Hormone research最新文献

Pituitary adenomas are being recognized and diagnosed with increasing frequency. One of the most common forms of pituitary lesion is the clinically non-functioning pituitary adenoma (NFPA), which is often diagnosed incidentally. The vast majority of pituitary adenomas are sporadic, but familial adenomas can occur in the multiple pituitary adenoma type 1 syndrome, in Carney complex or in familial isolated pituitary adenoma. Distinguishing NFPA from prolactinomas can occasionally cause a differential diagnostic problem due to the 'stalk effect'. NFPA often show hormone synthesis on tissue immunostaining without causing clinical symptoms. Most often these are silent gonadotroph adenomas, with silent corticotroph or somatotroph adenomas occurring less frequently. It is unclear why these silent adenomas do not release hormones at a clinically recognizable level, although it is probable that there is a continuum between fully functional and completely silent adenomas. Another intriguing feature of NFPAs is the lack of clinical response to somatostatin analogues, despite the presence of somatostatin receptors and an often good response in the in vitro setting. Temozolomide has been successfully used for the treatment of a few aggressive pituitary adenomas, and the response to this drug could be influenced by the expression of the DNA repair enzyme O-6-methylguanine DNA methyltransferase. The early diagnosis, prediction of long-term outcome and treatment of NFPAs remain a challenge for endocrinologists.

Progress in the identification of the (epi)genetic basis of imprinting disorders has provided greater insight into the central role of imprinted genes in regular human growth. In addition to the well-known Prader-Willi, Angelman, and Beckwith-Wiedemann syndromes, imprinting disturbances have recently been identified in transient neonatal diabetes mellitus, uniparental disomy (14) syndromes and Silver- Russell syndrome (SRS). Among these diseases, the growth retardation disorder SRS is unique because it is the first human disorder associated with epigenetic mutations that affect two different chromosomes. In addition to maternal uniparental disomy of chromosome 7, hypomethylation of the imprinting control region 1 in 11p15 and maternal duplication of 11p15 have recently been described as major (epi)genetic disturbances in SRS. Interestingly, opposite (epi)- mutations are involved in the overgrowth disease Beckwith-Wiedemann syndrome (BWS). Thus SRS and BWS can be regarded as two genetically and clinically opposite clinical pictures. Although not yet completely understood, SRS and BWS can be used as models to decipher the functional link between the observed (epi)genetic mutations and the clinical features in individuals with disturbed growth. Future studies will clarify the complex basis of human growth and hopefully contribute to better-directed therapies.

The network of European studies of genes in growth (NESTEGG) is an international growth genomics project, focusing on the birth size phenotypes of small for gestational age (SGA) and idiopathic short stature. Seven hundred controls and 1,275 cases with their parents have been recruited. Detailed clinical histories and auxological measurements are recorded in a clinical database. Candidate gene studies are being undertaken with the study DNA samples. These genetic data will be used to explore associations with the clinical phenotypes of short stature and SGA birth size, and, in a subset, response to growth hormone (GH) therapy. This article describes the study methodology and reviews the association of the exon 3-deleted genotype of the GH receptor with GH responsiveness in GH-treated children born SGA.

Short stature, with a mean final height almost two standard deviations below the normal mean, is a major feature of Noonan syndrome. The biological basis of the growth failure is not yet clear. The recent detection of mutations in the protein tyrosine phosphatase, non-receptor type 11 gene (PTPN11) in half of all individuals with Noonan syndrome has opened up a new perspective from the endocrine point of view, since the tyrosine phosphatase SHP2 encoded by PTPN11 is implicated in the downregulation of growth hormone (GH) receptor signalling. Current data show decreased insulin-like growth factor (IGF)-I and IGF-binding protein 3 (IGFBP-3) levels in those children with Noonan syndrome who carry PTPN11 mutations. GH responsiveness seems to be reduced in the presence of PTPN11 mutations, but, so far, data are too scarce to draw any final conclusions. Children with Noonan or Noonan-related syndromes carrying mutations in components of the Ras-mitogen-activated protein kinase (MAPK) signalling pathway downstream from SHP2 also have short stature, though less frequently in the case of SOS1 mutations. Therefore, apart from the disturbance of GH signalling, there must be other relevant mechanisms that influence longitudinal growth in Noonan syndrome. In a small subgroup of patients with Noonan syndrome and Noonan-related syndromes, tumour risk is increased. This susceptibility is relevant when GH therapy is considered. Progress in the understanding of cell regulation by Ras-MAPK signalling and its interconnection with other pathways will hopefully provide evidence on which therapy might be helpful and which might be nocuous in the care of children with Noonan syndrome.

Pituitary microadenomas are exceedingly common in the general population, and only a very few progress to a size of more than a few millimetres. The early and total, or near- total, growth arrest preventing the outgrowth of these adenomas calls to mind the phenomenon of oncogene- induced cellular senescence (OIS), a growth arrest response brought about by oncogenic signalling. In the past, OIS has been demonstrated in a variety of benign neoplastic lesions, in animal models as well as in man. OIS results from the activation of powerful antiproliferative signalling networks, and presumably acts as a protective response preventing the outgrowth of early neoplastic lesions that are driven by a single or a very few oncogenic lesions. A few recent studies on pituitary tumorigenesis in Rb+/- mice, as well as some preliminary observations in human pituitary adenomas, lend support to the idea that OIS is also an important mediator of growth arrest in these occult pituitary tumours. If so, the fact that over 99.9% of pituitary adenomas never produce clinical problems of mass effect attests to the efficacy of this response.

Genetic cases of congenital pituitary hormone deficiency are common and many are caused by transcription factor defects. Mouse models with orthologous mutations are invaluable for uncovering the molecular mechanisms that lead to problems in organ development and typical patient characteristics. We are using mutant mice defective in the transcription factors PROP1 and POU1F1 for gene expression profiling to identify target genes for these critical transcription factors and candidates for cases of pituitary hormone deficiency of unknown aetiology. These studies reveal critical roles for Wnt signalling pathways, including the TCF/LEF transcription factors and interacting proteins of the groucho family, bone morphogenetic protein antagonists and targets of notch signalling. Current studies are investigating the roles of novel homeobox genes and pathways that regulate the transition from proliferation to differentiation, cell adhesion and cell migration. Pituitary adenomas are a common human health problem, yet most cases are sporadic, necessitating alternative approaches to traditional Mendelian genetic studies. Mouse models of adenoma formation offer the opportunity for gene expression profiling during progressive stages of hyperplasia, adenoma and tumorigenesis. This approach holds promise for the identification of relevant pathways and candidate genes as risk factors for adenoma formation, understanding mechanisms of progression, and identifying drug targets and clinically relevant biomarkers.

Background: Growth failure occurs in children with chronic anemias and, in particular, in approximately 30% of those with thalassemia.

Methods: We assessed recombinant human growth hormone (rhGH) use in a large cohort of children with thalassemia enrolled in the Pfizer International Growth Study Database (KIGS).

Results: We identified 147 short children with thalassemia who were treated with rhGH in KIGS. Of these, approximately 40% had a primary diagnosis of GH deficiency (GHD). They had low birth weight, short parents, reduced genetic height potential, low insulin-like growth factor I levels and delayed bone age. Treatment with rhGH for 1 year resulted in a significantly increased growth rate regardless of underlying GH or pubertal status. Although the resultant growth rates for thalassemic children were significantly higher than at baseline, they were less than those seen in similarly treated short children with or without GHD.

Conclusions: GH testing should be performed in short thalassemic children, and those with GHD should be treated with rhGH. The value of rhGH therapy in short thalassemic children without GHD is less clear-cut and requires further study regarding final height outcome.

Background/aim: The relationship between the hypothalamic-pituitary-thyroid (HPT) axis and the serotonergic (5-hydroxytryptamine, 5-HT) system is not clear. The aim of the study was to determine platelet biochemical markers (5-HT concentration and monoamine oxidase B, MAO-B, activity) in hypothyroid patients.

Methods: The study included 25 medication-free female hypothyroid patients in postoperative follow-up after total thyroidectomy due to papillary thyroid carcinoma, who had not been treated with synthetic thyroxine (T(4)) for 4 weeks, and 44 age-matched euthyroid healthy women. The platelet 5-HT concentration, platelet MAO-B activity, total T(4) and thyroid-stimulating hormone (TSH) levels were determined using spectrofluorimetric methods, radioimmunoassay and fluoroimmunoassay, respectively.

Results: Hypothyroid patients had significantly higher TSH, significantly lower T(4) levels and platelet 5-HT concentrations, and unchanged platelet MAO-B activity than healthy subjects. A positive correlation was found between the 5-HT concentration and platelet MAO-B activity, and between the platelet MAO-B activity and T(4) in control subjects.

Conclusions: Reduced platelet 5-HT concentrations in hypothyroid patients suggests a complex interaction between the 5-HT system and HPT axis activity, which could be related to the frequent occurrence of depressive symptoms in hypothyroid patients. The determination of platelet 5-HT concentrations should be considered a diagnostic tool for the evaluation of depressive symptoms in hypothyroid patients during the hormone withdrawal procedure.

Background: Systemic administration of the nonaromatizable androgen oxandrolone stimulates growth in girls with Turner syndrome and boys with a constitutional delay of growth and puberty. It is unknown if oxandrolone acts locally at the growth plate level to stimulate longitudinal bone growth.

Methods: Metatarsal bones from female and male rat fetuses (day E20) were cultured for 14 days in the presence of oxandrolone, testosterone or the androgen receptor (AR) antagonist flutamide with/without insulin-like growth-factor-I (IGF-I) or charcoal-treated serum.

Results: The AR was found to be expressed in both male and female fetal rat metatarsal bones. Neither oxandrolone nor testosterone had any effect on metatarsal bone growth when tested at a wide concentration range (1 nM to 10 microM), not even in the presence of IGF-I (100 ng/ml) or charcoal-treated serum (10%). Bone growth was also unaffected when the AR was blocked by flutamide. Control experiments confirmed that metatarsal bone growth was significantly stimulated by IGF-I (p < 0.001).

Conclusion: Modulation of AR activity in the fetal rat growth plate does not affect linear bone growth. Extrapolating from these in vitro data, it could be speculated that oxandrolone stimulates longitudinal bone growth in treated children by acting indirectly rather than directly through AR activation in growth plate chondrocytes.

Aims: To investigate the metabolic consequences of long-term GH treatment in young women with Turner syndrome (TS), several years after GH discontinuation.

Methods: Follow-up study of a randomized GH dose-response trial, with 3 GH dosages (1.3, 2.0, and 2.7 mg/m(2)/day). Thirty-nine TS patients (20.0 +/- 2.1 years) participated 4.8 +/- 1.9 years after GH discontinuation. Mean GH treatment duration was 8.7 +/- 2.0 years. Fasting glucose, insulin, and serum lipids were measured.

Results: Several years after GH discontinuation, insulin sensitivity remained lower, while beta-cell function and fasting insulin levels remained higher than before treatment. Only BMI influenced beta-cell function. Serum total cholesterol (TC), low-density lipoprotein and high-density lipoprotein (HDL) had further increased compared to 6 months after GH, resulting in higher TC, but also higher HDL levels compared to controls. The atherogenic index remained constant, but lower than controls.

Conclusions: Besides height, GH therapy in girls with TS has additional beneficial effects on serum lipids. Nearly 5 years after discontinuation of GH therapy the favorable effect of GH was still noticeable. The GH-induced decrease in insulin sensitivity, however, remained unchanged, possibly due to having TS.