The pathogenesis of pituitary adenomas.
Explore the source record for details and available documents.
Adenoma↗
Biomedical subjects
S L Lightman
Publications and source records attributed to S L Lightman.
Substance P inhibits the release of anterior pituitary adrenocorticotrophin via a central mechanism involving corticotrophin-releasing factor-containing neurons in the hypothalamic paraventricular nucleus.
Chronic osmotic stimulation influences the hypothalamo-adenohypophysial axis by inhibiting the synthesis of hypothalamic corticotrophin-releasing factor (CRF-41) and subsequently the secretion of basal and adrenalectomy-elevated adrenocorticotrophin from the adenohypophysis. In the present study, we used a substance P antagonist to test the hypothesis that this inhibition is mediated centrally by substance P or other tachykinins. In control rats and rats given 2% saline to drink for 12 days, intracerebroventricular administration of a substance P antagonist elevated plasma adrenocorticotrophin and corticosterone levels. Using quantitative in situ hybridization histochemistry, it was also demonstrated that CRF mRNA increased in the medial parvocellular division of the paraventricular nucleus of saline-treated as well as control rats 6 h after intracerebroventricular administration of the antagonist, while vasopressin mRNA in the medial parvocellular division of the paraventricular nucleus was increased in the control animals only. These results provide evidence that central endogenous substance P has an inhibitory influence over the synthesis and release of CRF-41 both under normal conditions and during a chronic osmotic stimulus.
Adrenocorticotropic Hormone↗
Direct stimulation of the pituitary by transfer of activated leucocytes.
Some strains of rat develop arthritis, and have profoundly elevated adrenocorticotropin (ACTH) and corticosterone, following intradermal injection of an adjuvant containing heat-killed mycobacteria. Transfer to syngeneic recipients of immune spleen (IS) cells taken from arthritic rats 14 days after injection of the adjuvant, but not of non-immune cells, causes increased circulating ACTH and increased pituitary proopiomelanocortin (POMC) mRNA. Transfer of immune cells does not transfer the disease, but does protect recipients from subsequent challenge with the adjuvant. In these immune-protected rats, the secondary immune response raises ACTH and POMC to levels similar to those seen in arthritic rats. These data show that endogenous inflammatory mediators have direct actions on the neuroendocrine system.
Adrenocorticotropic Hormone↗
Transport into retina measured by short vascular perfusion in the rat.
1. The short duration cerebrovascular perfusion method for measuring permeability of the blood-brain barrier has been adapted to measuring transport into the retina. 2. The method has been characterized on the one hand by comparing uptakes of radiotracers during HCO3(-)-buffered saline perfusion with those occurring after intravenous bolus injection of radioisotopes, and on the other by comparing uptake into retina with the uptake into frontal cerebral cortex. The mean permeability-surface area (PS) products (ml s-1 g-1) for [14C]urea and [14C]thiourea in the perfused retina were 1.2 +/- 0.26 x 10(-3) and 2.1 +/- 0.01 x 10(-3) respectively. The intravenous injection method gave comparable values for [14C]urea and [14C]thiourea of 1.6 +/- 0.28 x 10(-3) and 3.24 +/- 0.55 x 10(-3). The rates of uptake of the hydrophilic solutes were 2- to 7-fold greater than in brain. 3. Retinal and choroidal capillary perfusion fluid flow rates were measured using a diffusible flow marker ([14C]diazepam) and a particulate indicator (15 microns cerium141-labelled microspheres). Results using both flow markers confirmed that both capillary networks supplying the retina were being adequately perfused.
Animals↗
HPA axis responses to acute stress and adrenalectomy during adjuvant-induced arthritis in the rat.
Adjuvant-induced arthritis results in chronic activation of the hypothalamo-pituitary-adrenal (HPA) axis. In the Piebald-Viral-Glaxo (PVG) rat, however, corticotropin-releasing factor (CRF) mRNA in the parvocellular paraventricular nucleus (pPVN) of the hypothalamus was reduced, and the normal corticosterone and CRF mRNA responses to acute stress were inhibited. The proenkephalin A mRNA response to stress in the pPVN was maintained, implying a specific inhibition of the CRF mRNA responses in this pathological situation. Adrenalectomy at day 0 (the time of adjuvant injection), day 13 (just before inflammation), or day 19 (submaximal inflammation) resulted in a marked increase in CRF mRNA compared with day 21 adrenal-intact arthritic animals. However, levels were below those of nonarthritic adrenalectomized rats, demonstrating that the inhibition of CRF mRNA associated with arthritis is not simply due to changes in glucocorticoid feedback. Proopiomelanocortin mRNA in the anterior pituitary was markedly increased in all adrenalectomized arthritic animals above the increase seen in sham-adrenalectomized day-21 arthritic rats. Adrenalectomy was always associated with an increase in the severity of the disease.
Acute Disease↗
Effects of adrenalectomy and hypertonic saline on neuropeptide Y content in the posterior pituitary of the rat.
We have examined the effects of adrenalectomy (ADX) on neuropeptide Y (NPY) content in the posterior pituitary of the rat. In rats given 2% saline to drink for 12 days, plasma osmolality increased to 343 +/- 18 compared to 291 +/- 5 mosm/kg in control animals on water (mean +/- SEM). Hypertonic saline treatment resulted in increased posterior pituitary NPY content measured by radioimmunoassay (2.42 +/- 0.36 ng) compared to the control group (1.18 +/- 0.16 ng). Total NPY immunoreactivity in tissue extracts coeluted with synthetic NPY(1-36) on reversed-phase high-performance liquid chromatography. In ADX rats given 2% saline to drink, plasma osmolality increased to 355 +/- 35 mosm/kg, but posterior pituitary NPY content was not different from the control group (1.41 +/- 0.11 ng). Immunohistochemical staining for NPY in the posterior pituitary also revealed a saline-induced increase in the number of NPY-immunoreactive nerve fibers, an increase which was not evident in the ADX group. No NPY immunoreactivity was observed in the intermediate zone. These results are the first evidence that the saline-induced increase in NPY in the posterior pituitary is under corticosteroid control.
Adrenalectomy↗
Hippocampal input to the hypothalamus inhibits thyrotrophin and thyrotrophin-releasing hormone gene expression.
We have used in situ hybridization histochemistry to determine the effect of hippocampal-hypothalamic disconnection on hypothalamic thyrotrophin-releasing hormone (TRH) and anterior pituitary thyrotrophin beta subunit (TSH beta) transcripts in adult male CFY rats. Electrothermal lesions of the fornix pathway significantly increased TRH and TSH transcripts and increased circulating levels of triiodothyronine (T3). Fornix transection did not, however, prevent feedback regulation of TRH and TSH transcripts during exogenous T3-induced hyperthyroidism or propylthiouracil-induced hypothyroidism. Hippocampal inputs to the hypothalamus contribute to setting the basal activity of the thyroid axis, but do not mediate the feedback effects of T3.
Animals↗
Regulation of the hypothalamic-pituitary-adrenal axis during water deprivation.
The contribution of the magnocellular vasopressinergic system to the regulation of ACTH secretion was studied by analysis of hypothalamic-adrenal axis function in rats subjected to water deprivation for 48 h. Water deprivation resulted in marked increases in plasma osmolarity and vasopressin (VP) levels and hypothalamic VP mRNA and immunoreactive (ir) VP in magnocellular neurons. While CRH mRNA levels in the paraventricular nucleus were decreased, irCRH accumulation in paraventricular nucleus neurons after colchicine treatment was normal or increased. Similarly, the irCRH content in the median eminence and its release under stress were similar in control and water-deprived rats. While basal plasma ACTH levels were similar in both groups (34.5 +/- 3.8 and 39.8 +/- 3.3 pg/ml), levels stimulated by CRH injection (10 micrograms, i.v.) or 15-min immobilization stress were reduced by 47% (P < 0.01) and 43% (P < 0.05), respectively, in water-restricted rats. The decreased ACTH responses were not prevented by injection of CRH (7.5 micrograms/day, sc) during the period of water deprivation. In contrast to the ACTH responses, basal and CRH-stimulated plasma corticosterone levels were significantly elevated (P < 0.001), and the responses to acute stress were normal. The inhibition of ACTH secretion was not due to increased glucocorticoid feedback, since similar blunted ACTH responses to acute immobilization stress were observed in adrenalectomized rats receiving corticosterone replacement. Despite similar levels of pituitary POMC mRNA, pituitary ACTH content was reduced in water-deprived rats, suggesting a posttranscriptional inhibition of POMC synthesis or processing. The data demonstrate that osmotic activation of the magnocellular VP system is accompanied by reduced responsiveness of the corticotrophs, an effect that is not due to increased glucocorticoid feedback or hypothalamic CRH deficiency. These findings suggest that the magnocellular vasopressinergic system does not play an important role in the regulation of ACTH secretion during chronic osmotic stimulation.
Adrenal Glands↗
Relationship between ovarian steroids, gonadotrophins and relaxin during the menstrual cycle.
The circulating levels of relaxin have been measured and their relationship with the plasma levels of oestradiol (E2), progesterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) have been investigated during the normal menstrual cycle. In addition, the effect of human chorionic gonadotrophin (hCG) on plasma relaxin levels has been studied. In the first part of the study, blood samples were obtained on days 5, 10 and 15 of the follicular phase and on alternate days from the day of the LH surge (detected in early-morning urine and confirmed by circulating levels of LH) until day 6 of the following follicular phase in nine normally cycling female volunteers. In the second part of the study, a single intramuscular dose of hCG (10,000 IU) was given on day 11 of the menstrual cycle. Relaxin was detectable from the mid-luteal phase until the onset of menstruation. The plasma levels of relaxin on days 10 and 12 of the luteal phase were significantly greater than on day 6. Positive associations between the circulating levels of relaxin and E2 and negative associations between the plasma levels of FSH and those of both relaxin and E2 were found on days 8, 10 and 12 of the luteal phase. The relationship between E2 and FSH was stronger than that between relaxin and FSH. Exogenous hCG had no effect on plasma relaxin levels. The pattern of the relationship between E2 and relaxin suggests that a common mechanism may regulate their release or that plasma relaxin levels are determined by those of E2.(ABSTRACT TRUNCATED AT 250 WORDS)
Chorionic Gonadotropin↗
Regulation of arginine vasopressin mRNA in rat fetal hypothalamic cell culture. Role of protein kinases and glucocorticoids.
Studies have been performed to investigate the regulation of arginine vasopressin (AVP) mRNA expression in fetal hypothalamic cultures. AVP mRNA-positive neurones were identified by in-situ hybridization histochemistry, and changes in mRNA expression were quantitated by nuclease protection assay. Both protein kinase C and protein kinase A activators increased the expression of AVP mRNA, in contrast to dexamethasone, which inhibited the responses to both protein kinase C and protein kinase A activation.
Animals↗
Effects of CD8 depletion on retinal soluble antigen induced experimental autoimmune uveoretinitis.
During the later stages of soluble-antigen (sAg)-induced experimental autoimmune uveoretinitis (EAU), an increase in the relative number of CD8+ lymphocytes has been observed at the site of inflammation in the retina. It has been suggested that these late-appearing CD8+ cells might down-regulate this acute disease process. To determine the role of the CD8+ cells in EAU, Lewis rats were depleted of CD8+ cells prior to and during disease and the enucleated eyes examined histologically. The spleen cells from CD8-depleted rats were also examined for their ability to respond to concanavalin A (Con A) and to allogeneic targets as determined by mixed lymphocyte reaction (MLR) and cytotoxicity assays. The results suggest that depleting CD8+ cells had no effect on the course of disease and that CD8+ cells do not play a crucial role in the immunoregulation of EAU.
Animals↗
The origin of keratopathy in chronic allergic eye disease: a histopathological study.
Although the clinical features of atopic keratoconjunctivitis have been well described, it is recognised that some adults with severe chronic allergic conjunctivitis do not develop a keratopathy despite having marked disease of their lid margins and conjunctiva. The aetiology of the keratopathy of chronic allergic eye disease is not known but may result from the release of toxic mediators from mast cells, eosinophils and neutrophils in the inflamed conjunctiva. To examine this theory we have counted these cells in tarsal and bulbar conjunctival biopsies from patients with severe allergic conjunctivitis and compared the numbers in samples from patients with or without keratopathy. Our results indicate that patients with chronic allergic conjunctivitis with keratopathy have higher cell numbers in their conjunctiva than patients with no keratopathy, especially those staining for eosinophil cationic protein in the tarsal epithelium. A statistically significant difference between disease groups could only be demonstrated, however, when the combined totals of mast cells, eosinophils and neutrophils were compared.
Adult↗
Detection of melanocytes from uveal melanoma in peripheral blood using the polymerase chain reaction.
PURPOSE: Uveal melanoma is the most common intraocular malignancy in adults and can cause loss of vision in the affected eye and death from metastasis, usually to the liver. The techniques currently used to detect cellular dissemination from the tumor are inadequate, and lack the sensitivity required for the detection of low levels of melanocytes in the peripheral blood of patients. The detection of circulating melanocytes is important as an early indication of the possibility of metastasis. METHODS: The viability of reverse transcription/polymerase chain reaction amplification of the tyrosinase gene to detect circulating melanocytes was examined as a first sign of dissemination from uveal melanoma. RESULTS: It was shown that it is possible to detect as few as ten circulating melanocytes in 5 ml of blood. Blood-borne dissemination was also detected in three of six patients with uveal melanoma examined. Two of these patients had clinically confirmed widespread metastases. A positive result was also recorded in one patient in whom there was no other evidence for tumor dissemination. Overt metastatic disease developed in this patient 9 months after blood collection. CONCLUSIONS: The success of this technique has important implications for the detection of circulating tumor cells from uveal melanoma, as an early indication of dissemination. This may be important when considering the administration of adjuvant therapy.
Adult↗
Neuropeptide Y mRNA and immunoreactivity in hypothalamic neuroendocrine neurons: effects of adrenalectomy and chronic osmotic stimulation.
Neuropeptide Y (NPY) coexists with vasopressin or oxytocin in magnocellular neurons of the hypothalamo-neurohypophysial tract. Using quantitative in situ hybridization histochemistry and immunohistochemistry, we have studied the effects of adrenalectomy and chronic osmotic stimulation, either alone or in combination, on NPY mRNA expression and NPY immunoreactivity in magnocellular neurons of the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei, and arcuate nucleus (Arc). Adrenalectomy and chronic osmotic stimulation each increased NPY mRNA levels in magnocellular neurons of the PVN and SON, while the combination of both treatments had an additive effect. In the Arc, only the combination of adrenalectomy and chronic osmotic stimulation increased NPY mRNA levels. Chronic osmotic stimulation also resulted in a marked increase of NPY-immunoreactive magnocellular perikarya in the PVN and SON. In contrast, adrenalectomy had only minor effects on the number of NPY-immunoreactive magnocellular PVN/SON perikarya. Neither chronic osmotic stimulation nor adrenalectomy affected the number of NPY-immunoreactive Arc perikarya. However, adrenalectomy decreased the number of NPY-immunoreactive nerve terminals in the external zone of the median eminence, while chronic osmotic stimulation increased the number of immunoreactive nerve fibers in the internal zone of the median eminence. The present study provides evidence that adrenalectomy and chronic osmotic stimulation can separately influence NPY gene transcription in magnocellular hypothalamo-neurohypophysial neurons, while only the combined effect of adrenalectomy and chronic osmotic stimulation increases NPY mRNA expression in neurons of the Arc.
Adrenalectomy↗
In vivo lymphokine production in experimental autoimmune uveoretinitis.
Experimental autoimmune uveoretinitis (EAU) is a well-characterized model of immune-mediated intraocular inflammation. The intraocular infiltrate in EAU consists predominantly of T lymphocytes. The in vivo production of interleukin-2 (IL-2), lymphotoxin and IL-4 by these T cells was investigated by in situ hybridization using cDNA probes to lymphokine mRNA. Localization of lymphokine mRNA was found simultaneous with disease onset in areas of T-cell infiltration. Positive signal was seen over cells in the uveal tract, retina and extraocular region. Less than 10% of the population of T cells defined immunohistochemically had positive localization of mRNA for these lymphokines. The number of positive cells was similar for each of the three probes and increased as the disease progressed. The findings suggest that these lymphokines are produced in vivo in immune-mediated intraocular inflammation and may play a role in the immunopathology seen in these conditions.
Animals↗
IGF-II mRNA expression in LI human glioblastoma cell line parallels cell growth.
A human glioblastoma cell line was found to express in vitro mRNA transcripts specific for insulin-like growth factor-II (IGF-II) and growth-hormone releasing-hormone (GHRH). In the absence of gross morphological changes, retinoic acid reduced the growth rate without major change of IGF-II mRNA expression, while alpha-difluoromethylornithine produced a complete growth arrest and a sharp decrease of IGF-II mRNA expression. Both reagents increased the expression of GHRH mRNA. Also in this glioblastoma cell line, like other neuroectodermal tumours, IGF-II mRNA is expressed independently from GHRH and seems to be parallel to growth rate.
Blotting, Northern↗
Alterations in hypothalamic-pituitary responsiveness during lactation.
Explore the source record for details and available documents.
Adrenalectomy↗
The effects of pituitary stalk transection, hypophysectomy and thyroid hormone status on insulin-like growth factor 2-, growth hormone releasing hormone-, and somatostatin mRNA prevalence in rat brain.
We have used in situ hybridization histochemistry to determine the effects of pituitary stalk transection, hypophysectomy and drug-induced changes in thyroid status on mRNA levels encoding insulin-like growth factor 2, somatostatin, and growth hormone-releasing factor in the choroid plexus, hypothalamic periventricular nucleus, and arcuate nucleus, respectively. Pituitary stalk transection and hypophysectomy in Sprague-Dawley rats decreased insulin-like growth factor 2 and somatostatin mRNA and increased growth hormone-releasing factor mRNA. In each case, the effect of hypophysectomy exceeded that of pituitary stalk transection. Treatment with propylthiouracil for 10 days decreased somatostatin mRNA, markedly increased growth hormone-releasing factor mRNA but had no significant effect on insulin-like growth factor 2 mRNA. Treatment with triiodothyronine had no effect on the mRNAs measured. These findings corroborate the clinical observation of abnormal somatic growth in disturbances of thyroid and growth hormone status and provide further evidence of the effects of these metabolic disturbances and of pituitary disconnection and hypophysectomy on insulin-like growth factor 2 mRNA prevalence.
Animals↗