568 research outputs found
Functional heterogeneity among cell types in the normal pituitary gland and in human and rat pituitary tumors.
Hormone secretion by the anterior pituitary gland
is under control of hypothalamic regulatory factorsjhormones
(see chapter I.l) and peripheral hormones. Apart from the
direct effects of these hormones on anterior pituitary
hormone secretion several fine- regulatory mechanisms may
play a role in determining the ultimate response of hormone
secretion by the anterior pituitary to the hypothalamic or
peripheral feedback hormones. These fine- regulatory
mechanisms include paracrine effects between anterior
pituitary cell types (see chapter I. 1. 2. 1) and functional
heterogeneity within anterior pituitary cell types (see
chapter I .1. 2. 2) . Whether these fine- regulatory mechanisms
may also occur within human pituitary adenomas is not known
(see chapter I.2.3).
It has been suggested that differences in the
hypothalamic input, due to a different intrapituitary
localization of cell types, may be a basis for normal rat
mammotrope heterogeneity. In addition it is not known whether
a similar "mechanism" may cause functional heterogeneity as
has been demonstrated within the normal rat somatotrope
population (see chapter I. 1. 2. 2) . One of the aims of this
thesis was to investigate whether normal rat mammotropes and
somatotropes are functionally heterogeneous with respect to
basal hormone release and responsiveness to secretagogues
when cultured in the absence of hypothalamic influence, in
order to provide additional evidence for the above
hypothesis. In chapter III the results of experiments are
described in which rat mammotrope and somatotrope subpopulations,
separated according to differences in their density, were
cultured during 7 days in the absence of hypothalamic hormones.
Subsequently, these subpopulations were tested for their
responses to the hypothalamic hormones which normally
regulate the secretion of PRL and GH.
As has been mentioned in chapter I. 2 functional
heterogeneity of cells (cell types) within experimental rat pituitary tumors and within human pituitary tumors has not
been studied extensively yet. The second aim of this thesis
was to investigate whether functional heterogeneity exists
among cells of pituitary adenomas. We have used for our
studies two types of pituitary adenomas, an experimental
prolactin-secreting rat pituitary tumor and human GHsecreting
pituitary adenomas. In chapters IV, V and VI the
results of experiments concerning intratumor heterogeneity of
an experimental rat pituitary tumor {chapter IV) and of GHsecreting
human pituitary adenomas {chapters v and VI) are
described. In chapter VII the results of a study concerning
heterogeneity between GH- secreting pituitary adenomas from
acromegalic patients are presente
The pathophysiological consequences of somatostatin receptor internalization and resistance
Somatostatin receptors expressed on tumor cells form the rationale for
somatostatin analog treatment of patients with somatostatin
receptor-positive neuroendocrine tumors. Nevertheless, although
somatostatin analogs effectively control hormonal hypersecretion by
GH-secreting pituitary adenomas, islet cell tumors, and carcinoid tumors,
significant differences are observed among patients with respect to the
efficacy of treatment. This may be related to a differential expression of
somatostatin receptor subtypes among tumors. In addition, the property of
somatostatin receptor subtypes to undergo agonist-induced internalization
has important consequences for visualizing, as well as for therapy, of
receptor-positive tumors using radioisotope- or
chemotherapeutic-compound-coupled somatostatin analogs. This review covers
the pathophysiological role of somatostatin receptor subtypes in
determining the efficacy of treatment of patients with somatostatin
receptor-positive tumors using somatostatin analogs, as well as the
preclinical and clinical consequences of agonist-induced receptor
internalization for somatostatin receptor-targeted radio- and
chemotherapy. Herein, the development and potential role of novel
somatostatin analogs is discussed
Epigenetic Mechanisms Modulated by Glucocorticoids With a Focus on Cushing Syndrome
In Cushing syndrome (CS), prolonged exposure to high cortisol levels results in a wide range of devastating effects causing multisystem morbidity. Despite the efficacy of treatment leading to disease remission and clinical improvement, hypercortisolism-induced complications may persist. Since glucocorticoids use the epigenetic machinery as a mechanism of action to modulate gene expression, the persistence of some comorbidities may be mediated by hypercortisolism-induced long-lasting epigenetic changes. Additionally, glucocorticoids influence microRNA expression, which is an important epigenetic regulator as it modulates gene expression without changing the DNA sequence. Evidence suggests that chronically elevated glucocorticoid levels may induce aberrant microRNA expression which may impact several cellular processes resulting in cardiometabolic disorders. The present article reviews the evidence on epigenetic changes induced by (long-term) glucocorticoid exposure. Key aspects of some glucocorticoid-target genes and their implications in the context of CS are described. Lastly, the effects of epigenetic drugs influencing glucocorticoid effects are discussed for their ability to be potentially used as adjunctive therapy in CS.</p
Epigenetic Mechanisms Modulated by Glucocorticoids With a Focus on Cushing Syndrome
In Cushing syndrome (CS), prolonged exposure to high cortisol levels results in a wide range of devastating effects causing multisystem morbidity. Despite the efficacy of treatment leading to disease remission and clinical improvement, hypercortisolism-induced complications may persist. Since glucocorticoids use the epigenetic machinery as a mechanism of action to modulate gene expression, the persistence of some comorbidities may be mediated by hypercortisolism-induced long-lasting epigenetic changes. Additionally, glucocorticoids influence microRNA expression, which is an important epigenetic regulator as it modulates gene expression without changing the DNA sequence. Evidence suggests that chronically elevated glucocorticoid levels may induce aberrant microRNA expression which may impact several cellular processes resulting in cardiometabolic disorders. The present article reviews the evidence on epigenetic changes induced by (long-term) glucocorticoid exposure. Key aspects of some glucocorticoid-target genes and their implications in the context of CS are described. Lastly, the effects of epigenetic drugs influencing glucocorticoid effects are discussed for their ability to be potentially used as adjunctive therapy in CS.</p
Role of somatostatin receptors in normal and tumoral pituitary corticotropic cells
Normal and tumoral pituitary corticotropic cells express sst2and sst5, of which sst5is the predominantly expressed receptor subtype. Somatostatin (SS) inhibits pituitary adrenocorticotropin hormone (ACTH) secretion in vitro, but the sensitivity to SS is strongly regulated by glucocorticoids. In pathological conditions of a low endogenous cortisol level, i.e. in patients with adrenal insufficiency and in patients with Nelson's syndrome, SS and sst2-preferring SS analogs (SSA), such as octreotide, are able to lower circulating ACTH and cortisol levels. On the other hand, sst2-preferring SSA seem not effective in lowering ACTH and cortisol levels in patients with untreated Cushing's disease (CD), in which circulating cortisol levels are high. This is likely due to the downregulation of sst2receptors by glucocorticoids. sst5receptor expression is more resistant to the inhibitory effect of glucocorticoids. In recent years, novel sst subtype-selective and universal SSA have been developed. In particular, SSA with a high sst5-binding affinity are potent inhibitors of ACTH secretion by pituitary corticotropic adenoma cells. This knowledge has initiated clinical trials evaluating the efficacy of these novel SSA in patients with CD, with the aim to lower circulating ACTH and cortisol levels by targeting multiple ssts on the corticotropic adenoma cells. In this minireview, the effects of SS in the regulation of normal and tumoral ACTH secretion, the role of sst subtypes involved herein, as well as the potentials of novel SSA in the treatment of patients with recurrent or persisting CD are discussed
Medical treatment of Cushing's syndrome: Adrenal-blocking drugs and ketaconazole
Cushing's syndrome is associated with serious morbidity and increased mortality. Irrespective of its cause, i.e. a pituitary adenoma, ectopic ACTH production or an adrenal neoplasia, Cushing's syndrome is primarily treated surgically. However, when surgery is unsuccessful or contraindicated, medical therapy is needed to treat hypercortisolism. The spectrum of available drugs includes adrenal-blocking agents, neuromodulatory drugs and glucocorticoid receptor antagonists. Adrenal blocking drugs suppress adrenal cortisol production via inhibition of steroidogenic enzymes. Ketoconazole and metyrapone are most frequently used for this purpose, but chronic treatment with these drugs can be limited by side effects like hepatotoxicity (ketoconazole) and increased androgen and mineralocorticoid production (metyrapone). Etomidate can be used to rapidly reverse cortisol excess in patients with acute complications of (severe) hypercortisolism like psychosis. In Cushing's disease, combination therapy with drugs that target the corticotropic adenoma, i.e. the universal somatostatin analogue pasireotide and/or the dopamine agonist cabergoline, and low-dose ketoconazole seems a rational approach to achieve biochemical control
The effect of clozapine on prolactin secretion at the level of the lactotroph
Abstract
Clozapine is an antipsychotic drug which is unusual in that it has no dopamine receptor-blocking activity. Previous studies gave conflicting results whether administration of clozapine induces hyperprolactinemia. In the present study it was shown that a wide concentration range of clozapine does not interfere with dopamine-mediated inhibition of prolactin (PRL) secretion by normal cultured rat pituitary cells. This in contrast to other neuroleptics, like haloperidol and trifluoperazine. Clozapine does also not antagonize norepinephrine-mediated inhibition of PRL secretion. Clozapine exerts at micromolar concentrations a direct inhibitory action on PRL release by cultured normal rat pituitary cells. In cultured rat pituitary tumor cells, these high concentrations of clozapine directly inhibit PRL release as well as the DNA content of the cells, suggesting a direct antimitotic action. In this model clozapine was about 5β10 times less potent than trifluoperazine. Clozapine and trifluoperazine exert an additive inhibitory action both on PRL release and on the DNA content of the pituitary tumor cells. It is concluded that clozapine does not interfere at the pituitary level with dopamine-mediated inhibition of PRL release. At micromolar concentrations clozapine may act on lactotrophs as a calmodulin-inhibitor. These observations suggest that the transient PRL-releasing effects which have been observed in both animal and human studies after clozapine administration are mediated via supra-pituitary actions of the drug
Percoll density gradient centrifugation of rat pituitary tumor cells
Abstract
Tumor cells prepared from PRL-secreting rat pituitary 7315b tumors of increasing weight were separated on continuous Percoll density gradients, according to differences in their density. Whether the cell subpopulations obtained by density gradient separation showed differences in protein content per cell, PRL production per cell, growth rates and responsiveness to the somatostatin analog SMS 201β995 in vitro was investigated. In addition, we studied PRL release by individual 7315b tumor cells, using the reverse hemolytic plaque assay (RHPA).
The tumor cells from tumors of increasing weight were recovered within a narrow density range (1.060β1.070 g/ml) and showed a normal distribution profile. There were no differences between the subpopulations with respect to the parameters mentioned above. Moreover, no differences were found with respect to these parameters between tumor cells derived from tumors of increasing weight. In agreement with the above data we found no evidence for subtypes of adenoma cells being preferentially responsive to SMS 201β995, using the RHPA. Conclusions: (1) the transplantable PRL-secreting rat pituitary tumor 7315b consists of a functionally homogeneous cell population; (2) growth of this tumor in vivo does not lead to the induction of functionally heterogeneous cell subpopulations within this tumor; (3) the escape of this tumor from the tumor growth-inhibitory effect of SMS 201β995, which has previously been demonstrated in vivo, may not have been the result of clonal selection of somatostatin-unresponsive cells
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