Biomedical subjects

G K Stalla

Publications and source records attributed to G K Stalla.

At least 37 records · Page 2Linked to original sources

PubMed2004

Expression of epidermal growth factor receptor in neoplastic pituitary cells: evidence for a role in corticotropinoma cells.

The oncogenic effects of epidermal growth factor (EGF) have long been established. EGF receptor (EGFr) is overexpressed in many types of tumors and constitutes a target for cancer treatment. The pituitary gland is a target of EGF action and it is very likely that EGFr plays a role in pituitary tumor formation and progression. However, there is a controversy in the literature concerning EGFr expression in the different types of pituitary adenomas. In the present study we investigated the expression pattern of the wild type EGFr (EGFrWT) and the constitutively active variant III (EGFrvIII) at the mRNA and protein levels in a large series of pituitary tumors. EGFrWT was found in a high percentage of hormone-secreting tumors, but only in a small fraction of non-functioning pituitary adenomas, while no expression of the EGFrvIII could be detected by nested RT-PCR in any tumor. Among the hormone-secreting adenomas, the highest incidence of EGFr expression was found in Cushing's pituitary adenomas. Furthermore, immunohistochemistry for the phosphorylated EGFr revealed the presence of activated EGFr in most Cushing's adenomas, compared with most pituitary adenomas. Taking into account that downregulation of p27/Kip1 plays a significant role in corticotrope tumorigenesis and that EGFr mitogenic signaling results in decreased p27/Kip1, we searched for a correlation between EGFr expression and p27/Kip1 levels in corticotropinomas. Low p27/Kip1 immunoreactivity was observed in corticotropinomas expressing EGFr. On the other hand, somatotropinomas expressing EGFr had high p27/Kip1 immunoreactivity. These data suggest a corticotrope-specific phenomenon and indicate that EGFr may have a role in the unbalanced growth of corticotrope tumoral cells.

Adenoma↗

PubMed2004

New perspectives in the treatment of Cushing's syndrome.

Regardless of etiology, all cases of endogenous Cushing's syndrome are due to increased production of cortisol by the adrenal gland. Most are caused by adrenocorticotrophic hormone (ACTH)-secreting pituitary adenomas. Alternatively, the glucocorticoid excess may be due to adrenal neoplasia or to ectopic ACTH-secreting tumors. Cushing's syndrome is characterized by endocrine and metabolic alterations such as truncal obesity, hypertension, weakness, amenorrhea, hyperglycemia, osteoporosis and depression. Unless treated, the disease is associated with high morbidity, and ultimately, mortality. Depending on the etiology of Cushing's syndrome two different treatment modalities are possible: reduction of pituitary ACTH production or reduction of adrenocortical cortisol secretion. In the absence of efficient drug therapy, transsphenoidal resection of the pituitary adenoma is the primary treatment of choice for the reduction of ACTH secretion. In the last years there was much progress in understanding the molecular mechanisms that control the function of the hypothalamic-pituitary-adrenal axis. Thus, new insights made it possible to identify potential drug targets for the treatment of Cushing's syndrome. The present article reviews different drug targets and therapeutic options including drugs that control the central ACTH regulation, e.g. by modulating signaling pathways and transcriptional regulation of ACTH biosynthesis, corticotrophin releasing hormone (CRH) or glucocorticoid receptor antagonists, inhibitors of glucocorticoid synthesis, ketoconazole, somatostatin and dopamine analogs. Some of these substances might be useful for the treatment of Cushing's syndrome.

Adrenocorticotropic Hormone↗

PubMed2003

Laminin inhibits lactotroph proliferation and is reduced in early prolactinoma development.

Laminin is a component of the extracellular matrix (ECM) that regulates cell proliferation and hormone secretion. Here we describe the effects of laminin on prolactin secretion in normal and tumor cells and analyze laminin expression pattern during prolactinoma development. Prolactin secretion and cell proliferation were inhibited by laminin in GH3 cells. In contrast, no effect was observed in normal pituitary cells. Laminin showed a dynamic expression pattern during prolactinoma development, which was: (a) strong in normal pituitaries from wild type or dopamine D2 receptor deficient mice, (b) lower in pituitary hyperplasia and (c) markedly reduced in prolactinomas from D2R -/- mice. A similar gradual decrease in laminin was found by comparing normal human pituitaries, human pituitary hyperplasia and human prolactinomas. These results show dynamic changes of laminin expression during prolactinoma formation which, due to laminin action on PRL production and cell proliferation, indicate a possible role for laminin in prolactinoma development.

Analysis of Variance↗

PubMed2003

Are patients with pituitary adenomas at an increased risk of mental disorders?

OBJECTIVE: Retrospective clinical studies suggest that patients with pituitary adenoma (PA) have an increased risk of mental disorders. However, empirical evidence for this hypothesis is deficient because of out-dated methodology. Therefore, we investigated the occurrence of mental disorders in 93 patients with PA within a limited time frame of 2 years. METHOD: Patients were subjected to a comprehensive, standardized lifetime and cross-sectional psychopathological symptom and diagnostic assessment, including an evaluation of psychosocial conditions and life events (CIDI, SCL-90) during the past years. RESULTS: We could not find an increased risk of mental disorders as compared with a representative population sample of 481 subjects matched by age and gender. CONCLUSION: As for our random sample, neither suffering from any type of PA nor the extent of the pituitary deficiency represent factors having significant effect on the risk of the subject to develop psychopathology as compared with the general population.

Adenoma↗

PubMed2003

Endogenous cannabinoid system as a modulator of food intake.

The ability of Cannabis sativa (marijuana) to increase hunger has been noticed for centuries, although intensive research on its molecular mode of action started only after the characterization of its main psychoactive component Delta(9)-tetrahydrocannabinol in the late 1960s. Despite the public concern related to the abuse of marijuana and its derivatives, scientific studies have pointed to the therapeutic potentials of cannabinoid compounds and have highlighted their ability to stimulate appetite, especially for sweet and palatable food. Later, the discovery of specific receptors and their endogenous ligands (endocannabinoids) suggested the existence of an endogenous cannabinoid system, providing a physiological basis for biological effects induced by marijuana and other cannabinoids. Epidemiological reports describing the appetite-stimulating properties of cannabinoids and the recent insights into the molecular mechanisms underlying cannabinoid action have proposed a central role of the cannabinoid system in obesity. The aim of this review is to provide an extensive overview on the role of this neuromodulatory system in feeding behavior by summarizing the most relevant data obtained from human and animal studies and by elucidating the interactions of the cannabinoid system with the most important neuronal networks and metabolic pathways involved in the control of food intake. Finally, a critical evaluation of future potential therapeutical applications of cannabinoid antagonists in the therapy of obesity and eating disorders will be discussed.

Animals↗

PubMed2003

Serum leptin monitoring in anorectic patients during refeeding therapy.

Circulating concentrations of leptin are exceedingly low in severe malnutrition as seen in the acute state of anorexia nervosa (AN). During refeeding therapy plasma leptin levels increase to normal and in some cases peak at values in excess of the BMI of matched controls even before a normal body weight has been achieved. Peak leptin levels are possibly the cause of an increased energy expenditure during this stage of the disorder and might predispose to renewed weight loss (rebound phenomenon). In this study we investigated the role of leptin fluctuations as a prognostic factor of therapeutic success in AN. In 11 anorectic female patients serum leptin levels, BMI and body fat percentage were evaluated in four-week intervals during a conventional refeeding program over three months (group 1). The results of the first two measurements were used to determine a range of increases in leptin levels in relation to increases in BMI. The values between the 25th and 75th percentiles determined the reference range. In a second group of 9 anorectic female patients serum leptin levels, BMI, body fat percentage and the increase in the leptin level in relation to the BMI of each subject were investigated for three months every two weeks. These patients were also treated according to the same conventional refeeding program, but the caloric intake was reduced or increased (+/-250 kcal/d) if the increase in the leptin level, in relation to the increase in the BMI, had exceeded or fallen short of the reference range. During the refeeding therapy every subject of each group experienced increases in serum leptin levels, BMI and body fat percentage. Six subjects of group 1 and six subjects of the second group had an increase in leptin levels in relation to the increase of the BMI out of the reference range at least once. To investigate the therapeutic outcome of leptin monitoring and the following alteration of caloric intake, weight gain of the patients of both groups during the whole treatment was compared. No significant difference was found. Our results probably do not support the findings that high leptin levels predispose to a renewed loss of weight. The outcome in our patients whose caloric intake was modified due to their serum leptin levels was not significantly improved.

Adipose Tissue↗

PubMed2002

The role of endothelins in the regulation of pituitary function.

The different members of the endothelin peptide family exhibit potent, long-lasting vasoconstrictive effects and thus play a central role in blood pressure regulation. However, endothelins have also been shown to modulate renal, cardiac and immune functions under physiological and pathophysiological conditions. In addition, endothelins are thought to be involved in the progression of some types of tumours. Soon after their discovery in 1988, it was shown that endothelins affect hormone release in the pituitary. Moreover, the intrapituitary production and expression of both endothelins and endothelin receptors have been described. This review summarises the present day knowledge concerning the expression and regulation of intrapituitary endothelins and their receptors. In addition, the effects of endothelins on hormone production by anterior, intermediate and posterior pituitary cell types are reviewed and their importance for pituitary physiology and pathophysiology is discussed.

Animals↗

PubMed2002

Transforming growth factor-beta stimulates vascular endothelial growth factor production by folliculostellate pituitary cells.

TGF-beta isoforms are expressed in the anterior pituitary and modulate the growth and function of endocrine pituitary cells. Recently, TGF-beta has been shown to stimulate growth and basic fibroblast growth factor secretion in nonendocrine folliculostellate (FS) pituitary cells. We therefore studied whether the production of FS cell-derived vascular endothelial growth factor (VEGF), the most important regulator of vascular permeability and angiogenesis, is affected by TGF-beta. We observed by RT-PCR that TtT/GF cells, which are FS mouse pituitary tumor cells, synthesize TGF-beta1, -beta2, and -beta3. They also express TGF-beta receptors types 1 and 2, as well as Smad2, Smad3, and Smad4 proteins, which are essential for TGF-betabinding and signaling. Stimulation of TtT/GF cells with either TGF-beta1 or TGF-beta3 induced a rapid translocation of Smad2 into the cell nuclei. Both TGF-beta isoforms dose dependently stimulated VEGF production in TtT/GF cells, but not in lactosomatotroph GH3 cells. Time-course studies and suppression of TGF-beta-induced VEGF production by cycloheximide suggest that TGF-beta induces de novo synthesis of VEGF in folliculostellate cells, which is completely blocked by dexamethasone. In primary rat pituitary cell cultures, TGF-beta1 and -beta3 stimulated VEGF production. TGF-beta stimulation of VEGF production by folliculostellate cells could modulate intrapituitary vascular permeability and integrity as well as angiogenesis in an auto-/paracrine manner.

Animals↗

PubMed2002

Retention of dopamine 2 receptor mRNA and absence of the protein in craniospinal and extracranial metastasis of a malignant prolactinoma: a case report.

OBJECTIVES: The case presented here describes the clinical evolution of a malignant prolactinoma with occurrence of intra- and extra-cranial metastases. In this case, the presence of dopamine 2 receptor (D2R) was studied at the mRNA and protein level, in order to understand the pathological background of the resistance to treatment with different dopamine agonists. DESIGN: Together with an extensive description of the clinical history of this case, a combination of in vitro and in vivo techniques was performed to provide the basis of the dopamine resistance developed in the course of the disease. METHOD: A comparison of the D2R was performed in specimens obtained at presentation of the disease compared with autoptic specimens derived from local invasion and metastasis using in situ hybridization and immunohistochemical techniques. RESULTS: Intact D2R mRNA was found in the primitive tumor and metastatic tissues, whereas protein for the same receptor was present only in the tissues derived from neurosurgical operations and not in the metastases obtained post-mortem. CONCLUSION: This is the first report of the absence of D2R protein despite the retention of the transcript in an advanced stage of a malignant prolactinoma. The findings of this single case suggest the hypothesis that postranscriptional mechanisms may contribute to the development of dopamine resistance in prolactinomas.

Brain Neoplasms↗

PubMed2001

[Cycle disorders, polydipsia, decline of vision. Is it the fault of the hypophysis?].

Apart from partial or complete insufficiency, further diseases of the pituitary with clinical impact are those associated with hormone overproduction such as acromegaly, Cushing's disease and prolactinoma. The cardinal symptom of pituitary insufficiency or disruption of the female cycle, loss of libido or sexual potency reflecting a lesion of the gonadotrophic axis. Hyperprolactinemia also results in a loss of gonadotrophic function. Macroadenomas of the pituitary gland often give rise to visual field defects, so that an ophthalmological work-up is a must. With the exception of hyperprolactinemia, measurement of basic hormone levels is not always sufficient to detect pituitary diseases. For the establishment of hormone deficiency, therefore, stimulation tests, and for detection of hypersecretion suppression tests, are carried out. Owing to the increasing utilization of cranial MRI, incidental detection of intrasellar tumors, the so-called incidentalomas, is becoming ever more common, and these lesions require at least an endocrinological investigation.

Acromegaly↗

PubMed2001

Extracellular matrix components regulate ACTH production and proliferation in corticotroph tumor cells.

The extracellular matrix (ECM) conveys signals through membrane receptors called integrins producing changes in cell morphology, proliferation, differentiation and apoptosis. Previous studies suggest that the ECM plays an important role in pituitary physiology and tumorigenesis. In the present work we studied for the first time the effects of fibronectin, laminin, collagen I and collagen IV on hormone secretion and cell proliferation in the corticotroph tumor cell line AtT-20 and in normal pituitary cells, examining the signal transduction mechanisms that mediate these effects. ACTH production in AtT-20 cells was inhibited by fibronectin, laminin and collagen I. A reporter construct with the POMC promoter showed similar results, indicating that the effects of the ECM take place at the level of POMC gene transcription. In contrast, ACTH production was not significantly altered in normal pituitary cells. AtT-20 cell proliferation was stimulated by collagen IV and fibronectin, but inhibited by collagen I and laminin. In parallel, the cell morphology was modified by the ECM. We found that the production of reactive oxygen species mediate the effects of laminin and collagen IV. On the other hand, the effect of fibronectin was mimicked by beta1-integrin and Rho activation. These results show for the first time that the ECM controls ACTH biosynthesis and proliferation in corticotroph tumor cells and suggest a role for the ECM in corticotroph adenoma development.

Adrenocorticotropic Hormone↗

PubMed2001

Effect of glucocorticoid excess on the cortisol/cortisone ratio.

OBJECTIVE: The conversion of cortisol, which binds avidly to the mineralocorticoid receptor, to cortisone, which no longer has mineralocorticoid function, is predominantly catalyzed by the 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD 2). It was the objective of the present study to examine the impact of different forms of glucocorticoid excess on the cortisol/cortisone ratio and to differentiate their role in the genesis of hypertension. DESIGN AND METHODS: Plasma cortisol and cortisone levels were determined in 12 adults with Cushing's disease, 12 adults with hypercortisolism due to an adrenal tumor, and 20 healthy volunteers before and after an intravenous ACTH test, using specific radioimmunoassays after automated Sephadex LH 20 chromatography. RESULTS: The cortisol/cortisone ratios were significantly higher in patients with Cushing's disease (13.9 +/- 1.1), adrenal tumors (11.5 +/- 2.3), and in healthy volunteers after ACTH stimulation (14.1 +/- 2.0) than in untreated controls (6.0 +/- 0.5) (P < 0.001, P < 0.05, and P < 0.001, respectively). Similar differences were seen for cortisol plasma concentrations, whereas cortisone concentrations did not differ among the groups. CONCLUSIONS: Our data suggest that the excessive mineralocorticoid effects in patients with hypercortisolism are inflicted by elevated cortisol/cortisone ratios possibly due to an insufficient conversion of cortisol to cortisone by 11beta-HSD 2. This may provide a possible explanation for the occurrence of hypertension. This effect seems to be independent of the role of ACTH in the mechanism of hypercortisolism.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed2001

The intrapituitary stimulatory effect of lipopolysaccharide on ACTH secretion is mediated by paracrine-acting IL-6.

During infection/inflammation bacterial lipopolysaccharide (LPS) activates the immune system and thus enhances the level of circulating cytokines. These circulating cytokines induce adaptive processes within the endocrine system and in particular stimulate the HPA axis to increase the level of anti-inflammatory-acting glucocorticoids in the circulation. We have shown recently that LPS stimulates intrapituitary IL-6 production in folliculostellate cells via specific receptors and the p38a mitogen-activated protein kinase/nuclear factor-kappa B pathway. To test the physiological relevance of these findings, we studied whether LPS could enhance ACTH secretion via paracrine-acting intrapituitary IL-6. Lipopolysaccharide stimulated IL-6 secretion both in monolayer and aggregate mouse pituitary cell cultures, but only in aggregates, ACTH secretion was significantly enhanced by LPS. Other hormones, such as GH or PRL, were less stimulated by LPS. My4, an antibody that blocks the interaction of LPS with the LPS receptor CD14, suppressed both LPS-induced IL-6 and ACTH secretion in aggregate cultures. A neutralizing antibody against mouse IL-6 also inhibited LPS-induced ACTH secretion in aggregates. In mouse pituitary fragments, LPS-induced ACTH secretion was blocked by My4 and IL-6 antibodies, identically to re-aggregate cell cultures. LPS-induced ACTH secretion, mediated by intrapituitary IL-6, may represent a pituitary-specific mechanism that stimulates the HPA axis during infection/inflammation.

Adrenocorticotropic Hormone↗

PubMed2001

Vascular endothelial growth factor production and regulation in rodent and human pituitary tumor cells in vitro.

Angiogenesis, the formation of a new blood supply, is an essential step in tumorigenesis. Although vascular endothelial growth factor (VEGF) is known to be a very potent angiogenic factor in most solid tumors, little is known about its production and regulation in pituitary adenomas. We have investigated basal and stimulated VEGF production by rodent pituitary tumor cells (mouse corticotrope AtT20, rat lactosomatotrope GH3, mouse gonadotrope alpha T3-1 and mouse folliculostellate TtT/GF cells), and by hormone-inactive (27), corticotrope (9), lactotrope (3) and somatotrope (21) human pituitary adenoma cell cultures. All 4 pituitary cell lines secreted VEGF, which in the case of AtT20, GH3 and TtT/GF cells was inhibited by approximately 50% by dexamethasone. TtT/GF cells were the most responsive to the different stimuli used since basal values were augmented by pituitary adenylate cyclase activating polypeptide-38 (PACAP-38), interleukin-6 (IL-6), transforming growth factor-alpha (TGF-alpha), IGF-I and the somatostatin analogue ocreotide. However, in GH3, AtT20 and alpha T3-1 cells, basal VEGF levels where not enhanced with any of the stimuli tested. The majority of the human adenomas tested (92%) basally secreted measurable VEGF which was inhibited by dexamethasone in most cases (84%). VEGF levels were increased in hormone inactive adenomas, somatotrope tumors and prolactinomas by TGF-alpha, PACAP-38, and 17 beta-estradiol, respectively. In conclusion, pituitary tumor cells are capable of producing VEGF which may be involved in tumoral angiogenesis. Our results concerning the suppression of VEGF by dexamethasone suggest that glucocorticoids may have anti-angiogenic properties and therefore therapeutic relevance for the treatment of pituitary adenomas.

Adenoma↗

PubMed2001

Retinoic acid prevents experimental Cushing syndrome.

Cushing syndrome is caused by an excess of adrenocorticotropic hormone (ACTH) production by neuroendocrine tumors, which subsequently results in chronic glucocorticoid excess. We found that retinoic acid inhibits the transcriptional activity of AP-1 and the orphan receptors Nur77 and Nurr1 in ACTH-secreting tumor cells. Retinoic acid treatment resulted in reduced pro-opiomelanocortin transcription and ACTH production. ACTH inhibition was also observed in human pituitary ACTH-secreting tumor cells and a small-cell lung cancer cell line, but not in normal cells. This correlated with the expression of the orphan receptor COUP-TFI, which was found in normal corticotrophs but not in pituitary Cushing tumors. COUP-TFI expression in ACTH-secreting tumor cells blocked retinoic acid action. Retinoic acid also inhibited cell proliferation and, after prolonged treatment, increased caspase-3 activity and induced cell death in ACTH-secreting cells. In adrenal cortex cells, retinoic acid inhibited corticosterone production and cell proliferation. The antiproliferative action and the inhibition of ACTH and corticosterone produced by retinoic acid were confirmed in vivo in experimental ACTH-secreting tumors in nude mice. Thus, we conclude that the effects of retinoic acid combine in vivo to reverse the endocrine alterations and symptoms observed in experimental Cushing syndrome.

Adrenocorticotropic Hormone↗

PubMed2001

Expression of CRHR1 and CRHR2 in mouse pituitary and adrenal gland: implications for HPA system regulation.

Deficiency of corticotropin-releasing hormone receptor I (CRHR1) reduces anxiety-related behavior in mice and severely impairs the stress response of the hypothalamic-pituitary-adrenocortical (HPA) system. Most recently, we could show that severe emotional stressors induce a significant rise in plasma ACTH even in mice deficient for the CRHR1 (Crhr1-1-) which is, however, not accompanied by an increase in plasma corticosterone concentration, suggesting that CRHR1 might be directly involved in the regulation of adrenal corticosterone release. We therefore used the Crhr1-1- mouse model to clarify the potential role of adrenal CRHR1 in the regulation of the HPA system and, in particular, of corticosterone secretion. In Crhr1-/- mice, intravenous ACTH administration failed to stimulate corticosterone secretion despite a significant upregulation of ACTH receptor mRNA levels in the adrenal cortex of these mutants. Further, by means of RT-PCR and in situ hybridization analyses, we could provide first evidence that both CRHR1 and CRHR2 are expressed in the mouse pituitary and adrenal cortex. Stimulation of pituitary CRHR2 does not induce ACTH secretion either in vitro or in vivo. Our data strongly suggest that CRHR1 plays a crucial role in the release of corticosterone from the adrenal cortex, independently of pituitary function. The existence of an intra-adrenal CRH/CRHR1 regulatory system which contributes to the corticosteroid secretory activity adds to the complexity of HPA system regulation and stress hormone homeostasis.

Adrenal Cortex↗

PubMed2001

Normal human pituitary gland and pituitary adenomas express cannabinoid receptor type 1 and synthesize endogenous cannabinoids: first evidence for a direct role of cannabinoids on hormone modulation at the human pituitary level.

Little is known about the expression and function of cannabinoid receptor type 1 (CB1) in the human pituitary gland. The aim of this study was to investigate CB1 expression in human normal and tumoral pituitaries by in situ hybridization and immunohistochemistry using an antibody against CB1. CB1 was found in corticotrophs, mammotrophs, somatotrophs, and folliculostellate cells in the anterior lobe of normal pituitary. After examination of 42 pituitary adenomas, CB1 was detected in acromegaly-associated pituitary adenomas, Cushing's adenomas, and prolactinomas, whereas faint or no expression was found in nonfunctioning pituitary adenomas. Experiments with cultured pituitary adenoma cells showed that the CB1 agonist WIN 55,212--2 inhibited GH secretion in most of acromegaly-associated pituitary adenomas tested and that the CB1 antagonist SR 141716A was generally able to reverse this effect. Moreover, WIN 55,212--2 was able to suppress GHRH-stimulated GH release, and this effect was not blocked by coincubation with SR 141716A, possibly indicating a non-CB1-mediated effect. In contrast, WIN 55,212--2 was ineffective on GH-releasing peptide-stimulated GH release. In four Cushing's adenomas tested, WIN 55,212--2 was not able to modify basal ACTH secretion. However, simultaneous application of CRF and WIN 55,212--2 resulted in a synergistic effect on ACTH secretion, and this effect could be abolished by SR 141716A, demonstrating a CB1-mediated effect. In the single case of prolactinomas tested, WIN 55,212--2 was able to inhibit basal secretion of PRL. Finally, the presence of endocannabinoids (anandamide and 2-arachidonoylglycerol) was investigated in normal and tumoral pituitaries. All tumoral samples had higher contents of anandamide and 2-arachidonoylglycerol compared with the normal hypophysis. Moreover, endocannabinoid content in the different pituitary adenomas correlated with the presence of CB1, being elevated in the tumoral samples positive for CB1 and lower in the samples in which no or low levels of CB1 were found. The results of this study point to a direct role of cannabinoids in the regulation of human pituitary hormone secretion.

Adenoma↗

PubMed2001

Effects of the gp130 cytokines ciliary neurotropic factor (CNTF) and interleukin-11 on pituitary cells: CNTF receptors on human pituitary adenomas and stimulation of prolactin and GH secretion in normal rat anterior pituitary aggregate cultures.

Two of the most potent cytokines regulating anterior pituitary cell function are leukemia inhibitory factor (LIF) and interleukin (IL)-6, which belong to the cytokine family using the common gp130 signal transducer. Recently, the expression and action of two other members of this family, IL-11 and ciliary neurotrophic factor (CNTF), on different cell lines has also been demonstrated. We studied the expression of the specific receptor subunits for CNTF in mammotropic, non-functioning and somatotropic tumors and the action of CNTF and IL-11 in the regulation of hormone secretion in these and normal pituitary cells. The mRNA for the alpha chain specific for the CNTF receptor was detected by Northern blot in tumors secreting prolactin (PRL) and GH and in non-functioning tumors. We found that both IL-11 and CNTF exerted a similar stimulatory effect on GH mRNA expression in somatotropic monolayer cell cultures from acromegalic tumors, but these cytokines had no significant influence on GH secretion. CNTF stimulates prolactin secretion in lactotropic monolayer cell cultures from patients with prolactinoma. In monolayer cell cultures from normal rat anterior pituitary, IL-11 and CNTF had no significant effect on the release of either GH or PRL, or on GH mRNA. However, when the cells were cultured in aggregate cultures, in which the three-dimensional structure of the cells is reconstituted, both cytokines, in doses at which they had no effect on monolayer cultures, significantly stimulated both PRL and GH secretion. These data show that IL-11 and CNTF may act as regulatory factors in anterior pituitary cells, in which the three-dimensional structure of the gland is of critical importance.

Adenoma↗