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PubMed2001

Interaction between paracrine tumor necrosis factor-alpha and paracrine angiotensin II during myocardial ischemia.

OBJECTIVES: The purpose of this study was to explore interactions between paracrine angiotensin II (Ang-II) and tumor necrosis factor-alpha (TNF-alpha) during myocardial ischemia. BACKGROUND: Ischemic myocardium releases significant amounts of TNF-alpha. This paracrine release correlated with postischemic myocardial injury. Other studies showed myocardial protection obtained by the use of angiotensin-converting enzyme inhibitors (i.e., captopril) and the Ang-II type 1 receptor antagonist losartan after ischemia. The possibility that these agents decrease TNF-alpha synthesis has not yet been investigated. METHODS: Using the modified Langendorff model, isolated rat hearts underwent either 90 min of nonischemic perfusion (control group) or 1 h of global cardioplegic ischemia. In both groups, either captopril (360 micromol/liter) or losartan (182.2 micromol/liter) was added before ischemia. The hearts were assayed for messenger ribonucleic acid (mRNA) expression and effluent TNF-alpha levels. In addition, cardiac myocytes were incubated in cell culture with Ang-II. RESULTS: After ischemia, TNF-alpha mRNA expression intensified from 0.63 +/- 0.06 (control group) to 0.92 +/- 0.12 (p < 0.03), and effluent TNF-alpha levels were 711 +/- 154 pg/ml. The TNF-alpha mRNA expression declined to 0.46 +/- 0.07 (p < 0.01) and 0.65 +/- 0.08 (p < 0.02) in captopril- and losartan-treated hearts, respectively. Effluent TNF-alpha was below detectable levels. Concentrations of TNF-alpha in supernatants of incubated cardiac myocytes treated with 10 and 50 nmol/liter of Ang-II were 206.0 +/- 47.0 pg/ml and 810 +/- 130 pg/ml, respectively (p < 0.004). When pretreated with 700 micromol/liter of losartan, TNF-alpha was below detectable levels. CONCLUSIONS: This study presents an original explanation for previously reported myocardial protection after ischemia, obtained by the use of captopril and losartan. These drugs reduce TNF-alpha synthesis, providing strong evidence of active interactions between paracrine TNF-alpha and Ang-II in the evolution of the ischemic cascade.

Angiotensin II↗
PubMed2000

Expression of insulin-like growth factor-I (IGF-I) and IGF-II in the avian brain: relationship of in situ hybridization patterns with IGF type 1 receptor expression.

Insulin-like growth factors (IGFs) are expressed in defined spatiotemporal patterns during the development of the mammalian central nervous system (CNS). Since IGF expression in avian species is less well documented, we studied here the expression of IGF-I and IGF-II during chicken CNS development, using in situ hybridization and reverse transcriptase-PCR, and compared the results with the expression of the IGF type 1 receptor (IGF-1R). IGF-II expression started early in embryonic life, shortly after the onset of IGF-1R expression. During organogenesis, IGF-II was strongly expressed in kidney, liver and gut primordia, in contrast with IGF-1R mRNA, which is highly enriched in proliferating neuroepithelia. During the second half of embryonic development, IGF-I and IGF-II had distinct expression patterns, suggesting specific roles for each ligand during brain maturation. IGF-II mRNA was found in numerous brainstem nuclei and in the optic tectum, whereas IGF-I mRNA was found predominantly in telencephalic regions. Both ligands were expressed in the cerebellum, but each by different cell layers. Some brain regions (olfactory bulb and olivo-cerebellar system) did not exhibit the postnatal downregulation typical of extrahepatic IGF-I expression, but continued to express IGF-I into adulthood. Purkinje cells expressed IGF-II in the embryo, but switched to IGF-I expression in the adult. The conservation of embryonic and postnatal IGF expression patterns in the CNS between avians and mammals suggests that the involvement of the IGF system in neurogenesis and differentiation, and possibly in neural plasticity and learning, may have arisen early during tetrapode/vertebrate evolution.

Age Factors↗
PubMed1998

Growth hormone: a paracrine growth factor in embryonic development?

Although pituitary growth hormone is obligatory for normal postnatal growth and development, early embryonic and fetal growth is generally considered to be independent of pituitary GH. Indeed, in chickens, somatotrophs and serum GH are not detectable until late in embryogenesis, and neither partial decapitation nor pre-hatch GH administration greatly affects embryonic growth. However, since it is now known that GH can be produced and act in many extra-pituitary tissues, early embryonic growth may be independent of pituitary GH but dependent upon the paracrine actions of extra-pituitary GH. The possibility that growth hormone may be a paracrine growth factor during early development will therefore be considered in this brief review, which is based on the embryogenesis of the domestic fowl.

Animals↗
PubMed2001

Top-DER- and Dpp-dependent requirements for the Drosophila fos/kayak gene in follicular epithelium morphogenesis.

The Drosophila fos (Dfos)/kayak gene has been previously identified as a key regulator of epithelial cell morphogenesis during dorsal closure of the embryo and fusion of the adult thorax. We show here that it is also required for two morphogenetic movements of the follicular epithelium during oogenesis. Firstly, it is necessary for the proper posteriorward migration of main body follicle cells during stage 9. Secondly, it controls, from stage 11 onwards, the morphogenetic reorganization of the follicle cells that are committed to secrete the respiratory appendages. We demonstrate that DER pathway activation and a critical level of Dpp/TGFbeta signalling are required to pattern a high level of transcription of Dfos at the anterior and dorsal edges of the two groups of cells that will give rise to the respiratory appendages. In addition, we provide evidence that, within the dorsal-anterior territory, the level of paracrine Dpp/TGFbeta signalling controls the commitment of follicle cells towards either an operculum or an appendage secretion fate. Finally, we show that Dfos is required in follicle cells for the dumping of the nurse cell cytoplasm into the oocyte and the subsequent apoptosis of nurse cells. This suggests that in somatic follicle cells, Dfos controls the expression of one or several factors that are necessary for these processes in underlying germinal nurse cells.

Animals↗
PubMed1999

Repression by Notch is required before Wingless signalling during muscle progenitor cell development in Drosophila.

The larval muscles of Drosophila arise from the fusion of muscle founder cells, which give each individual muscle its identity, with myoblasts (reviewed in [1]). Muscle founder cells arise from the asymmetric division of muscle progenitor cells, each of which develops from a group of cells in the somatic mesoderm that express lethal of scute [2]. All the cells in a cluster can potentially form muscle progenitors, but owing to lateral inhibition, only one or two develop as such [2] [3] [4] [5]. Muscle progenitors, and the subsequent founder cells, then express transcription factors such as Krüppel, S59 and Even-skipped, which confer identity on the muscle [6] [7] [8]. Definition of some muscle progenitors, including three groups that express S59, depends on Wingless signalling [9]. Lateral inhibition requires Delta signalling through Notch and the transcription factor Suppressor of Hairless [3] [4] [5]. As the Wingless and lateral-inhibition signals are sequential [8], one might expect that muscle progenitors would fail to develop in the absence of Wingless signalling, regardless of the presence or absence of lateral-inhibition signalling. Here, we examine the development of the S59-expressing muscle progenitor cells in mutant backgrounds in which both Wingless signalling and lateral inhibition are disrupted. We show that progenitor cells failed to develop when both these processes were disrupted. Our analysis also reveals a repressive function of Notch, required before or concurrently with Wingless signalling, which is unrelated to its role in lateral inhibition.

Animals↗
PubMed2001

Paracrine regulation of keratinocyte proliferation and differentiation.

The histoarchitecture and function of the epidermis depend on a well-controlled balance between keratinocyte proliferation and differentiation. This balance is perturbed after skin injury, and imbalance is a characteristic feature of major human skin diseases such as psoriasis and epidermal cancers. Recent studies have highlighted the importance of fibroblast-derived soluble factors for the regulation of keratinocyte proliferation and differentiation. Therefore, identification of these paracrine-acting factors and the elucidation of their mechanisms of action are necessary for understanding epidermal homeostasis, repair and disease, and these approaches will offer new potential targets for drug therapy. Here, we review exciting recent findings on the identification, regulation and function of paracrine-acting cytokines in the skin. In particular, we describe the role of fibroblast-derived mitogens as regulators of keratinocyte proliferation and differentiation, and we summarize the regulation of these factors by keratinocyte-derived interleukin 1 that involves the transcription factors c-Jun and JunB.

Animals↗
PubMed2001

Plasma and pericardial fluid natriuretic peptide levels in postinfarction ventricular dysfunction.

AIMS: In the present study we examined plasma and pericardial fluid ANP and BNP concentrations in postinfarction ventricular dysfunction. The association of peptide levels to left ventricular (LV) dysfunction and to the localization of the myocardial infarction (MI) was studied. METHODS AND RESULTS: Plasma and pericardial fluid samples were obtained from 37 patients undergoing coronary bypass surgery. According to the ECG and preceding coronary angiography, the patients were divided into three groups: previous anterior myocardial infarction (MI) (n=12), previous inferior/posterior MI (n=15) and no history of MI (n=10). When compared to the control group with no MI, the patients with anterior MI had elevated plasma ANP and BNP (134+/-13 vs. 81+/-15 pg/ml, P<0.01 and 95+/-10 pg/ml vs. 26+/-8 pg/ml, P<0.01, respectively) and pericardial fluid BNP (473+/-60 pg/ml vs. 57+/-8 pg/ml, P<0.001) levels. The plasma natriuretic peptide concentrations were not increased in the patients with inferior/posterior MI, but the pericardial fluid BNP concentrations were greater than in the patients with no history of MI (129+/-35 pg/ml vs. 57+/-8 pg/ml, P<0.05). Six of the 12 patients with previous anterior MI had LVEF> or =45%. Despite their normal LV systolic function, these patients had increased plasma and pericardial fluid BNP levels when compared to the group with no history of MI (68+/-18 pg/ml vs. 26+/-8 pg/ml, P<0.05 and 534+/-258 pg/ml vs. 57+/-8 pg/ml, P<0.01, respectively). CONCLUSIONS: Previous anterior myocardial infarction was associated with increased cardiac BNP production even if the LV systolic function was normal (LVEF> or =45%). The high pericardial fluid BNP concentrations in postinfarction patients suggest that the BNP synthesis and release are augmented in the ventricular myocardium independent from the LVEF.

Adult↗
PubMed2001

Recombinant human extracellular matrix protein 1 inhibits alkaline phosphatase activity and mineralization of mouse embryonic metatarsals in vitro.

Two mRNAs are transcribed from the extracellular matrix protein 1 gene (Ecm1): Ecm1a and an alternatively spliced Ecm1b. We studied Ecm1 mRNA expression and localization during endochondral bone formation and investigated the effect of recombinant human (rh) Ecm1a protein on organ cultures of embryonic mouse metatarsals. Of the two transcripts, Ecm1a mRNA was predominantly expressed in fetal metacarpals from day 16 to 19 after gestation. Ecm1 expression was not found in 16- and 17-day-old metatarsals of which the perichondrium was removed. In situ hybridization and immunohistochemistry demonstrated Ecm1 expression in the connective tissues surrounding the developing bones, but not in the cartilage. Biological effects of rhEcm1a protein on fetal metatarsal cultures were biphasic: at low concentrations, Ecm1a stimulated alkaline phosphatase activity and had no effect on mineralization, whereas at higher concentrations, Ecm1a dose dependently inhibited alkaline phosphatase activity and mineralization. These results suggest that Ecm1a acts as a novel negative regulator of endochondral bone formation.

Alkaline Phosphatase↗
PubMed1997

Mechanically regulated expression of a neural glutamate transporter in bone: a role for excitatory amino acids as osteotropic agents?

Without habitual exercise, bone is lost from the skeleton. Interactions between the effects of loading of bone and other osteotropic influences are thought to regulate bone mass. In an attempt to identify potential targets for therapeutic manipulation of bone mass, we used differential RNA display to investigate early changes in osteocyte gene expression following mechanical loading of rat bone in vivo. One gene found to be down-regulated by loading had high homology to a glutamate/ aspartate transporter (GLAST) previously identified only the mammalian CNS. RT-PCR analysis using primers targeted to the coding region of the published GLAST sequence amplified identical products from bone and brain (but not a range of other tissues). The amplicons were sequenced and found to be identical to the published CNS GLAST sequence. Northern analysis confirmed expression of GLAST mRNA in bone and brain, but not other tissues. In situ hybridization localized GLAST mRNA expression in rat bone to osteoblasts and osteocytes. A GLAST antibody localized high levels of protein expression to osteoblasts, and newly incorporated osteocytes. Interestingly, older osteocytes also expressed detectable levels of GLAST. Another neural glutamate transporter, GLT-1 was immunolocalized to the pericellular region of mononuclear bone marrow cells, while a further antibody to the EAAC-1 transporter failed to bind to bone cells. Five days after loading, GLAST protein expression was undetectable in osteocytes of loaded bone but present in control nonloaded sections, confirming the downregulation detected by differential display. On quiescent periosteal surfaces, GLAST expression was almost absent, while on surfaces where loading had induced cellular proliferation and bone formation, GLAST protein expression was elevated. In the CNS, the expression of glutamate transporters on neuronal membranes is associated with reuptake of released neurotransmitters at synapses, where they have a role in the termination of transmitter action. In this study, we describe for the first time, the expression of GLAST (and GLT-1) in bone, raising the possibility that excitatory amino acids may have a role in paracrine intercellular communication in bone. Manipulation of bone cell function by moderators of glutamate action could therefore provide novel treatments for bone diseases such as osteoporosis.

ATP-Binding Cassette Transporters↗
PubMed1998

Melanocortin receptor binding determinants in the agouti protein.

The agouti protein plays an important role in the development of diabetes and obesity in rodents and has been shown to be a potent antagonist of melanocortin receptors. For this reason alanine-scanning mutagenesis was performed on the agouti protein carboxyl terminus to locate residues important for melanocortin receptor binding inhibition. When agouti residues Arg116 and Phe118 are changed to alanine, very large decreases in agouti affinity for melanocortin receptor 1, 3, and 4 result. Mutation of Phe117 to alanine causes a similar increase in agouti KI app at melanocortin receptor 4. Substitution of agouti residue Asp108 with alanine results in large increases in KI app for all three melanocortin receptors examined. All of these residues are conserved in the agouti-related transcript, ART, whose expression is up-regulated in animal models of obesity. The three-dimensional structure of the agouti carboxyl terminus was modeled, and residues which decrease receptor binding by a factor of > or = 15 when mutated to alanine localize to one side of the structure. These agouti variants with altered receptor selectivity may be useful in determining the role of melanocortin receptors in diabetes and obesity.

Agouti Signaling Protein↗
PubMed2000

Paracrine effects of a uterine agglutinin are mediated via the sialic acids present in the rat uterine endometrium.

A 32 kDa estrogen-induced, sialic acid-specific agglutinin (P-SAS) was isolated from rat endometrium in its proestrus stage. To investigate the functional importance of P-SAS in the uterine milieu, specific binding assays were carried out with 125I-labeled P-SAS and different cellular components of the uterus (epithelial, stromal and myometrial cells), that were isolated from different stages of the estrus cycle. The results indicate that although the protein is secreted from the epithelial cells in the estrogenic phase, it binds specifically to the stromal cells, especially to those isolated from the diestrus stage of the estrus cycle. The specific binding, however, is seen to decrease with the progression of pregnancy. Scatchard analysis performed with varying amounts of 125I-P-SAS in the presence of excess cold P-SAS revealed that the binding occurs with a Ka = 1.69 x 10(8) M(-1). As P-SAS binds specifically to sialic acids on the stromal cell surface, further characterization of the sialic acid molecule to which P-SAS binds was carried out by gas liquid chromatography (GLC). The studies revealed that P-SAS preferentially binds to N-glycolylneuraminic acid, which is attached to the penultimate sugar of the stromal cell surface glycoprotein chain via alpha2,6 linkage. As P-SAS is further known to be mitogenic, the effect of P-SAS on cultured stromal cells was studied in vitro. The growth regulatory assays revealed that P-SAS induced 3H-thymidine uptake by stromal cells in culture. Thus, from the above observations, paracrine effects of P-SAS on the stromal cells and on the subsequent growth and development of the uterus can be assumed.

Agglutinins↗
PubMed2001

Retinoic acid-induced apoptosis in leukemia cells is mediated by paracrine action of tumor-selective death ligand TRAIL.

The therapeutic and preventive activities of retinoids in cancer are due to their ability to modulate the growth, differentiation, and survival or apoptosis of cancer cells. Here we show that in NB4 acute promyelocytic leukemia cells, retinoids selective for retinoic-acid receptor-alpha induced an autoregulatory circuitry of survival programs followed by expression of the membrane-bound tumor-selective death ligand, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand, also called Apo-2L). In a paracrine mode of action, TRAIL killed NB4 as well as heterologous and retinoic-acid-resistant cells. In the leukemic blasts of freshly diagnosed acute promyelocytic leukemia patients, retinoic-acid-induced expression of TRAIL most likely caused blast apoptosis. Thus, induction of TRAIL-mediated death signaling appears to contribute to the therapeutic value of retinoids.

Antineoplastic Agents↗
PubMed2000

Effect of neutral endopeptidase inhibitor on endogenous atrial natriuretic peptide as a paracrine factor in cultured cardiac fibroblasts.

1. Cardiac remodelling is a fundamental response to hypertension, myocardial infarction and chronic heart failure, and involves cardiac fibroblast proliferation and production of extracellular matrix components such as collagen. The present study was performed to examine the role of endogenous atrial natriuretic peptide (ANP) as a possible paracrine factor for cardiac fibroblasts, and to examine the effects of three neutral endopeptidase (NEP) inhibitors, thiorphan, phosphoramidon and ONO-BB-039-02 (ONO-BB) on endogenous ANP-induced changes in collagen synthesis by cultured neonatal rat cardiac fibroblasts. 2. Each NEP inhibitor singly had no significant effect on collagen synthesis by cardiac fibroblasts, except for maximum concentration (10(-3) M) of thiorphan. 3. Exogenous ANP inhibited collagen synthesis in a concentration-dependent manner (10(-8) - 10(-6) M). Thiorphan (10(-4) and 10(-3) M) and phosphoramidon (10(-5) and 10(-4) M) enhanced the ANP (10(-7) M)-induced decrease in collagen synthesis. ONO-BB (10(-5) and 10(-4) M) slightly enhanced the ANP-induced decrease in collagen synthesis. 4. Myocyte-conditioned medium (MC-CM), as well as exogenous ANP, inhibited collagen synthesis dose-dependently. The decrease in collagen synthesis at 100% MC-CM was augmented by thiorphan (10(-3) M), phosphoramidon (10(-4) M) and ONO-BB (10(-4) M). 5. HS-142-1, a natriuretic peptide receptor antagonist, significantly reduced the MC-CM plus thiorphan- and MC-CM plus ONO-BB-induced decrease in collagen synthesis, by 92 and 62%, respectively and showed a tendency to attenuate the MC-CM plus phosphoramidon-induced decrease in collagen synthesis by 40%. 6. Our observations suggested that endogenous ANP released from cardiomyocytes inhibited collagen synthesis as a paracrine factor and that NEP inhibitors enhanced the activity of this peptide in cardiac fibroblasts.

Animals↗
PubMed2001

Paracrine regulation of apoptosis by steroid hormones in the male and female reproductive system.

In males, androgens are essential in maintaining the integrity of the prostate. Androgen-ablation induces apoptosis of the prostatic epithelium. In females, ovariectomy induces apoptosis in uterine epithelium while progesterone inhibits this process. The objective of this study was to determine whether androgen and progesterone inhibit apoptosis, respectively, in mouse prostatic and uterine epithelia via steroid receptors in the epithelium or in the stroma. To address this question, prostatic tissue recombinants were prepared with rat urogenital sinus mesenchyme plus bladder epithelium from wild-type or testicular feminization mutant (Tfm) mice. Thus, prostatic tissue was generated having androgen receptor (AR) in both epithelium and stroma or in the stroma only. Castration of hosts induced apoptosis in the AR-negative Tfm prostatic epithelium with an epithelial apoptotic index virtually identical to prostatic tissue recombinants containing wild-type epithelium. Moreover, this castration-induced prostatic epithelial apoptosis was blocked by testosterone and dihydrotestosterone in both wild-type and Tfm prostatic tissue recombinants. Likewise, uterine tissue recombinants were prepared in which epithelium and/or stroma was devoid of progesterone receptor (PR) by using uterine epithelium and stroma of wild-type and PR knockout mice. Progesterone inhibited uterine epithelial apoptosis only in tissue recombinants prepared with PR-positive stroma. The PR status of the epithelium did not affect epithelial apoptotic index. Therefore, the apoptosis in prostatic and uterine epithelia is regulated by androgen and progesterone via stromal AR and PR, respectively. In both cases, epithelial AR or PR is not required for hormonal regulation of epithelial apoptosis in prostatic and uterine epithelium.

Androgens↗
PubMed1998

Adipose tissue as an endocrine and paracrine organ.

The discovery of leptin has imparted great impetus to adipose tissue research by demonstrating a more active role for the adipocyte in energy regulation. Besides leptin, however, the adipose tissue also secretes a large number other signals. Cytokine signals, TNFalpha and IL-6, and components of the alternative pathway of complement influence peripheral fuel storage, mobilization and combustion, as well as energy homeostasis. In addition to the acute regulation of fuel metabolism, adipose tissue also influences steroid conversion and sexual maturation. In this way, adipose tissue is an active endocrine organ, influencing many aspects of fuel metabolism through a network of local and systemic signals, which interact with the established neuroendocrine regulators of adipose tissue. Thus, insulin, catecholamines and anterior pituitary endocrine axes interact at multiple levels with both cytokines and leptin. It may be proposed that the existence of this network of adipose tissue signalling pathways, arranged in an hierarchical fashion, constitutes a metabolic repertoire which enables the organism to adapt to a range of different metabolic challenges, including starvation, reproduction, times of physical activity, stress and infection, as well as short periods of gross energy excess. However, the occurrence of more prolonged periods of energy surplus, leading to obesity, is an unusual state in evolutionary terms, and the adipose tissue signalling repertoire, although sophisticated, adapts poorly to these conditions. Rather, the responses of the adipose tissue endocrine network to obesity are maladaptive, and lay the foundations of metabolic disease.

Adipose Tissue↗
PubMed2000

Growth factor-extracellular matrix synergy in the control of trophoblast invasion.

At the periphery of the human placenta, trophoblast attaches to the uterine wall. The tissue interface contains many anchoring sites, with cytotrophoblast columns that form bridges between the overlying extraembryonic (villous) mesenchyme and the maternal decidual stroma beneath. From the periphery of these columns, large numbers of trophoblast cells detach, migrate through the decidua and eventually colonize and transform maternal arteries. In this way the placenta increases and gives priority to the maternal blood supply to the conceptus. We have shown that when early villous tissue is explanted on a collagen gel in serum-free medium, anchoring-site morphogenesis occurs. Thus, in the presence of placental mesenchyme but in the absence of maternal cells, contact with a permissive extracellular matrix (ECM) is necessary and sufficient for cytotrophoblast column development. Proliferation of trophoblast occurs, followed by differentiation into a columnar cell phenotype in which cells remain attached to one another and to the ECM. At this stage, interaction between fibronectin and integrin alpha5beta1 at the cell surface stabilizes the column and the cells remain as a contiguous multilayered sheet. However, the addition of serum-free conditioned medium from first-trimester placental fibroblasts stimulates cytotrophoblast to detach from the distal column and migrate in streams across the ECM. The removal of insulin-like growth factor I (IGF-I) from the fibroblast medium decreases streaming activity, whereas the addition of exogenous IGF-I (10 ng/ml) to serum-free medium produces a streaming phenotype. In contrast, transforming growth factor beta1 (10 ng/ml) maintains the cells in a tight sheet. These results suggest the possibility of a paracrine interaction between villous mesenchyme and cytotrophoblast in anchoring sites to stimulate the infiltration of the maternal ECM by trophoblast. Such a mechanism would be self-limiting because the signal diminishes with distance from the placenta.

Animals↗
PubMed1998

Growth hormone and prolactin responses to corticotrophin-releasing-hormone in patients with Cushing's disease: a paracrine action of the adenomatous corticotrophic cells?

OBJECTIVE: In patients with Cushing's disease multihormonal responses to ovine corticotrophin releasing hormone (oCRH) have been detected in blood from inferior petrosal sinuses. This finding has been explained by co-secretion of other hormones, in addition to ACTH, by the pituitary adenoma itself or by paracrine effects exerted by the adenoma on normal periadenomatous pituitary cells. To assess these hypotheses we compared the presence of a CRH induced GH and/or PRL response during inferior petrosal sinus sampling to the immunohistochemical detection of PRL and GH in adenomatous tissue removed from patients with Cushing's disease. PATIENTS AND MEASUREMENTS: Twenty-two patients with Cushing's disease and two patients with ectopic ACTH syndrome due to a bronchial carcinoid were studied; each patient had undergone preoperative inferior petrosal sinus sampling for diagnostic purposes with determination of GH and PRL in addition to ACTH, before and after administration of oCRH. Immunohistochemical studies for ACTH, GH and PRL detection were carried out on adenomatous tissue removed at surgery in the patients with pituitary dependent Cushing's disease and on the carcinoid tumours from the two patients with ectopic ACTH syndrome. RESULTS: All pituitary adenomas immunostained for ACTH, and four adenomas immunostained for GH or PRL in addition to ACTH. A PRL increase in the inferior petrosal sinus after oCRH administration was found in 11 of 22 patients, but none of their tumours immunostained for PRL. Immunostaining for PRL was found in the pituitary tumours from two patients but in neither patient was there a PRL response after oCRH. A GH response was found in 13 of 20 patients in whom it was sought; no patient showed immunostaining in their tumour. GH immunostaining was found in two tumours but in neither patient was there a GH response after oCRH. The oCRH-induced increase of GH and PRL was always recorded in the dominant inferior petrosal sinus. The ACTH response to oCRH was significantly higher in patients who showed oCRH induced increases in GH and/or PRL than in patients who did not, both in terms of area under the response-curve (22,032 +/- 9876 vs. 4371 +/- 2870 ng/l/10 min; P < 0.05) or mean percentage increase above baseline (754 +/- 229% vs. 147.2 +/- 67%, P < 0.02). A significant correlation was observed between ACTH and GH responses to oCRH. The two patients with ectopic Cushing's syndrome did not show ACTH, GH or PRL increases after oCRH administration and did not show immunostaining for GH or PRL in their tumours. CONCLUSIONS: The present data do not support the hypothesis of co-secretion of hormones by the pituitary adenoma as the cause of the GH and PRL responses to ovine corticotrophin releasing hormone observed in patients with Cushing's disease; it is suggested that a different mechanism, possibly involving an interaction between the ACTH secreting adenoma and the normal periadenomatous GH and PRL secreting cells, may be responsible.

Adenoma↗
PubMed2001

The release of leptin and its effect on hormone release from human pituitary adenomas.

BACKGROUND: Leptin is the protein product of the obese gene, known to play an important role in body energy balance. The leptin receptor exists in numerous isoforms, the long isoform being the major form involved in signal transduction. Leptin expression has recently been demonstrated in the human pituitary, both in normal tissue and in pituitary adenomas. The long isoform of the leptin receptor has also been shown to be present in pituitary adenomas; however, contrasting results have been obtained regarding its expression in the normal human pituitary. AIM: The aim of this study was (i) to investigate the presence and pattern of distribution of leptin mRNA and the long isoform of its receptor mRNA in the normal pituitary and in different types of pituitary adenomas with RT-PCR; (ii) to study leptin secretion from human pituitary tumours in culture and (iii) to assess in vitro pituitary hormone release following stimulation with human leptin. RESULTS: Leptin receptor long isoform expression was detected in 2/4 GH-secreting adenomas, 12/17 non-functioning adenomas, 5/9 ACTH-secreting adenomas, 1/2 prolactinomas, 2/2 FSH-secreting adenomas and 5/5 normal pituitaries. The receptor long isoform did not segregate with any particular tumour type, and varying levels of expression were detected between the tissues studied. Leptin mRNA was detected at a low level of expression in 2/7 GH-secreting adenomas, 9/14 non-functioning adenomas, 2/3 ACTH-secreting adenomas, 1/3 prolactinomas and 1/3 FSH-secreting adenomas. We were unable to detect leptin mRNA in any of the five normal pituitaries removed at autopsy; however, immunostaining of a non-tumorous pituitary adjacent to an adenoma removed at transsphenoidal surgery showed scattered leptin positive cells. Culture of pituitary adenomas showed that 16/47 released leptin into the incubation media. Leptin release did not correlate with tumour type or with any of the other pituitary hormones released. In vitro leptin stimulation of pituitary tumours caused stimulation of FSH and alpha-subunit secretion from a non-functioning adenoma and TSH secretion from a somatotroph adenoma. CONCLUSION: We conclude that not only is leptin stored within the pituitary, but it may also be released from pituitary cells and modulate other pituitary hormone secretion. Pituitary leptin may therefore be a novel paracrine regulator of pituitary function.

Adenoma↗