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T Brue

Publications and source records attributed to T Brue.

At least 19 recordsLinked to original sources
PubMed2007

Gamma knife radiosurgery is a successful adjunctive treatment in Cushing's disease.

OBJECTIVE: Though transsphenoidal surgery remains the first-line treatment of Cushing's disease, recurrence occurs frequently. Conventional radiotherapy and anticortisolic drugs both have adverse effects. Stereotactic radiosurgery needs to be evaluated more precisely. The aim of this study was to determine long-term hormonal effects and tolerance of gamma knife (GK) radiosurgery in Cushing's disease. DESIGN: Forty patients with Cushing's disease treated by GK were prospectively studied over a decade, with a mean follow-up of 54.7 months. Eleven of them were treated with GK as a primary treatment. METHODS: Radiosurgery was performed at the Department of Functional Neurosurgery of Marseille, France, using the Leksell Gamma Unit B and C models. Median margin dose was 29.5 Gy. Patients were considered in remission if they had normalized 24-h free urinary cortisol and suppression of plasma cortisol after low-dose dexamethasone suppression test. RESULTS: Seventeen patients (42.5%) were in remission after a mean of 22 months (range 12-48 months). The two groups did not differ in terms of initial hormonal levels. Target volume was significantly higher in uncured than in remission group (909.8 vs 443 mm(3), P = 0.038). We found a significant difference between patients who were on or off anticortisolic drugs at the time of GK (20 vs 48% patients in remission respectively, P = 0.02). CONCLUSION: With 42% of patients in remission after a median follow-up of 54 months, GK stereotactic radiosurgery, especially as an adjunctive treatment to surgery, may represent an alternative to other therapeutic options in view of their adverse effects.

Adolescent↗
PubMed2006

Clinical characterization of familial isolated pituitary adenomas.

CONTEXT: Familial pituitary adenomas occur rarely in the absence of multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). OBJECTIVE: Our objective was to characterize the clinical and genealogical features of non-MEN1/CNC familial isolated pituitary adenomas (FIPA). DESIGN AND SETTING: We conducted a retrospective study of clinical and genealogical characteristics of FIPA cases and performed a comparison with a sporadic population at 22 university hospitals in Belgium, Italy, France, and The Netherlands. RESULTS: Sixty-four FIPA families including 138 affected individuals were identified [55 prolactinomas, 47 somatotropinomas, 28 nonsecreting adenomas (NS), and eight ACTH-secreting tumors]. Cases were MEN1/PRKAR1A-mutation negative. First-degree relationships predominated (75.6%) among affected individuals. A single tumor phenotype occurred in 30 families (homogeneous), and heterogeneous phenotypes occurred in 34 families. FIPA cases were younger at diagnosis than sporadic cases (P = 0.015); tumors were diagnosed earlier in the first vs. the second generation of multigenerational families. Macroadenomas were more frequent in heterogeneous vs. homogeneous FIPA families (P = 0.036). Prolactinomas from heterogeneous families were larger and had more frequent suprasellar extension (P = 0.004) than sporadic cases. Somatotropinomas occurred as isolated familial somatotropinoma cases and within heterogeneous FIPA families; isolated familial somatotropinoma cases represented 18% of FIPA cases and were younger at diagnosis than patients with sporadic somatotropinomas. Familial NS cases were younger at diagnosis (P = 0.03) and had more frequently invasive tumors (P = 0.024) than sporadic cases. CONCLUSIONS: Homogeneous and heterogeneous expression of prolactinomas, somatotropinomas, NS, and Cushing's disease can occur within families in the absence of MEN1/CNC. FIPA and sporadic cases have differing clinical characteristics. FIPA may represent a novel endocrine neoplasia classification that requires further genetic characterization.

Adenoma↗
PubMed2006

Pituitary deficiency after brain radiation therapy.

Brain radiotherapy is a frequent and overlooked cause of pituitary deficiency in adults which may alter patients' health and quality of life. Hormonal consequences have been better studied in children. The onset of hormonal deficiencies depends on the dose delivered to the pituitary-hypothalamic region while their incidence and severity depends on dose fractionating and follow-up duration. Somatotrophic function is the first affected, 90% of patients being GH deficient 10 years after radiotherapy. Other anterior pituitary functions are affected later and less frequently. While initial damage occurs in the hypothalamus, accounting for mild hyperprolactinemia in 30-50% of cases, diabetes insipidus is never observed. Direct pituitary deficiency may occur later. Responses to ACTH or GHRH-arginine tests may be normal for several years though an ACTH and/or GH deficiency has been demonstrated by an insulin tolerance test, which is considered as the gold standard. When the cranio-spinal area--including the neck--has been irradiated, primary thyroid deficiency might occur. Repeated cervical ultrasonographic follow-up is mandatory to exclude radiation-induced thyroid cancer. The gonadotrophic function might be altered after small doses of irradiation causing precocious puberty, while at higher doses delayed puberty or true gonadotrophic deficiencies are more often observed. Combined radio- and chemotherapy might result in mixed central and peripheral deficiencies that might be difficult to diagnose. When radiotherapy is performed in adulthood, GH deficiency is less common, although the sequence of hormonal deficiencies is similar to that observed in children. Prospective longitudinal studies are required to determine the time course and sequence of onset of each deficiency, in order to tailor the monitoring of these patients to their specific needs.

Adrenocorticotropic Hormone↗
PubMed2006

[KIMS observational study of GH therapy in GH-deficient adults: 12-month follow-up analysis of the French cohort].

KIMS study is an international, observational study initiated in 1994 in which France has been involved since 2003. Its aim is to collect on a widespread basis long-term data from GH-deficient adults treated or not treated with growth hormone in daily practice. Among 330 patients already enrolled by 128 centers in France at the data lock point for this first interim analysis, 122 patients were followed up for at least 12 months and their results are presented herein. After one year of treatment, IGF-1 level adjusted for age and sex was normalized for 77% of patients naive of GH-treatment, 71% of semi-naive patients and 85% of non naive patients. Lean mass increase was 5.1% and fat mass decrease 5.7%. Quality of life assessed through QoL-AGHDA questionnaire was improved with a median score decrease from 10 to 6. These are the first results available from French patients and suggest that growth hormone is an appropriate indication for adults with severe GH deficiency.

Adult↗
PubMed2006

Pituitary transcription factors: from congenital deficiencies to gene therapy.

Despite the existence of interspecies phenotypic variability, animal models have yielded valuable insights into human pituitary diseases. Studies on Snell and Jackson mice known to have growth hormone, prolactin and thyroid-stimulating hormone deficiencies involving the hypoplastic pituitary gland have led to identifying alterations of the pituitary specific POU homeodomain Pit-1 transcription factor gene. The human phenotype associated with rare mutations in this gene was found to be similar to that of these mice mutants. Terminal differentiation of lactotroph cells and direct regulation of the prolactin gene both require interactions between Pit-1 and cell type specific partners, including panpituitary transcriptional regulators such as Pitx1 and Pitx2. Synergistic activation of the prolactin promoter by Pitx factors and Pit-1 is involved not only in basal condition, but also in responsiveness to forskolin, thyrotrophin-releasing-hormone and epidermal growth factor. In corticotroph cells, Pitx1 interacts with Tpit. Tpit mutations have turned out to be the main molecular cause of neonatal isolated adrenocorticotrophin deficiency. This finding supports the idea that Tpit plays an essential role in the differentiation of the pro-opiomelanocortin pituitary lineage. The effects of Pit-1 are not restricted to hormone gene regulation because this factor also contributes to cell division and protects the cell from programmed cell death. Lentiviral vectors expressing a Pit-1 dominant negative mutant induced time- and dose-dependent cell death in somatotroph and lactotroph adenomas in vitro. Gene transfer by lentiviral vectors should provide a promising step towards developing an efficient specific therapeutic approach by which a gene therapy programme for treating human pituitary adenomas could be based.

Animals↗
PubMed2004

Gamma knife surgery for epilepsy related to hypothalamic hamartomas.

OBJECTIVE: Drug resistant epilepsy associated with hypothalamic hamartoma (HH) can be cured by microsurgical resection of the lesion. Morbidity and mortality risks of microsurgery in this area are significant. Gamma Knife Surgery's (GKS) reduced invasivity seems to be well adapted. In view of the severity of the disease and risks of surgical resection it is crucial to evaluate GKS for this indication. A first retrospective study has shown a very good safety and efficacy level but for a more reliable evaluation a prospective study would be required. METHODS: Between Oct 1999 and July 2002, 30 patients with HH and associated severe epilepsy were included. Seizure semiology (video EEG) and frequency, behavioural disturbances, neuropsychological performance, endocrinological status, sleep electroclinical abnormalities, MR imaging, and visual function were systematically evaluated before and after GKS (6, 12, 18, 24, 36 months). Twenty patients had experienced precocious puberty at a median age of 3,7 (0-9). Range of maximum diameter was from 7,5 to 23 mm with only 3 larger than 18 mm. The median marginal dose was 17 gy (14-20). RESULTS: Sufficient follow up for final evaluation is not yet available. Only 6 patients have a follow-up of more than 12 months and 19 more than 6 months. However a lot of very dramatic changes did occur during that period in this group. Among the 19 patients with more than 6 months of follow-up, a lot had already experienced an increase of gelastic seizures around 3 months (3), an improvement in their seizure rate (18), behaviour (9), sleep (3), and EEG background activity (3), a cessation of partial complex seizures (7). No complications have occurred till now except one patient experiencing at 5 months a hyperthermia without infection and concomitant increase of gelastic seizures both ceasing suddenly and spontaneously after 15 days. CONCLUSION: Our first results indicate that GKS is as effective as microsurgical resection and very much safer. GKS also allows to avoid the vascular risk related to radiofrequency lesioning or stimulation. The disadvantage of radiosurgery is its delayed action. Longer follow-up is mandatory for a serious evaluation of the role of GKS. Results are faster and more complete in patients with smaller lesions inside the 3rd ventricle (grade II). The early effect on subclinical discharges turns out to play a major role in the dramatic improvement of sleep quality, behaviour, developmental acceleration at school.

Adolescent↗
PubMed2004

Pituitary hormone deficiencies due to transcription factor gene alterations.

Mechanisms that control pituitary development are gradually better understood. They involve molecular signals from surrounding structures and the expression of a cascade of homeodomain transcription factors. Mutations of these transcription factors cause defects of embryologic development of the anterior pituitary responsible for isolated or multiple pituitary hormone deficiencies (respectively, IPHD and MPHD) in both rodents and humans. In this review we emphasize the description of human phenotypes associated with genetic alterations found in IPHD (e.g. isolated corticotroph deficiency and Tpit mutations) and MPHD (mutations of POU1F1, PROP1, Hesx1, Lhx3, Lhx4, Ptx2).

Cell Differentiation↗
PubMed2002

Pseudotumor of the pituitary due to PROP-1 deletion.

Hypopituitarism associated with pituitary mass in childhood is most frequently the consequence of craniopharyngioma or Rathke's cleft cyst. We report a patient with an intrasellar pseudotumor associated with hypopituitarism, which led us to a misdiagnosis of intrasellar craniopharyngioma. After spontaneous involution of the mass, diagnosis was revised. DNA analysis showed a deletion in the Prophet of Pit-1 (PROP-1) gene, a pituitary transcription factor. It is important to recognize that a PROP-1 deletion can cause pituitary pseudotumor that can be mistaken for a craniopharyngioma or Rathke's pouch cyst.

Child↗
PubMed2001

A pituitary cell-restricted T box factor, Tpit, activates POMC transcription in cooperation with Pitx homeoproteins.

The pituitary gland has provided unique insight into molecular mechanisms and regulatory factors controlling both differentiation and gene transcription. We identified Tpit, a novel T box factor only present in the two pituitary POMC-expressing lineages, the corticotrophs and melanotrophs, and apparently in no other tissue, including hypothalamic POMC neurons. In pituitary cells, Tpit activation of POMC gene transcription requires cooperation with Pitx1, the two factors binding to contiguous sites within the same regulatory element. In gain-of-function experiments, Tpit induces POMC expression in undifferentiated pituitary cells, indicating that it can initiate differentiation into POMC-expressing lineages. TPIT gene mutations were found in patients with isolated deficiency of pituitary POMC-derived ACTH, in support of an essential role of Tpit for differentiation of the pituitary POMC lineage.

Adrenocorticotropic Hormone↗
PubMed2001

PROP1 gene screening in patients with multiple pituitary hormone deficiency reveals two sites of hypermutability and a high incidence of corticotroph deficiency.

Alterations of the gene encoding the pituitary transcription factor PROP1 were associated with congenital forms of multiple pituitary hormone deficiencies in several families. Among 23 patients with multiple pituitary hormone deficiencies screened for a PROP1 gene abnormality, nine belonging to eight unrelated families had homozygous PROP1 gene defects. All mutations were located in exon 2 and affected only two different sites: a homozygous AG deletion at codons 99/100/101 (n = 5); homozygous point mutations affecting codon 73: R73C (n = 2) or R73H (n = 1), and a R73C/R99X double-heterozygous mutation (n = 1). R73H and R99X were never described. All patients were born to unaffected parents, and consanguinity was documented in two patients. They had complete GH, LH-FSH, and TSH deficiencies and normal basal levels of PRL. Delayed ACTH deficiency was diagnosed in four of nine patients. At magnetic resonance imaging the anterior pituitary was hypoplastic in seven patients and hyperplastic in two. This study found two novel mutations (R73H and R99X) and underlines the high incidence of PROP1 gene alterations in patients with multiple pituitary hormone deficiencies. A corticotroph deficiency was frequently observed in association with GH, TSH, and gonadotropin deficiencies and should be carefully sought during follow-up.

Adolescent↗
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↗