RESUMO
Patients with Xq26.3 microduplication present with X-linked acrogigantism (X-LAG) syndrome, an early-childhood form of gigantism due to marked growth hormone (GH) hypersecretion from mixed GH-PRL adenomas and hyperplasia. The microduplication includes GPR101, which is upregulated in patients' tumor tissue. The GPR101 gene codes for an orphan G protein coupled receptor that is normally highly expressed in the hypothalamus. Our aim was to determine whether GPR101 loss of function mutations or deletions could be involved in patients with congenital isolated GH deficiency (GHD). Taking advantage of the cohort of patients from the GENHYPOPIT network, we studied 41 patients with unexplained isolated GHD. All patients had Sanger sequencing of the GPR101 gene and array comparative genome hybridization (aCGH) to look for deletions. Functional studies (cell culture with GH secretion measurements, cAMP response) were performed. One novel GPR101 variant, c.589 G>T (p.V197L), was seen in the heterozygous state in a patient with isolated GHD. In silico analysis suggested that this variant could be deleterious. Functional studies did not show any significant difference in comparison with wild type for GH secretion and cAMP response. No truncating, frameshift, or small insertion-deletion (indel) GPR101 mutations were seen in the 41 patients. No deletion or other copy number variation at chromosome Xq26.3 was found on aCGH. We found a novel GPR101 variant of unknown significance, in a patient with isolated GH deficiency. Our study did not identify GPR101 abnormalities as a frequent cause of GH deficiency.
Assuntos
Nanismo Hipofisário/congênito , Nanismo Hipofisário/genética , Mutação/genética , Receptores Acoplados a Proteínas G/genética , Sequência de Aminoácidos , Criança , Estudos de Coortes , Simulação por Computador , Feminino , Humanos , Masculino , Receptores Acoplados a Proteínas G/química , Alinhamento de SequênciaRESUMO
Over the last two decades, the understanding of the mechanisms involved in pituitary ontogenesis has largely increased. Since the first description of POU1F1 human mutations responsible for a well-defined phenotype without extra-pituitary malformation, several other genetic defects of transcription factors have been reported with variable degrees of phenotype-genotype correlations. However, to date, despite the identification of an increased number of genetic causes of isolated or multiple pituitary deficiencies, the etiology of most (80-90 %) congenital cases of hypopituitarism remains unsolved. Identifying new etiologies is of importance as a post-natal diagnosis to better diagnose and treat the patients (delayed pituitary deficiencies, differential diagnosis of a pituitary mass on MRI, etc.), and as a prenatal diagnosis to decrease the risk of early death (undiagnosed corticotroph deficiency for instance). The aim of this review is to summarize the main etiologies and phenotypes of combined pituitary hormone deficiencies, associated or not with extra-pituitary anomalies, and to suggest how the identification of such etiologies could be improved in the near future.
Assuntos
Hipopituitarismo/diagnóstico , Hipopituitarismo/etiologia , Animais , Previsões , Humanos , Hipopituitarismo/genética , Mutação/genética , Fenótipo , Hipófise/crescimento & desenvolvimento , Hipófise/metabolismo , Hormônios Hipofisários/genética , Hormônios Hipofisários/metabolismoRESUMO
Short stature in children can be caused by congenital pituitary disorders involving at least one form of growth hormone deficiency. Clinical and radiological evaluations of the index case and family history assessments are essential to guide genetic diagnostic testing and interpret results. The first-line approach is panel testing of genes involved in pituitary development with variants known to be pathogenic in this context. It identifies a genetic cause in less than 10% of cases, however. Whole-exome and whole-genome sequencing techniques may provide original information but also raise new questions regarding the pathophysiological role of identified variants. These new tools can make genetic counselling more complex. The role of clinicians in these interpretations is therefore important. © 2022 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.
RESUMO
Lanreotide is an eight-amino acid peptide, which is an analog of the native somatostatin peptide, physiological inhibitor of growth hormone (GH). The drug shows high binding affinity for somatostatin receptors, SSTR2 and SSTR5, which is the primary mechanism considered to be responsible for decreasing GH secretion and GH cell proliferation in acromegaly. Two different formulations of lanreotide are currently available: lanreotide slow release, which requires intramuscular injection every 7-14 days, and lanreotide autogel, which requires deep subcutaneous injection every 4-8 weeks. Several studies have been published to date on the use of lanreotide in acromegaly. Antisecretory efficacy has been reported in 35%-70% of cases; this huge variability is probably explained by different indications (eg, primary or adjunctive postsurgical treatment), or the fact that some studies were based on patients known to be responders to somatostatin analogs. As a primary treatment, antisecretory efficacy was very similar, confirming the possibility of lanreotide as an option in cases of unsuccessful surgery, contraindication, or surgery refusal. Lanreotide also has antitumoral effects as it induces a decrease in tumor volume of [Symbol: see text]25% in 30%-70% of patients. This could be beneficial before transsphenoidal surgery, as a pretreatment, to decrease tumor volume and ease surgery; however, to date, advantages in terms of final remission or uncured status remain a matter of debate. Side effects are rare; the most frequent being gastrointestinal discomfort and increased risk of gallstone formation, and glucose metabolism modifications. Comparison with the other somatostatin analog, octreotide, tends to show identical levels of efficacy between both drugs. Lanreotide thus seems to be an effective treatment in acromegaly. To date, however, lanreotide is still considered as only suspending GH secretion, thus requiring prolonged and costly treatment.
Assuntos
Acromegalia/tratamento farmacológico , Peptídeos Cíclicos/uso terapêutico , Somatostatina/análogos & derivados , Antineoplásicos/uso terapêutico , Hormônio do Crescimento Humano/efeitos dos fármacos , Humanos , Peptídeos Cíclicos/efeitos adversos , Neoplasias Hipofisárias/tratamento farmacológico , Somatostatina/efeitos adversos , Somatostatina/uso terapêuticoRESUMO
CONTEXT: LHX4 is a LIM homeodomain transcription factor involved in pituitary ontogenesis. Only a few heterozygous LHX4 mutations have been reported to be responsible for congenital pituitary hormone deficiency. SUBJECTS AND METHODS: A total of 136 patients with congenital hypopituitarism associated with malformations of brain structures, pituitary stalk, or posterior pituitary gland was screened for LHX4 mutations. RESULTS: Three novel allelic variants that cause predicted changes in the protein sequence of LHX4 (2.3%) were found (p.Thr99fs, p.Thr90Met, and p.Gly370Ser). On the basis of functional studies, p.Thr99fs mutation was responsible for the patients' phenotype, whereas p.Thr90Met and p.Gly370Ser were likely polymorphisms. Patients bearing the heterozygous p.Thr99fs mutation had variable phenotypes: two brothers presented somato-lactotroph and thyrotroph deficiencies, with pituitary hypoplasia and poorly developed sella turcica; the youngest brother (propositus) also had corpus callosum hypoplasia and ectopic neurohypophysis; their father only had somatotroph deficiency and delayed puberty with pituitary hyperplasia. Functional studies showed that the mutation induced a complete loss of transcriptional activity on POU1F1 promoter and a lack of DNA binding. Cotransfection of p.Thr99fs mutant and wild-type LHX4 failed to evidence any dominant negative effect, suggesting a mechanism of haploinsufficiency. We also identified prolactin and GH promoters as potential target genes of LHX4 and found that the p.Thr99fs mutant was also unable to transactivate these promoters. CONCLUSIONS: The present report describes three new exonic LHX4 allelic variants with at least one being responsible for congenital hypopituitarism. It also extends the phenotypical heterogeneity associated with LHX4 mutations, which includes variable anterior pituitary hormone deficits, as well as pituitary and extrapituitary abnormalities.
Assuntos
Proteínas de Homeodomínio/genética , Hipopituitarismo/genética , Mutação , Fatores de Transcrição/genética , Adulto , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Genótipo , Humanos , Hipopituitarismo/congênito , Íntrons , Proteínas com Homeodomínio LIM , Masculino , Pessoa de Meia-Idade , Linhagem , FenótipoRESUMO
DEFINITION: Congenital hypopituitarism is characterized by multiple pituitary hormone deficiency, including somatotroph, thyrotroph, lactotroph, corticotroph or gonadotroph deficiencies, due to mutations of pituitary transcription factors involved in pituitary ontogenesis. INCIDENCE: Congenital hypopituitarism is rare compared with the high incidence of hypopituitarism induced by pituitary adenomas, transsphenoidal surgery or radiotherapy. The incidence of congenital hypopituitarism is estimated to be between 1:3000 and 1:4000 births. CLINICAL SIGNS: Clinical presentation is variable, depending on the type and severity of deficiencies and on the age at diagnosis. If untreated, main symptoms include short stature, cognitive alterations or delayed puberty. DIAGNOSIS: A diagnosis of combined pituitary hormone deficiency (CPHD) must be suspected when evident causes of hypopituitarism (sellar tumor, postsurgical or radioinduced hypopituitarism...) have been ruled out. Clinical, biological and radiological work-up is very important to better determine which transcription factor should be screened. Confirmation is provided by direct sequencing of the transcription factor genes. AETIOLOGY: Congenital hypopituitarism is due to mutations of several genes encoding pituitary transcription factors. Phenotype varies with the factor involved: PROP1 (somatolactotroph, thyrotroph, gonadotroph and sometimes corticotroph deficiencies; pituitary hyper and hypoplasia), POU1F1 (somatolactotroph and thyrotroph deficiencies, pituitary hypoplasia), HESX1 (variable pituitary deficiencies, septo-optic dysplasia), and less frequently LHX3 (somatolactotroph, thyrotroph and gonadotroph deficiencies, limited head and neck rotation) and LHX4 (variable pituitary deficiencies, ectopic neurohypophysis, cerebral abnormalities). MANAGEMENT: An appropriate replacement of hormone deficiencies is required. Strict follow-up is necessary because patients develop new deficiencies (for example late onset corticotroph deficiency in patients with PROP1 mutations). GENETIC COUNSELLING: Type of transmission varies with the factor and the mutation involved (recessive transmission for PROP1 and LHX3, dominant for LHX4, autosomal or recessive for POU1F1 and HESX1). PROGNOSIS: It is equivalent to patients without pituitary deficiencies if treatment is started immediately when diagnosis is confirmed, and if a specialized follow-up is performed.
Assuntos
Hipopituitarismo/genética , Hormônios Hipofisários/deficiência , Diagnóstico Diferencial , Proteínas de Homeodomínio/genética , Terapia de Reposição Hormonal , Humanos , Hipopituitarismo/congênito , Hipopituitarismo/diagnóstico , Hipopituitarismo/terapia , Hormônios Hipofisários/uso terapêutico , Fator de Transcrição Pit-1/genéticaRESUMO
People are at higher risk of cancer as they get older or have a strong family history of cancer. The potential influence of environmental and behavioral factors remains poorly understood. Earlier population and case control studies reported that upper quartile of circulating IGF-I is associated with a higher risk of developing cancer suggesting possible involvement of the growth hormone (GH)/IGF system in initiation or progression of cancer. Since GH therapy increases IGF-1 levels, there have been concerns that GH therapy in hypopituitarism might increase the risk of cancer. We report a 42-year-old female patient who presented with subacute onset of symptoms of meningitis and with the absence of fever which resulted in death 70 days after the onset of symptoms. The patient together with her younger brother was diagnosed at the age of 5 years with familial congenital hypopituitarism, due to homozygous mutation c.150delA in PROP1 gene. Due to evolving hypopituitarism, she was replaced with thyroxine (from age 5), hydrocortisone (from age 13), GH (from age 13 until 17), and sex steroids in adolescence and adulthood. Her consanguineous family has a prominent history of malignant diseases. Six close relatives had malignant disease including her late maternal aunt with breast cancer. BRCA 1 and BRCA 2 mutational analysis in the patient's mother was negative. Histology after autopsy disclosed advanced ovarian cancer with multiple metastases to the brain, leptomeninges, lungs, heart, and adrenals. Low circulating IGF-1 did not seem to protect this patient from cancer initiation and progression in the context of strong family history of malignancies.
Assuntos
Carcinoma/secundário , Hipopituitarismo/congênito , Carcinomatose Meníngea/secundário , Neoplasias Ovarianas/patologia , Adulto , Evolução Fatal , Feminino , Hormônio do Crescimento/deficiência , Proteínas de Homeodomínio/genética , Terapia de Reposição Hormonal , Humanos , Hipopituitarismo/tratamento farmacológico , Hipopituitarismo/genética , Ovário/patologia , LinhagemRESUMO
OBJECTIVE: This study compared the potency of a somatostatin receptor (sstr)2-sstr5 analog, BIM-23244, of an sstr2-dopamine D2 receptor (sstr2-DAD2) molecule, BIM-23A387 and of new somatostatin-dopamine chimeric molecules with differing, enhanced affinities for sstr2, sstr5 and DAD2, BIM-23A758, BIM-23A760 and BIM-23A761, to suppress GH and prolactin (PRL) from 18 human GH adenomas that are partially responsive to octreotide or lanreotide. MATERIALS AND METHODS: The sstr2, sstr5 and DAD2 mRNA levels were determined by RT-PCR. The effect of drugs was tested in cell cultures at various concentrations. RESULTS: In all tumors, the sstr2, sstr5 and DAD2 mRNA levels were coexpressed (mean levels+/-s.e.m. 0.4+/-0.1, 5.3+/-1.9 and 2.0+/-0.4 copy/copy beta-glucuronidase). In 13 tumors, the maximal suppression of GH secretion produced by BIM-23A387 (30+/-3%) and BIM-23244 (28+/-3%) was greater than that produced by octreotide (23+/-3%). In six out of 13 tumors, BIM-23A758, BIM-23A760 and BIM- 23A761 produced greater maximal suppression of GH secretion than octreotide (33+/-5, 38+/-2 and 41+/-2 vs 24+/-2%). Their EC(50) values were 10, 2 and 4 pmol/l. BIM-23A761 was more effective than BIM-23A387 in GH suppression (41+/-2 vs 32+/-4%). The new chimeric molecules produced maximal PRL suppression greater than octreotide (62+/-8 to 74+/-5 vs 46+/-11%). CONCLUSIONS: Novel dopamine-somatostatin chimeric molecules with differing, enhanced activity at sstr2, sstr5 and DAD2, consistently produced significatly greater suppression of GH and PRL than either octreotide or single-receptor-interacting ligands in tumors from patients classified as only partially responsive to octreotide therapy. The higher efficacy of the chimeric compounds was, at least partially, linked to their high affinity for sstr2 (IC50 1-10 pmol/l). The other mechanisms by which such molecules produce an enhanced inhibition of GH remain to be elucidated.
Assuntos
Dopamina/análogos & derivados , Neoplasias Hipofisárias/tratamento farmacológico , Prolactinoma/tratamento farmacológico , Receptores de Dopamina D2/administração & dosagem , Receptores de Somatostatina/administração & dosagem , Somatostatina/análogos & derivados , Acromegalia/sangue , Acromegalia/tratamento farmacológico , Adulto , Antineoplásicos Hormonais/administração & dosagem , Dopamina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Feminino , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/metabolismo , Humanos , Masculino , Octreotida/administração & dosagem , Neoplasias Hipofisárias/sangue , Neoplasias Hipofisárias/genética , Prolactina/sangue , Prolactina/metabolismo , Prolactinoma/sangue , Prolactinoma/genética , RNA Mensageiro/análise , Receptores de Dopamina D2/genética , Receptores de Somatostatina/genética , Proteínas Recombinantes de Fusão/administração & dosagem , Somatostatina/administração & dosagem , Células Tumorais CultivadasRESUMO
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.
Assuntos
Adenoma/metabolismo , Hormônio do Crescimento Humano/antagonistas & inibidores , Hormônio do Crescimento Humano/metabolismo , Octreotida/uso terapêutico , Neoplasias Hipofisárias/metabolismo , Receptores de Somatostatina/uso terapêutico , Somatostatina/análogos & derivados , Acromegalia/tratamento farmacológico , Acromegalia/metabolismo , Adenoma/tratamento farmacológico , Adulto , Resistência a Medicamentos , Feminino , Hormônios/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/tratamento farmacológico , Prolactina/metabolismo , RNA Mensageiro/metabolismo , Receptores de Somatostatina/agonistas , Receptores de Somatostatina/genética , Somatostatina/uso terapêutico , Células Tumorais CultivadasRESUMO
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.
Assuntos
Adenoma/metabolismo , Hormônio do Crescimento Humano/metabolismo , Neoplasias Hipofisárias/metabolismo , Prolactina/metabolismo , Adulto , Aminoquinolinas/farmacologia , Células Cultivadas , Agonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Sinergismo Farmacológico , Feminino , Hormônios/farmacologia , Hormônio do Crescimento Humano/antagonistas & inibidores , Humanos , Masculino , Octreotida/farmacologia , Peptídeos Cíclicos/farmacologia , Isoformas de Proteínas/genética , RNA Mensageiro/metabolismo , Receptores de Dopamina D2/genética , Receptores de Somatostatina/antagonistas & inibidores , Receptores de Somatostatina/genética , Somatostatina/agonistas , Somatostatina/análogos & derivados , Somatostatina/farmacologiaRESUMO
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.
Assuntos
Acromegalia/metabolismo , RNA Mensageiro/metabolismo , Receptores da Somatotropina/genética , Adenoma/metabolismo , Adulto , Células Cultivadas , Combinação de Medicamentos , Feminino , Hormônios/farmacologia , Hormônio do Crescimento Humano/antagonistas & inibidores , Hormônio do Crescimento Humano/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Octreotida/farmacologia , Oligopeptídeos/farmacologia , Fenótipo , Piperazinas/farmacologia , Prolactina/antagonistas & inibidores , Receptores de Somatostatina/agonistas , Receptores de Somatostatina/genética , Somatostatina/análogos & derivados , Somatostatina/farmacologiaRESUMO
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.
Assuntos
Expressão Gênica , Neoplasias Hipofisárias/metabolismo , Prolactinoma/metabolismo , Receptores de Somatostatina/genética , Adulto , Aminoquinolinas/farmacologia , Agonistas de Dopamina/farmacologia , Feminino , Hormônios/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Octreotida/farmacologia , Oligopeptídeos/farmacologia , Piperazinas/farmacologia , Prolactina/antagonistas & inibidores , Prolactina/metabolismo , RNA Mensageiro/análise , Somatostatina/análogos & derivados , Somatostatina/farmacologia , Células Tumorais CultivadasRESUMO
The first part of this contribution reviews the current knowledge about endocrine and neuromodulatory actions of somatostatin. These biological actions are exerted according to endocrine, paracrine and autocrine modes of action and involve five distinct types of membrane receptors belonging to the 'super-family' of G-protein-coupled receptors. A new concept concerning a juxtacrine mode of action has recently been introduced to refer to the intervention of cytokines and growth factors in direct, cell-to-cell communication. The evidence in favor of juxtacrine actions of somatostatin will be presented in the second part of this review and illustrated by our own results on macrophage-lymphocyte T interactions in the immune system and spermatogonia-Sertoli cell interactions in mammalian testis. Another phenomenon such as ligand-induced somatostatin receptor homo- and hetero-dimerization resulting in 'poly'-receptors (with characteristics different from those of each of the two receptors forming the complex) is also at the origin of a novel mode of somatostatin action. The latter will be illustrated by the data obtained on human pituitary adenomas with somatostatin analogs specific for either 'poly'-receptor or relevant individual receptors. The arguments in favor of the analogous mode of actions among different families of chemical messengers such as peptides, cytokines and growth factors are discussed in the concluding section. The emerging unifying concepts on such functional analogies might provide a useful basis for the development of synthetic analogs not only for bioactive peptides but also for other types of chemical messengers.
Assuntos
Somatostatina/fisiologia , Animais , Humanos , Neoplasias/fisiopatologia , Receptores de Somatostatina/genética , Receptores de Somatostatina/fisiologia , Somatostatina/farmacologiaRESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Peptídeos Cíclicos/farmacologia , Neoplasias Hipofisárias/tratamento farmacológico , Prolactinoma/tratamento farmacológico , Somatostatina/análogos & derivados , Somatostatina/farmacologia , Adulto , Aminoquinolinas/farmacologia , Antineoplásicos/uso terapêutico , Agonistas de Dopamina/farmacologia , Feminino , Subunidade alfa de Hormônios Glicoproteicos/antagonistas & inibidores , Subunidade alfa de Hormônios Glicoproteicos/metabolismo , Humanos , Oligopeptídeos/farmacologia , Peptídeos Cíclicos/uso terapêutico , Piperazinas/farmacologia , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/metabolismo , Prolactina/antagonistas & inibidores , Prolactina/metabolismo , Prolactinoma/genética , Prolactinoma/metabolismo , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Receptores de Somatostatina/classificação , Receptores de Somatostatina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Somatostatina/uso terapêuticoRESUMO
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).
Assuntos
Deficiências Nutricionais/genética , Hormônios Hipofisários/deficiência , Fatores de Transcrição/genética , Diferenciação Celular/genética , Linhagem da Célula , Proteínas de Ligação a DNA/genética , Deficiências Nutricionais/patologia , Proteínas de Homeodomínio/genética , Humanos , Hipopituitarismo/genética , Proteínas com Homeodomínio LIM , Mutação , Adeno-Hipófise/crescimento & desenvolvimento , Adeno-Hipófise/patologia , Fator de Transcrição Pit-1 , Proteína Homeobox PITX2RESUMO
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.
Assuntos
Hormônio Adrenocorticotrópico/sangue , Ensaio Imunorradiométrico/métodos , Adulto , Anticorpos Monoclonais , Dexametasona , Feminino , Glucocorticoides , Humanos , Hipoglicemia/sangue , Insulina , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/sangue , Valores de Referência , Sensibilidade e EspecificidadeRESUMO
UNLABELLED: From the first 198 patient files included into the French Acromegaly Registry, we analyzed 68 patients harboring a somatotroph adenoma with extrasellar extension, after exclusion of those treated by stereotactic or conventional radiotherapy. In these patients (including 37 women), aged 21-77 yr. (45.7 +/- 13.3), GH concentrations ranged from 2-260 microg/L (38.6 +/- 44.3), and IGF I from 86-967% of age-matched upper limit of normal (303 +/- 164). Maximal diameter of the adenoma at MRI was 11-36.5 mm (20.4 +/- 6.5), with cavernous sinus involvement in 68% of cases. Three subgroups were defined: 20 patients treated by long-acting somatostatin analogs only (group M), for a mean duration of 3 yr. (extremes 1-7 yr.), 48 patients initially treated by transsphenoidal surgery (group C), of whom 21 were secondarily treated by long-acting somatostatin analogs (group CM) for a mean duration of 1.2 yr. (extremes 0.2-2 yr.). All 3 groups were not statistically different in terms of tumor mass and initial levels of GH and IGF-1. Patients from group M were significantly older than those of the other groups (p<0.05). RESULTS: 46% of patients from group C after surgery vs. 45% of patients from group M had a mean GH below 2.5 microg/L. Biochemical remission (GH<2.5 microg/L and normal IGF1 normal) was obtained in 31% of cases in group C, vs. 25% in group M. In this group, a decrease of the largest tumor diameter was observed in 10 patients (71.5%), ranging from 10-25% in 7 (50%) and exceeded 50% in 3 (21.5%). In group CM, the biochemical remission rate (42%) and final GH or IGF1 values were not significantly different from group M. In conclusion, these data suggest that surgery or long-acting somatostatin analogs have a comparable efficacy in terms of remission rates in somatotroph macroadenomas with extrasellar extensions.
Assuntos
Adenoma/cirurgia , Hormônio do Crescimento Humano/metabolismo , Neoplasias Hipofisárias/cirurgia , Acromegalia/etiologia , Acromegalia/cirurgia , Adenoma/tratamento farmacológico , Adenoma/metabolismo , Adenoma/patologia , Adenoma/radioterapia , Adulto , Idoso , Seio Cavernoso/patologia , Terapia Combinada , Feminino , Humanos , Hipofisectomia/métodos , Fator de Crescimento Insulin-Like I/análise , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Octreotida/uso terapêutico , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/radioterapia , Radioterapia Adjuvante , Sistema de Registros , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Resultado do TratamentoRESUMO
CONTEXT: Congenital isolated ACTH deficiency (IAD) is a rare disease characterized by low plasma ACTH and cortisol levels and preservation of all other pituitary hormones. This condition was poorly defined before we identified TPIT, a T-box transcription factor with a specific role in differentiation of the corticotroph lineage in mice and humans, as its principal molecular cause. OBJECTIVE: We have enlarged our series of IAD patients to better characterize the phenotype and the genotype of this rare disease. DESIGN: Each exon of the TPIT gene was amplified and sequenced in IAD patients without any identified cause. A functional analysis of each new TPIT mutation was performed. RESULTS: We described the largest series of 91 IAD patients and identified three distinct groups: neonatal onset complete or partial IAD or late onset IAD. We did not identify any TPIT mutation in patients with partial or late-onset IAD. However, we found a TPIT mutation in 65% of patients with neonatal-onset complete IAD. These patients are homozygous or compound heterozygous for TPIT mutations, and their parents are healthy heterozygous carriers. We identified nine new mutations: four missense, one one-nucleotide deletion, three splice-site mutations, and one large deletion. TPIT mutations lead to loss of function by different mechanisms, such as non-sense-mediated mRNA decay, abnormal mRNA splicing, loss of TPIT DNA binding or protein-protein interaction defects. CONCLUSION: TPIT mutations are responsible for two thirds of neonatal-onset complete IAD but can not be detected in partial or late-onset IAD.
Assuntos
Hormônio Adrenocorticotrópico/deficiência , Doenças Genéticas Inatas/genética , Proteínas de Homeodomínio/genética , Doenças Hipotalâmicas/genética , Proteínas com Domínio T/genética , Adolescente , Hormônio Adrenocorticotrópico/genética , Adulto , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Masculino , FenótipoRESUMO
Congenital growth hormone deficiency (GHD) is a rare cause of growth delay. It should be suspected when other causes of hypopituitarism (sellar tumor, postsurgical or radioinduced hypopituitarism, etc.) have been ruled out. GHD can be isolated (IGHD) or associated with at least one other pituitary hormone deficiency (CPHD) including thyrotroph, lactotroph, corticotroph, or gonadotroph deficiencies. CPHD is caused by mutations of genes coding for pituitary transcription factors involved in pituitary ontogenesis or in the hypothalamic-pituitary axis. Clinical presentation varies, depending on the type and severity of GHD, the age at diagnosis, the association with other pituitary hormone deficiencies, or extrapituitary malformations. Clinical, biological, and radiological work-up is very important to determine for which transcription factor the patient should be screened. There is a wide variety of phenotypes depending on the transcription factor involved: PROP1 (somatolactotroph, thyrotroph, gonadotroph, and sometimes corticotroph deficiencies ; pituitary hyper- or hypoplasia), POU1F1 (somatolactotroph and thyrotroph deficiencies, pituitary hypoplasia), HESX1 (variable pituitary deficiencies, septo-optic dysplasia), and less frequently LHX3 (somatolactotroph, thyrotroph, and gonadotroph deficiencies, deafness, and limited head and neck rotation), LHX4 (variable pituitary deficiencies, ectopic neurohypophysis, cerebral abnormalities), and OTX2 (variable pituitary deficiencies, ectopic neurohypophysis, ocular abnormalities). Mutations of PROP1 remain the first identified cause of CPHD, and as a consequence the first to be sought. POU1F1 mutations should be looked for in the postpubertal population presenting with GH/TSH deficiencies and no extrapituitary malformations. Once genetic diagnosis has been concluded, a strict follow-up is necessary because patients can develop new deficiencies (for example, late-onset corticotroph deficiency in patients with PROP1 mutations). Identification of gene defects allows early treatment of pituitary deficiency and prevention of their potentially lethal consequences. If untreated, the main symptoms include short stature, cognitive alterations, or delayed puberty. An appropriate replacement of hormone deficiencies is therefore required. Depending on the type of transmission (recessive transmission for PROP1 and LHX3, dominant for LHX4, autosomal dominant or recessive for POU1F1 and HESX1), genetic counseling might be proposed. Genotyping appears highly beneficial at an individual and familial level.
Assuntos
Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/genética , Hipopituitarismo/genética , Árvores de Decisões , Humanos , Hipopituitarismo/diagnóstico , MutaçãoRESUMO
BACKGROUND: Pituitary stalk interruption syndrome (PSIS) is a particular entity in the population of patients with hypopituitarism. Only rare cases have a known genetic cause. OBJECTIVES: i) To compare subgroups with or without extra-pituitary malformations (EPM) in a cohort of PSIS patients to identify predictive factors of evolution, ii) to determine the incidence of mutations of the known pituitary transcription factor genes in PSIS. Study design We analyzed features of 83 PSIS patients from 80 pedigrees and screened HESX1, LHX4, OTX2, and SOX3 genes. RESULTS: PSIS had a male predominance and was rarely familial (5%). Pituitary hypoplasia was observed only in the group with EPM. Multiple hormone deficits were observed significantly more often with versus without EPM (87.5 vs 69.5% respectively). Posterior pituitary location along the stalk was a significant protective factor regarding severity of hormonal phenotype. A novel HESX1 causative mutation was found in a consanguineous family, and two LHX4 mutations were present in familial PSIS. CONCLUSION: PSIS patients with EPM had a more severe hormonal disorder and pituitary imaging status, suggesting an antenatal origin. HESX1 or LHX4 mutations accounted for <5% of cases and were found in consanguineous or familial cases.