethasone, blunted ACTH response to corticotropin releasing hormone). Ectopic ACTH secretion was investigated while pituitary ACTH secretion was suppressed by dexamethasone. A paradoxical rise of ACTH from 384 to 717 pg/mL was observed after subcutaneous administration of 500 micrograms octreotide. A right lung tumor that remained occult for 7 years was only revealed by octreotide scintigraphy, despite annual chest tomodensitometric examinations. Right inferior lung lobectomy allowed allowed for removal of a 13 mm tumor corresponding to a bronchial neuroendocrine carcinoma with positive immunostaining for ACTH. Mediastinal lymph nodes were histologically normal. Perioperative ACTH measurements, showing a more than 50% decrease from baseline at 15 minutes after tumor resection, were suggestive of complete tumor removal. This was confirmed 10 days postoperatively by undetectable ACTH levels and by a negative octreotide scintigraphy after surgery. This case report of an occult ACTH secreting bronchial neuroendocrine carcinoma illustrates the diagnostic value of octreotide scintigraphy, and the prognostic value of perioperative ACTH measurements in such cases.

ACTH Syndrome, Ectopic↗
PubMed1997

[Congenital multiple anterior pituitary hormone deficiencies. An approach of pituitary ontogenesis].

A number of transcription factors evidenced in the pituitary may play a part in the development of this gland, namely Pit-1, Prop-1, P-Lim, Ptx1, Rpx, Dax-1, SF-1. Several of these factors are involved in animal models of hypopituitarism, while up to now only Pit-1 gene alterations have been shown to be responsible for hypopituitarism in man. These factors are briefly presented, and current data on genetically determined uni- or multi-hormonal pituitary deficiencies are reviewed. In particular, data on combined somatotroph, lactotroph and thyrotroph deficiencies due to Pit-1 gene alterations are detailed. Analysis of phenotype-genotype relationships in this syndrome and in other pathological models of multiple pituitary hormone deficiencies will provide useful information on the complex sequence of events that contribute to the development of the pituitary gland and to differentiation and regulation of the different pituitary cell lines.

Animals↗
PubMed1996

[Prolactin-secreting adenoma].

Prolactinoma, a benign tumor originating from the lactotroph cells of the anterior pituitary, is responsible for signs and symptoms related to both hypersecretion of prolactin and tumor mass. Hyperprolactinemia frequently causes menstrual cycle disturbances, galactorrhea and infertility in women, sexual disorders in men. Microadenomas, characterized by a largest diameter less than 10 mm, may induce frontal headaches, and macroadenomas (more than 10 mm in diameter) may also impair visual function through chiasma compression. Treatment modalities include dopamine agonist therapy such as bromocriptine which allows normalization of prolactin levels, restoration of gonadal functions and tumor shrinkage in most cases. In microadenomas a definitive cure may be achieved by transsphenoidal total selective adenomectomy.

Bromocriptine↗
PubMed1996

A new mutation of the gene encoding the transcription factor Pit-1 is responsible for combined pituitary hormone deficiency.

The pituitary-specific transcription factor Pit-1/GHF1 regulates the expression of PRL, GH, and TSH beta genes through binding to specific regions of the promoters of these genes. Mutations of the Pit-1 gene have been shown to be responsible for a syndrome of combined pituitary hormone deficiency (CPHD), including complete GH and PRL deficiencies and central hypothyroidism. We studied four siblings presenting with CPHD born to healthy consanguinous parents. All four affected children had complete GH deficiency diagnosed in early childhood. They later developed hypothyroidism and were found to have undetectable PRL levels. The pituitary gland was hypoplastic at magnetic resonance examination in one of the patients. Amplification of genomic DNA and subsequent sequencing of the six exons of the Pit-1 gene allowed identification in the four patients with CPHD of an as yet undescribed mutation in exon 3. A substitution of T go G induced a change from a Phe to a Cys residue at position 135 within the hydrophobic core of the POU-specific DNA-binding domain of the Pit-1 protein. All affected children were homozygous for the mutation, whereas the mother was heterozygous, suggesting a recessive mode of inheritance. Molecular studies in other affected families will allow instructive genotype-phenotype correlations concerning the Pit-1 gene.

Adolescent↗
PubMed1996

Prolactinomas resistant to bromocriptine: long-term efficacy of quinagolide and outcome of pregnancy.

Resistance to bromocriptine, defined as the absence of normalization of prolactin (PRL) levels despite a 15-30 mg daily dose of bromocriptine during at least 6 months, has been observed in 5-17% of the prolactinomas according to the literature. The recent availability of a new potent dopamine agonist, quinagolide, prompted us to analyze its long-term therapeutic effects in 28 patients with prolactinomas resistant to bromocriptine. Before bromocriptine, their PRL levels were 520 +/- 185 micrograms/l (mean +/- SEM) and decreased to 291 +/- 154 micrograms/l after a 6-21 month period of bromocriptine treatment. All the women (N = 20) remained amenorrheic and hypogonadism was not improved in men (N = 8). Subsequently, after 1 year of 150-300 micrograms/day quinagolide, 12/28 patients of the present series recovered normal gonadal function and their initial mean baseline PRL value (404 +/- 180 micrograms/l) was 16 +/- 2 micrograms/l after 1 year of treatment. A significant tumor shrinkage was observed in 5/8 macroadenomas (62%). During the 3-year follow-up period under quinagolide, a similar good control was achieved in these patients, with the exception of one man presenting with a secondary rise of PRL under quinagolide. In contrast, 15 other patients (one patient interrupted quinagolide at 6 months because of poor tolerance) were not normalized under 150-450 micrograms/day quinagolide. Their initial PRL levels (606 +/- 298 micrograms/l) were reduced to 343 +/- 187 micrograms/l (versus 463 +/- 265 micrograms/l under bromocriptine after the same duration of treatment). Despite such a partial inhibitory effect of quinagolide, 7/12 women resumed menstrual cycles and three pregnancies occurred. In no case was any tumor shrinkage noticed during the 3-4-year follow-up. Three patients even presented, after 2 years of quinagolide treatment, with a secondary rise of PRL values associated with a further tumor growth in two patients. During the 3-year follow-up period, nine pregnancies occurred in seven women. In five women, after quinagolide withdrawal, the plasma PRL baseline values ranged from 52 to 158 micrograms/l and from 65 to 192 micrograms/l, respectively, at the first trimester and at the end of uneventful pregnancies. In contrast, in two women a rapid increase of PRL (240-400 micrograms/l) correlated with tumor growth during the first trimester. Such a tumor progression was blocked by quinagolide treatment but not by bromocriptine. These data, although observed in a limited series, justify the careful follow-up of pregnancies in this subclass of patients at risk. Finally, in the whole population, long-term control of hyperprolactinemia by quinagolide was obtained in 11/28 patients (39%) previously resistant to bromocriptine, and 15/20 women (75%) resumed normal gonadal function with a quinagolide daily dose of 300 micrograms in most of them.

Aminoquinolines↗
PubMed1996

Insulin-induced lipoatrophy in type I diabetes. A possible tumor necrosis factor-alpha-mediated dedifferentiation of adipocytes.

OBJECTIVE: To test the hypothesis that tumor necrosis factor (TNF)-alpha may mediate the loss and the dedifferentiation of subcutaneous fat tissue in the insulin-induced lipoatrophies of a diabetic patient who presented extensive lesions. RESEARCH DESIGN AND METHODS: An in vitro exploration of cytokine production by peripheral blood mononuclear cells (PBMC) from the reported case was performed and compared with the same explorations of PBMC from three nondiabetic subjects and three diabetic patients without lipoatrophic lesions. A proliferation test and an evaluation of TNF-alpha and interleukin (IL)-6 production from PBMC in presence of insulin were studied. RESULTS: The production of TNF-alpha and IL-6 by the macrophages of the patient in presence of insulin were dramatically increased in comparison with control subjects. This process needed cooperation with other lymphoid cells and was abrogated by dexamethasone. CONCLUSIONS: In our reported case, a local hyperproduction of TNF-alpha from macrophages that was induced by the injected insulin could explain the dedifferentiation of the adipocytes of the subcutaneous tissue and the reversion that was induced by the local injection of dexamethasone.

Adipocytes↗
PubMed1995

Glycosylated and non-glycosylated prolactin forms are increased after opioid administration as part of surgical anaesthesia.

OBJECTIVE: Previous studies have shown that non-glycosylated prolactin (NG-PRL) increased more markedly than glycosylated hormone (G-PRL) after TRH or metoclopramide stimulation. The aim of the present study was to determine whether such results could be extended to opioid-induced PRL stimulation. DESIGN: Open and prospective study. Using a newly developed IRMA specific for NG-PRL, we determined G-PRL and NG-PRL immunoreactivities after administration of 0.8-1.2 mg of the opioid drug phenoperidine as part of an anaesthesia. PATIENTS: Ten male patients anaesthetized for surgical treatment of a prolapsed lumbar intervertebral disc. MEASUREMENTS: Samples were obtained hourly pre and post-operatively, and every 15 minutes during operation for determination of plasma PRL, NG-PRL and G-PRL. Plasma cortisol, ACTH and GH levels were measured in an attempt to differentiate the respective roles of stress and opiate agonists in the variations of PRL levels during surgery. RESULTS: A dramatic increase in PRL levels was observed in all patients from an average of 300 +/- 90 to 1200 +/- 330 mU/l (mean + SEM) 30 minutes after drug administration. The proportion of G-PRL immunoreactivity was not significantly different when basal (25.2%) and stimulated (27%) values were compared (P > 0.05), and when mean increments of NG-PRL and G-PRL were compared (345 and 348%, respectively). The opioid drug induced a significant decrease in cortisol levels after injection and during operation (from 585 +/- 63 to 99 +/- 51 nmol/l) with a concomitant decrease in ACTH levels. GH levels were not significantly altered during anaesthesia but were significantly greater (P < 0.05) after than before surgery (5.0 +/- 1.3 vs 0.98 +/- 0.54 mU/l, respectively). CONCLUSIONS: We conclude from the present and from previous data that opioid induced anaesthesia is accompanied by an increase in both glycosylated and non-glycosylated PRL and that different PRL secretagogues may induce distinct responses in terms of PRL molecular forms.

Adult↗
PubMed1995

Pattern of prolactin diurnal secretion in normal humans: evidence for nonlinear dynamics.

Prolactin (PRL) circadian profiles were analyzed using methods of nonlinear dynamics, directly from the experimental data, by combining in a single time-series (432 measurements), six individual 24-hour PRL profiles (72 measurements per profile, sampling interval = 20 min), obtained from young healthy human volunteers (4 males, 2 females), under basal conditions. Significant autocorrelation exists between any given point of the time series and a limited number of its successors. Fourier analysis showed a dominant frequency of 1 cycle/24 h, without sub-24-hour harmonics. Poincaré section indicated the presence of a fractal attractor and a sketch of the attractor revealed a highly convoluted geometric structure with a conical contour. The box-counting dimension (D0), information dimension (D1) and correlation dimension (D2) of the attractor had low, fractal values, did not differ significantly from each other, and exhibited saturation at an embedding dimension of 2. The evidence taken together suggests that, under basal conditions, the daily changes in the peripheral blood levels of PRL are governed by nonlinear deterministic dynamics, with a dominant rhythm of 1 cycle/day mixed with a higher-frequency, low-amplitude signal.

Adult↗