Reversible transdifferentiation: interconversion of somatotrophs and lactotrophs in pituitary hyperplasia.
(49/672)
Previous studies conclusively demonstrated transformation of somatotrophs into bihormonal mammosomatotrophs in gestational lactotroph hyperplasia during pregnancy. Similar transdifferentiation of somatotrophs into thyrotrophs through bihormonal intermediate thryrosomatotrophs was documented during thyrotroph hyperplasia in both rodent and human pituitaries in hypothyroidism. The cessation of the stimulation resulted in reversal of the process in both conditions. The conversion of lactotrophs into somatotrophs was suggested but not documented previously in the human gland. The present study was undertaken to investigate cases of somatotroph hyperplasia by transmission electron microscopy, immunoelectron microscopy using double immunogold labeling for growth hormone and prolactin, as well as combined immunocytochemistry and in situ hybridization. Adenohypophysial tissue was removed from a 38-year-old man and a 29-year-old woman with long-standing acromegaly due to ectopic overproduction of growth hormone-releasing hormone (GRH) by bronchial carcinoid tumors. For comparison, two pituitary biopsies were studied: one from a 38-year old woman with idiopathic lactotroph hyperplasia and one from a 14-year-old boy with secondary lactotroph hyperplasia due to a suprasellar craniopharyngioma. In the patients with somatotroph hyperplasia, the prevailing cell type was the hyperplastic somatotroph joined by mammosomatotroph deriving from lactotrophs, whereas monohormonal lactotrophs were rare. The predominance of mammosomatotrophs and active lactotrophs was documented in the patient with idiopathic lactotroph hyperplasia, whereas the case of the patient with secondary lactotroph hyperplasia was characterized by monohormonal lactotrophs and somatotrophs, but mammosomatotrophs were rare. That finding in the pituitary of the boy suggests that participation of mammosomatotrophs in lactotroph hyperplasia is not unconditional Our findings conclusively demonstrate conversion of lactotrophs into mammosomatotrophs during somatotroph hyperplasia, providing further evidence for the potential of reversible transdifferentiation between somatotrophs and lactotrophs in response to functional demand. (+info)
Imprinting of the G(s)alpha gene GNAS1 in the pathogenesis of acromegaly.
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Approximately 40% of growth hormone-secreting pituitary adenomas have somatic mutations in the GNAS1 gene (the so-called gsp oncogene). These mutations at codon 201 or codon 227 constitutively activate the alpha subunit of the adenylate cyclase-stimulating G protein G(s). GNAS1 is subject to a complex pattern of genomic imprinting, its various promoters directing the production of maternally, paternally, and biallelically derived gene products. Transcripts encoding G(s)alpha are biallelically derived in most human tissues. Despite this, we show here that in 21 out of 22 gsp-positive somatotroph adenomas, the mutation had occurred on the maternal allele. To investigate the reason for this allelic bias, we also analyzed GNAS1 imprinting in the normal adult pituitary and found that G(s)alpha is monoallelically expressed from the maternal allele in this tissue. We further show that this monoallelic expression of G(s)alpha is frequently relaxed in somatotroph tumors, both in those that have gsp mutations and in those that do not. These findings imply a possible role for loss of G(s)alpha imprinting during pituitary somatotroph tumorigenesis and also suggest that G(s)alpha imprinting is regulated separately from that of the other GNAS1 products, NESP55 and XLalphas, imprinting of which is retained in these tumors. (+info)
Craniofacial abnormalities and their relevance for sleep apnoea syndrome aetiopathogenesis in acromegaly.
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OBJECTIVE: To explain the effect of craniofacial relations on the development of the sleep apnoea syndrome (SAS) in acromegaly, and to elucidate how the activity of acromegaly affects the severity of SAS. DESIGN: Prospective observational study. METHODS: Cephalometry and sleep ventilation measurements were performed in 26 acromegalic men and in 96 men with SAS. RESULTS: SAS was found in 20 acromegalic men. Compared with non-acromegalic men with SAS, patients with acromegaly and SAS were found to have: enlargement of almost all linear dimensions; increased angle indicating mandibular protrusion; increased difference between maxillary and mandibular protrusion; articular angle decrease; soft palate lengthening; and pharyngeal airway space (PAS) enlargement in the palatal and uvular-tip planes. A comparison of acromegalic men with and without SAS revealed no significant difference in the craniofacial skeleton, although there was a narrowing of the minimal PAS (MinPAS) and of PAS in the uvular-tip plane in patients with SAS. SAS was more frequent in the patients with active acromegaly. MinPAS in the patients with active acromegaly was narrower than in those without disease activity. CONCLUSION: Skeletal abnormalities in acromegalic men with SAS were different from those in SAS patients without acromegaly. Upper airway narrowing due to changes in pharyngeal soft tissues takes a more relevant share in the development of SAS in acromegalic men than skeletal anomalies. (+info)
Hemorrhagic gastric carcinoma in an acromegalic patient.
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A rare case of hemorrhagic gastric carcinoma in an acromegalic patient is reported. A 79-year-old Japanese man was referred to our hospital with diagnoses of upper gastrointestinal hemorrhage and angina pectoris. This patient showed typical clinical features of acromegaly, with increased serum growth hormone (GH) and insulin-like growth factor I (IGF-I) level. A high titer of serum anti-Helicobacter pylori (H. pylori) IgG was also observed. After percutaneous transluminal coronary angioplasty treatment for stenosis of the right coronary artery, the patient underwent distal gastrectomy. Gastric cancer was Type 2 macroscopically and was diagnosed histologically as a papillary and well to moderately differentiated tubular adenocarcinoma. Reverse transcription-polymerase chain reaction analysis estimated that the amount of IGF-I receptor mRNA expression in the gastric cancer tissue was 1.6 times higher than that in the adjacent atrophic mucosa, whereas the amount of IGF-I mRNA expression in the cancer tissue was only half that in the atrophic mucosa. Both the stimulatory effects of GH and/or IGF-I on cell proliferation and H. pylori infection in gastric tumorigenesis may have been responsible for the development and growth of gastric carcinoma in this patient. (+info)
Increased glucose-dependent insulinotropic polypeptide (GIP) secretion in acromegaly.
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OBJECTIVE: Acromegaly is often associated with fasting and postprandial hyperinsulinemia, and the mechanisms involved are only partly understood. Hypersecretion of incretins such as glucose-dependent insulinotropic polypeptide (GIP) could play a role in determining hyperinsulinemia in acromegaly, but the available data are inconsistent. The aim of this study was to characterize the fasting and postprandial pattern of plasma GIP and insulin in a group of acromegalic patients. DESIGN AND METHODS: Eleven non-diabetic patients with newly diagnosed acromegaly and 11 sex- and age-matched healthy subjects were studied. Blood samples were taken at regular intervals in fasting conditions and for 3 h after a standard solid-liquid meal for growth hormone (GH), GIP and insulin measurements. RESULTS: Not only insulin, but also fasting and postprandial GIP levels were significantly higher in the patients with acromegaly than the healthy subjects (P<0.01). In the former group fasting GIP levels and the integrated GIP response to the meal correlated significantly with GH basal levels (r=0.83, P<0.01 and r=0.65, P<0.05, respectively). Moreover, multivariate linear regression analysis showed that the presence of acromegalic status was associated with higher fasting and postprandial GIP levels independently of sex, age, fasting and postprandial plasma glucose and insulin levels, and the occurrence of normal or impaired glucose tolerance. CONCLUSION: This study provides evidence that in patients with acromegaly fasting and postprandial GIP levels are abnormally high. GIP hypersecretion in turn might play a role in the pathogenesis of hyperinsulinemia that characterizes acromegaly. (+info)
Effects of preoperative octreotide treatment on different subtypes of 90 GH-secreting pituitary adenomas and outcome in one surgical centre.
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OBJECTIVE: To investigate the possible impact of pretreatment with octreotide on different subtypes of GH-secreting pituitary adenomas and on the outcome of transnasal surgery. METHODS: We reviewed a consecutive series of 90 acromegalic patients treated with octreotide alone before transnasal surgery. On the basis of magnetic resonance imaging, the tumours were classified into four groups: group A, microadenoma (n=7); group B, transnasally resectable macroadenoma (n=21); group C, invasive, potentially transnasally resectable macroadenoma (n=43); group D, non-resectable grossly invasive macroadenoma (n=19). All patients were treated for at least 3 months before surgery, with a mean daily dose of 221+/-31 microg octreotide. The mean follow-up was 51.7+/-1.4 months. The comparative group included 57 acromegalic patients who were not receiving octreotide treatment. RESULTS: After pretreatment with octreotide, tumour shrinkage was clearly observed in 28 of the 90 patients (31%). At surgery, the tumours after octreotide treatment were more often white or grey in colour (91% compared with 75%) and were observed to be slightly more often fluid or soft in texture (86% compared with 79%) than those in the comparative series. Endocrinological remission was achieved in all patients in group A, 95.2% in group B, and 81.4% in group C. In only 10 of the 14 patients with tumour shrinkage in group C, endocrinological remission was also achieved (71.4%). In the comparative series, endocrinological remission was achieved in 92.9% of group A, 87.5% of group B, and 73.9% of group C. CONCLUSIONS: Octreotide treatment slightly improved the already relatively high rate of endocrinological remission in invasive, potentially transnasally resectable macroadenomas. The rate of tumour shrinkage was found to decrease with extrasellar size. With the exception of tumour growth in approximately 7% of invasive adenomas and pituitary apoplexy in one patient, there was no disadvantage associated with the octreotide pretreatment. (+info)
Skin morphological changes in growth hormone deficiency and acromegaly.
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OBJECTIVE: To evaluate the histomorphology of skin and its appendages, especially eccrine sweat glands, in patients with GH disorders, because reduced sweating ability in patients with growth hormone deficiency (GHD) is associated with increased risk of hyperthermia under stressed conditions. DESIGN AND METHODS: A skin biopsy was obtained from 17 patients with GHD treated with GH, five patients with untreated GHD, 10 patients with active acromegaly and 13 healthy controls. RESULTS: The sweat secretion rate (SSR) was significantly decreased in both the untreated (median 41 mg/30 min, range 9-79 mg/30 min) and the GH-treated (median 98 mg/30 min, range 28-147 mg/30 min) patients with GHD compared with that in controls (median 119 mg/30 min, range 90-189 mg/30 min; P=0.001 and 0.01 respectively). Epidermal thickness was significantly decreased in both untreated (median 39 microm, range 28-55 microm) and GH-treated patients with GHD (median 53 microm, range 37-100 microm), compared with that in controls (median 66 microm, range 40-111 microm; P<0.02). A statistically non-significant tendency towards thinner epidermis (median 59 microm, range 33-83 microm) was recorded in acromegalic patients (P=0.08) compared with controls. There was no significant difference in the area of the sebaceous glands in the biopsies between the three groups and the controls. The area of eccrine sweat gland glomeruli was significantly decreased in the untreated patients with GHD (median 16407 microm2, range 12758-43976 microm2) compared with that in controls (median 29446 microm2, range 13511-128661 microm2; P=0.03), but there was no significant difference between the GH-treated patients with GHD and controls. CONCLUSIONS: We conclude that GH, either directly or via IGF-I, may have both a structural and a functional effect on human skin and its appendages, and that patients with GHD have histomorphological changes in skin compared with controls. Importantly, these changes are not fully reversed despite long-term and adequate GH treatment in patients with childhood onset GHD. (+info)
Altered circadian blood pressure profile in patients with active acromegaly. Relationship with left ventricular mass and hormonal values.
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To determine the relationships between the circadian blood pressure profile and left ventricular mass, hormonal pattern and insulin sensitivity indices in patients with active acromegaly, ambulatory 24-h blood pressure monitoring (ABPM) was recorded in 25 subjects (47.0 +/- 15.1 years, range 23-72). Serum growth hormone (GH) and insulin-like growth factor-1, fasting and mean plasma glucose and insulin during oral glucose tolerance test (OGTT), insulinogenic index, the sum of the plasma insulin levels and the homeostasis model insulin resistance index (Homa's index) were determined. Left ventricular mass index (LVMI) was calculated from two-dimensional guided M-mode echocardiogram. The prevalence of hypertension was 56% (n = 14) and 40% (n = 10) according to sphygmomanometric measurements and ABPM, respectively. Non-dipping profile was observed in six of 10 hypertensives and in six of 15 normotensives. Serum growth hormone, fasting glucose, the area under the serum insulin curve and LVMI were higher for acromegalics with non-dipping profile than for dippers (all of them, P < 0.05). In non-dippers daytime heart rate was higher than night time (P < 0.001). In conclusion, the main observations in the present study suggested that both normotensive and hypertensive acromegalics had a highly prevalent non-dipping profile with a preserved circadian pattern of heart rate, that was associated with higher levels of serum GH. The disturbance in nocturnal blood fall in normotensives was associated with a decreased insulin sensitivity. The role of GH in blood pressure circadian rhythm regulation in essential hypertension deserves further studies. (+info)