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P Jaquet

Publications and source records attributed to P Jaquet.

At least 19 recordsLinked to original sources
PubMed2002

Demonstration of enhanced potency of a chimeric somatostatin-dopamine molecule, BIM-23A387, in suppressing growth hormone and prolactin secretion from human pituitary somatotroph adenoma cells.

In acromegaly, the combination of somatostatin (SS) and dopamine (DA) agonists has been shown to enhance suppression of GH secretion. In the present study, a new chimeric molecule, BIM-23A387, which selectively binds to the SS subtype 2 receptor (sst(2); K(i) = 0.10 nM) and to the DA D2 receptor (D2DR; K(i) = 22.1 nM) was tested in cultures prepared from 11 human GH-secreting tumors for its ability to suppress GH and prolactin (PRL) secretion. The chimeric compound was compared with individual sst(2) and D2DR agonists of comparable activity at the individual receptors. All tumors expressed both sst(2) and D2DR mRNAs (0.8 +/- 0.2 and 4.7 +/- 0.7 copy/copy beta-glucuronidase mRNA, respectively). In cell cultures from seven octreotide-sensitive tumors, the maximal inhibition of GH release induced by the individual sst(2) and D2DR analogs and by BIM-23A387 was similar. However, the mean EC(50) for GH suppression by BIM-23A387 (0.2 pM) was 50 times lower than that of the individual sst(2) and D2DR analogs, either used individually or combined. Similar data were obtained in four tumors that were only partially responsive to octreotide. The inhibition of GH release by BIM-23A387 was only partially reversed by the D2R2 antagonist, sulpiride, or by the sst(2) antagonist, BIM-23454. Only when both antagonists were combined was the GH suppressive effect of BIM-23A387 totally reversed. Finally, BIM-23A387 produced a mean 73 +/- 6% inhibition of PRL in six mixed GH plus PRL tumors. These data demonstrate an enhanced potency of the chimeric molecule, BIM-23A387, in suppressing GH and PRL secretion from acromegalic tumors, which cannot be explained merely on the basis of binding affinity for SS and/or DA receptors.

Adenoma↗
PubMed2001

Bim-23244, a somatostatin receptor subtype 2- and 5-selective analog with enhanced efficacy in suppressing growth hormone (GH) from octreotide-resistant human GH-secreting adenomas.

Although both somatostatin receptor subtype 2 (SSTR2) and SSTR5 messenger ribonucleic acid (mRNA) are consistently expressed in GH-secreting adenomas, SSTR2 has been believed to be the key modulator of somatostatin-mediated inhibition of GH release. The somatostatin agonists currently in clinical use, octreotide and lanreotide, are directed mainly to SSTR2 (IC(50) 12- to 18-fold higher than for SSTR5). Recently, however, it was demonstrated that an SSTR5 preferential agonist, BIM-23268, not only suppressed PRL release from prolactinomas and mixed GH-PRL adenomas, but also inhibited GH release in about half of GH adenomas. In addition, the SSTR5-preferring analog showed a slight additive effect when used in combination with SSTR2 preferential drugs at submaximal concentrations in octreotide partially sensitive adenomas. In the present study we quantified SSTR2 and SSTR5 mRNA expression and the GH-suppressive effects of somatostatin-14; octreotide; a SSTR2-preferential compound, BIM-23197; a SSTR5-preferential compound, BIM-23268; and a new SSTR2- and SSTR5-bispecific compound, BIM-23244, in GH-secreting tumors classified as either full responders to octreotide (n = 5) or partially sensitive to octreotide (n = 5). The octreotide-sensitive GH secretory adenomas presented with a high level of both SSTR2 and SSTR5 mRNA expression [222 +/- 61 and 327 +/- 136 pg/pg glyceraldehyde-3-phosphate dehydrogenase (GAPDH), respectively]. In these tumors the suppression of GH release was similarly achieved at picomolar ranges by octreotide, BIM-23197, and BIM-23244 (EC(50) = 25 +/- 15, 3 +/- 2, and 3 +/- 3 pmol/L, respectively). The compounds preferential for only SSTR5 were unable to inhibit GH release in such tumors. Among the octreotide partially responsive tumors, SSTR2 mRNA expression was 9-fold lower than in the octreotide-sensitive tumors (25 +/- 12 vs. 222 +/- 61 pg/pg GAPDH; P < 0.015), whereas SSTR5 mRNA expression was approximately 7-fold higher than in the octreotide-sensitive tumors (2271 +/- 1197 pg/pg GAPDH). In these octreotide partially responsive tumors, the SSTR5-preferential compound, BIM-23268, and the SSTR2- and SSTR5-bispecific compound, BIM-23244, were quite effective in suppressing GH secretion (EC(50) = 25 +/- 13 and 50 +/- 31 pmol/L, respectively). Similarly, BIM-23244, was able to suppress by 51 +/- 5% PRL release from five mixed GH- and PRL-secreting adenomas. These data indicate that due to heterogeneous expression of SSTR2 and SSTR5 receptor subtypes, in GH-secreting tumors, a bispecific analog, such as BIM-23244, that can activate both receptors could achieve better control of GH hypersecretion in a larger number of acromegalic patients.

Acromegaly↗
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

A luteinizing hormone-, alpha-subunit- and prolactin-secreting pituitary adenoma responsive to somatostatin analogs: in vivo and in vitro studies.

OBJECTIVE: Evaluation of the efficiency of somatostatin analogues in the treatment of a mixed luteinizing hormone (LH)-, alpha-subunit-, prolactin (PRL)-secreting pituitary adenoma. DESIGN: A 30-year-old woman, with amenorrhaea-galactorrhaea, presented with a pituitary macroadenoma. The endocrine evaluation showed high plasma levels of PRL, LH, and alpha-subunit inhibited by 65%, 65% and 33% respectively under octreotide test (200 microg, s.c.). Long-term treatment with slow release (SR) lanreotide (30 mg/10 days, i.m.) restored menstrual cycles and normalized PRL values. Due to persisting supranormal levels of LH and alpha-subunit, and to the absence of tumoral shrinkage, the adenoma was resected by the transsphenoidal route. METHODS: In vitro characterization of the somatostatin receptor subtypes (SSTR) expression and functionality. Real-time polymerase chain reaction was performed to quantify the expression of SSTR mRNAs and functionality of the SSTRs was assessed in cell culture studies with various concentrations of native somatostatin (SRIF-14) and of analogues preferential for SSTR2 or SSTR5. RESULTS: This adenoma presented with high levels of SSTR2, SSTR3 and SSTR5 mRNAs, as compared with a series of gonadotroph adenomas. In cell culture studies, PRL, LH and alpha-subunit were inhibited by 60%, 47% and 33% respectively by SRIF-14 at a concentration of 10 nmol/l. The SSTR2 (BIM-23197, lanreotide) and SSTR5 (BIM-23268) preferential analogues both produced a partial 21-38% inhibition of PRL, LH, and alpha-subunit release. DISCUSSION: In this plurihormonal-secreting adenoma, the high efficacy of somatostatin analogues to inhibit PRL, LH and alpha-subunit secretion in vivo may be explained by the unusually high level of expression and by the functionality of both SSTR2 and SSTR5 receptor subtypes.

Adult↗
PubMed2000

Human somatostatin receptor subtypes in acromegaly: distinct patterns of messenger ribonucleic acid expression and hormone suppression identify different tumoral phenotypes.

Recently, studies using somatostatin (SRIF) analogs preferential for either the SRIF receptor 2 (SSTR2) or the SSTR5 subtype demonstrated a variable suppression of GH and PRL release from GH-secreting human adenomas. These data suggested the concept of SSTR subtype specificity in such tumors. In the present study the quantitative expression of messenger ribonucleic acid (mRNA) for the 5 SSTR subtypes and the inhibitory effects of SRIF14; SRIF28; octreotide; the SSTR2-preferential analog, BIM-23197; and the SSTR5-preferential analog, BIM-23268, on GH and PRL secretion were analyzed in cells cultured from 15 acromegalic tumors. RT-PCR analysis revealed a consistent pattern of SSTR2 and SSTR5 mRNA expression. SSTR5 mRNA was expressed at a higher level (1052 +/- 405 pg/pg glyceraldehyde-3-phosphate dehydrogenase) than SSTR2 mRNA (100 +/- 30 pg/pg glyceraldehyde-3-phosphate dehydrogenase). However, only SSTR2 mRNA expression correlated with the degree of GH inhibition induced by SRIF14, SRIF28, and BIM-23197. The SSTR5-preferential compound inhibited GH release in only 7 of 15 cases. In cells cultured from the 10 mixed adenomas that secreted both GH and PRL, RT-PCR analysis revealed a consistent coexpression of SSTR5, SSTR2, and SSTR1 mRNA. In all cases SRIF14, SRIF28, and the SSTR5-preferential analog, BIM-23268, significantly suppressed PRL secretion, with a mean maximal inhibition of 48 +/- 4%. In contrast, the SSTR2-preferential analogs, BIM-23197 and octreotide, were effective in suppressing PRL in only 6 of 10 cases. In cells cultured from adenomas taken from patients partially responsive to the SRIF analog, octreotide, partial additivity in suppressing both GH and PRL secretion was observed when the SSTR2- and SSTR5-preferring analogs, BIM-23197 and BIM-23268, were tested in combination. Our data show a highly variable ratio of the SSTR2 and SSTR5 transcripts, according to tumors. The SSTR2-preferring compound consistently inhibits GH release, whereas the SSTR5-preferring compound is the main inhibitor of PRL secretion. When both drugs are combined, the partial additivity observed in mixed GH- plus PRL-secreting adenomas may be of interest in the therapeutic approach of such tumors.

Acromegaly↗
PubMed2000

Variable growth hormone profiles following withdrawal of long-term 30mg slow-release lanreotide treatment in acromegalic patients: clinical implications.

OBJECTIVE: Intramuscular injections of 30mg slow-release (SR) lanreotide (every 10 to 14 days) are an effective treatment in acromegalic patients. Because of an ongoing need to assess the efficacy and the tolerance of a new formulation of a depot preparation of lanreotide, we have evaluated prospectively GH profiles following withdrawal of 30mg slow-release lanreotide in a cohort of acromegalic patients. PATIENTS: Fifty-one acromegalic patients, controlled during long-term 30mg SR lanreotide treatment (GH: 1.44 +/- 0.64 microgram/l, IGF-I: 316 +/- 145ng/ml) (mean +/- s.d.), were studied following the withdrawal of the drug. MEASUREMENTS: Mean GH (half-hour samples, 0800-1200h), IGF-I and lanreotide levels were evaluated 14, 28, and 42 days following the last 30mg SR lanreotide injection. RESULTS: Mean GH levels remained below 2.5 microgram/l in 32 patients (group 1) twenty-eight days following SR lanreotide withdrawal. In these patients, mean GH and IGF-I levels had increased from 1.2 +/- 0.6 to 1.7 +/- 0.5 microgram/l (P < 0001), and from 283 +/- 138 to 359 +/- 168ng/ml (P < 0.001) respectively. In the 19 other patients (group 2), mean GH concentrations had risen above 2.5 microgram/l at 28 days following SR lanreotide withdrawal. Mean GH and IGF-I levels had increased from 1.9 +/- 0.4 to 5.1 +/- 2.8 microgram/l (P < 0.001), and from 371 +/- 143 to 568 +/- 206ng/ml (P < 0.001) respectively. Patients of groups 1 and 2 were comparable with regard to age, sex, tumoral status, mean GH levels before somatostatin analogue treatment, and previous treatments such as radiotherapy and duration of somatostatin analogue therapy, but 75% of group 1 patients underwent surgery compared with 37% of group 2 patients (P < 0.01). Twenty-eight days following SR lanreotide withdrawal, mean lanreotide levels in group 1 and group 2 had decreased from 1.6 +/- 0.7 to 0.6 +/- 0.3ng/ml (P < 0.001), and from 2.7 +/- 2.0 to 0.7 +/- 0.7ng/ml (P < 0.001) respectively. A negative correlation was observed between the lanreotide levels and GH and IGF-I concentrations in the two groups of patients, but the inhibition of GH/IGF-I concentrations by lanreotide levels was higher in group 1 patients than in those of group 2. Six patients of group 1 were treated with 30mg SR lanreotide injected at monthly intervals. During monthly follow-up, mean GH levels increased above 2.5 microgram/l in 2 patients. After 12 months follow-up, mean GH and IGF-I levels from 4 other patients were similar to those obtained with previous therapeutic sequence (i.e. intramuscular injections every 14 days). CONCLUSION: The degree of responsiveness to lanreotide and the duration of somatotroph suppression following lanreotide withdrawal are variable in acromegalic patients controlled during long-term 30mg SR lanreotide treatment. In patients displaying high sensitivity to lanreotide, the interval between i.m. 30mg SR lanreotide injections can be increased to one month, thus reducing the cost of the therapy, without altering its efficacy upon GH/IGF-I control.

Acromegaly↗
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↗
PubMed1999

Expression of functional growth hormone secretagogue receptors in human pituitary adenomas: polymerase chain reaction, triple in-situ hybridization and cell culture studies.

We examined the expression of functional growth hormone secretagogue receptors (GHS-R) in a series of 30 human pituitary adenomas-six secreting GH, three GH-PRL, six prolactin (PRL), five adrenocorticotrophic hormone (ACTH), one thyroid stimulating hormone (TSH), four gonadotroph and five non-secreting adenomas. By reverse transcriptase polymerase chain reaction (RT-PCR), the coexpression of the two GHS-R isoforms (Ia and Ib) was found in all the GH-, GH-PRL- and PRL-secreting adenomas, and only in two out of three corticotroph, two out of four gonadotroph and one out of five non-secreting tumours. They were absent in the TSH-secreting adenoma. The PCR products of GHS-R Ia and Ib were identical in size to those from two normal pituitaries. PCR cloning and sequencing of isoforms performed in two somatotroph adenomas revealed only two single, silent base mutations. Triple in-situ hybridization showed colocalization of GHS-R mRNA with messengers of GH and PRL, conjointly or separately, in individual cells of somatotroph, mammosomatotroph, and lactotroph adenomas. The presence of GHS-R mRNA in cells expressing PRL mRNA is emphasized. In cultured cells from six somatotroph and two mammosomatotroph adenomas, the powerful GHS MK-0677 stimulated GH release in a dose-dependent manner, with maximal effect at 6 h. Contrarily, when GHRH was applied, only three somatotrophs and two mamosomatotrophs were stimulated. In the two mammosomatotrophs, the PRL response to MK-0677 and to GHRH was similar to the GH response. An homologous desensitization of the GHS-R and the GHRH receptor was observed 24 h after a first stimulation by a single dose of the corresponding agonist. Heterologous desensitization was not observed. Interestingly, MK-0677 also stimulated, in a dose-dependent way, the hormone release of cells from all tested lactotroph and corticotroph adenomas. The existence of a functional expression of GHS-R in somatotroph, mammosomatotroph, lactotroph and corticotroph adenomas rises the question of the role played by GHS-R in pituitary adenomas, particularly those not engaged in GH secretion.

Adenoma↗
PubMed1999

Expression of the members of the Ptx family of transcription factors in human pituitary adenomas.

A number of putative transcription factors described in the pituitary have been implicated as key elements in the processes that direct pituitary development. Three recently described proteins, Ptx1, Ptx2, and Ptx3, define a new family of transcription factors, the Ptx subfamily, within the paired-like class of homeodomain factors. In mice, Ptx1 and Ptx2 gene expression has been detected in the area of the pituitary primordium and is maintained throughout development in Rathke pouch and adult pituitary. In the present study, the expression of the Ptx1, Ptx2, and Ptx3 genes was characterized in the normal human pituitary and in the different types of human pituitary adenomas. Although no Ptx3 gene expression could be detected in these tissues, Ptx1 presented with a quite ubiquitous pattern of distribution, being expressed at quite constant levels in normal tissues and in all 60 pituitary tumors analyzed. The pattern of expression of the Ptx2 gene among the different subsets of pituitary adenomas was even more varied. No Ptx2 expression could be detected in corticotroph tumors. In contrast, high levels of Ptx2 messenger ribonucleic acid were measured in the gonadotroph tumors, although no specific correlation to other markers of the gonadotroph lineage differentiation, such as alphaGsu, LHbeta, or FSHbeta, could be evidenced. Finally, Ptx2 was also expressed in pure lactotroph adenomas and not in somatotroph adenomas. Ptx2 is, therefore, the first paired homeodomain pituitary transcription factor differentially expressed in these two lineages, which derive from a common precursor. These results support a role for Ptx2 in the terminal differentiation of somatotroph and lactotroph cell phenotypes.

Adenoma↗
PubMed1999

Impact of gsp oncogene on the expression of genes coding for Gsalpha, Pit-1, Gi2alpha, and somatostatin receptor 2 in human somatotroph adenomas: involvement in octreotide sensitivity.

The impact of the gsp oncogene on the expression of genes engaged in the somatotroph cell phenotype remains poorly understood in human somatotroph adenomas. As the gsp oncogene is associated with an increased octreotide (somatostatin agonist) sensitivity, a group of 8 somatotroph adenomas bearing the gsp mutation (gsp+) and another group of 16 adenomas without the mutation (gsp-) were analyzed, all of them presenting variable octreotide sensitivities. The expressions of genes encoding for G(s)alpha, Pit-1, G(i2)alpha, and SSTR2, involved in the regulation of secretory activity in somatotroph cells, were assessed by Northern blot. A decreased expression of the G(s)alpha gene was found in gsp + tumors, suggesting the existence of a negative feedback of the oncogenic protein upon its own messenger ribonucleic acid (mRNA). In contrast, G(i2)alpha, Pit-1, and GH messengers were not significantly different in the groups. A positive correlation between the in vitro and in vivo GH octreotide-induced secretory inhibition and the expression of SSTR2 mRNA was found. However, the expression of the gene for SSTR2 appeared not to be different between gsp + and gsp-, even when the octreotide sensitivity was significantly higher in the adenomas carrying the mutation. Interestingly, the SSTR2 gene expression was significantly correlated to those of G(i2)alpha and Pit-1. In the same way, the G(s)alpha mRNA expression was positively correlated with those of Gi2alpha and Pit-1. Such correlations strongly suggest a concerted dysregulation of the expression of these genes in both categories of adenomas. The loss of the octreotide sensitivity represents one aspect of the dysregulation process that partially results from the decreased SSTR2 expression. However, the improvement of the sensitivity associated with the presence of the gsp oncogene seems to proceed in a way different from SSTR2 expression.

Adenoma↗
PubMed1999

Quantitative and functional expression of somatostatin receptor subtypes in human prolactinomas.

Recently, it was demonstrated that somatostatin analogs preferential for the SSTR5 subtype suppress PRL release from prolactinoma cell cultures by 30-40%. These data supported the idea of somatostatin receptor subtype-specific control of PRL secretion in such tumors. The present study examines the quantitative profile of SSTRs messenger ribonucleic acid (mRNA) in 10 PRL-secreting tumors and correlates the expression with the ability of native somatostatins (SS14 and SS28), SSTR2 preferential analogs (octreotide and BIM-23197), and the SSTR5 preferential analog BIM-23268 to suppress PRL secretion. RT-PCR quantitative analysis showed a large predominance of SSTR5 mRNA [5648 +/- 1918 pg/pg glyceraldehyde-3-phosphate dehydrogenase (GAPDH)] vs. SSTR2 mRNA (148 +/- 83 pg/pg GAPDH). The SSTR1 transcript was also highly expressed in prolactinomas (1296 +/- 669 pg/pg GAPDH). SSTR5 mRNA expression correlated with PRL inhibition induced by both SRIF14 and SRIF28. Among the different analogs tested, only BIM-23268 produced inhibition of PRL release similar to that achieved with the native peptides. Its EC50 for PRL suppression was 0.28 +/- 0.10 nmol/L. No additive effects on PRL suppression were achieved by cotreatment of the tumor cells with SSTR2 and SSTR5 preferential analogs. In the same tumor cell cultures, quinagolide, a potent dopamine agonist, produced a dose-dependent inhibition of PRL with an EC50 at least 10 times lower than that of BIM-23268. Coincubation of quinagolide and BIM-23268, particularly in tumor cells resistant to dopamine agonist treatment, did not produce additive effects on PRL suppression. In conclusion, prolactinomas have a specific pattern of SSTR subtype mRNA expression (SSTR5 and SSTR1). SSTR5 expression is correlated to PRL regulation. These inhibitory effects are superimposable, at a higher concentration, to those of the dopamine agonists, but are not additive, particularly in the adenomas resistant to dopaminergic suppression of PRL release.

Adult↗
PubMed1999

GH deficiency in adults: an epidemiological approach.

OBJECTIVE: The prevalence of adult onset GH deficiency (GH-D) is poorly documented. Epidemiological data are now required to estimate the financial cost of GH treatment in adults. The aim of the present study was to estimate the prevalence of GH-D, from a cohort of 1652 adult patients with hypothalamo-pituitary diseases. DESIGN: The hormonal status of all patients presenting with pituitary diseaseand observed during the year 1994 in 15 endocrine units was retrospectively analyzed, irrespective of the date of disease onset, of the nature and date of pituitary investigations, and whether or not they included specific testing of the GH axis. Of the whole population of 1652 patients, a selected group (RG2) was chosen after exclusion of patients with active acromegaly (n=1414). RESULTS: GH stimulation tests had been performed in 549 patients of the RG2 group and a documented GH-D was found in 301. A relationship between the value of the GH peak and the number of pituitary deficits was evaluated. For instance, it was shown that 93% of patients with three deficits had GH-D. These results constituted the basis for estimating the number of GH-D in the group of untested patients. The number of GH-D deduced from the number of established GH-D (n=301) and from the number of GH-D hypothesized from other pituitary deficits (n=406) was 707 cases. Prevalence and annual incidence were calculated from data recorded in a referral center with a well-defined catchment area, Marseilles (Bouches du Rhône department). We projected a prevalence of 2638 for France and an annual incidence of 12 GH-D per million of the adult population.

Adult↗
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

[Evaluation of an immunoradiometric assay for succinylated ACTH].

A new immunoradiometric assay for succinylated ACTH using 3 monoclonal antibodies has been developed by Immunotech (I-IRMA). It was compared to a commercial immunoradiometric assay of ACTH (Nichols Institute, N-IRMA). The functional sensitivity of I-IRMA assay was estimated at 1.5 ng/L. The comparison of both methods on plasma samples withdrawn at 8 h from 47 normal subjects showed a good correlation coefficient (r = 0.83; P < 0.001). The 24-hours secretion profiles obtained by both methods were similar in 14 normal subjects. Nevertheless, the I-IRMA mean values were about 30% lower than the corresponding N-IRMA values. This difference increased to 50% when the ACTH concentrations were low, as it the case at 24 h or during the dexamethasone suppression test. During insulin hypoglycemia stimulation test, the two procedures gave similar values. Both methods applied to a pathologic population gave similar result to those obtained on normals. In 10 patients bearing corticotroph adenomas, the profiles of ACTH secretions during 24 h were similar using both methods. The I-IRMA values were lower about 30% than N-IRMA values during the base state or after the 8 mg-dexamethasone suppression test. This difference was also observed in 6 patients with corticotroph insufficiency. In conclusion, the comparison of N-IRMA and I-IRMA methods showed the validity of the new succinylated-ACTH assay which is more efficient in the lower range of ACTH concentration. This significant decrease in the sensitivity threshold may be useful in the establishment of the cure criteria in Cushing disease.

Adrenocorticotropic Hormone↗
PubMed1998

Gamma-knife surgery for secreting pituitary adenomas.

We report our preliminary results concerning 25 patients with secreting pituitary adenomas treated with stereotactic radiosurgery after partial transsphenoidal surgery and followed over a 6-36 month-period. Among the 15 acromegalic patients, a decrease of 65% in mean GH levels was achieved after 6 months and of 77% at 12 months after radiosurgery. Presently, only 3 patients (20%) are considered as in remission (mean GH and IGF1 level into the normal range). A decrease of 46% and 64% was observed at 6 and 12 months after radiosurgery in 4 patients with prolactinomas although no normalization of PRL levels occurred. Presently, 3/4 patients have individual PRL level slightly above the normal range. A normalization of Urinary Free Cortisol (UFC) was noticed in 4/6 (66%) patients with Cushing's disease within 6-12 months. No pituitary deficiency was noticed in this series with the exception of 4/25 patients (16%) who received subtotal or total pituitary irradiation for post-operative remnants of secreting adenomas poorly defined on MRI. One woman, who had undergone previously a conventional irradiation and presenting with a cavernous sinus adenoma reaching the optic nerve, developed an optic neuropathy. A second woman, with a cavernous sinus remnant, presented a cranial nerve palsy (VI) after the irradiation. We can conclude that radiosurgery using the Cobalt-60 Gamma-unit is, at least, as effective as conventional radiotherapy in the control of pituitary hormone hypersecretion from postoperative adenomas remnants with less adverse effects.

Acromegaly↗