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Biomedical subjects

I Shimon

Publications and source records attributed to I Shimon.

At least 19 recordsLinked to original sources
PubMed2001

Transsphenoidal surgery for acromegaly: endocrinological follow-up of 98 patients.

OBJECTIVE: Transsphenoidal surgery is the preferred treatment modality for growth hormone (GH)-secreting pituitary adenomas. In many series, the reported postoperative remission is based mainly on achievement of GH levels less than 2 ng/ml. Strict criteria for insulin-like growth factor I normalization and even lower GH levels (<1 ng/ml) are now suggested to define cure of acromegaly, but the evidence does not yet support such low GH levels in epidemiological follow-up. We analyzed our postoperative results in a large cohort of patients with acromegaly. METHODS: Ninety-eight patients harboring GH-secreting adenomas (46 microadenomas and 52 macroadenomas) underwent transsphenoidal surgery between 1990 and 1999. Ninety-one patients were operated for the first time, and 12 patients underwent reoperations because of previous surgical failure (7 had undergone surgery elsewhere previously). Biochemical remission was defined as a repeated fasting or glucose-suppressed GH level of 2 ng/ml or less, and a normal insulin-like growth factor I level. RESULTS: Remission was achieved in 74% of all patients after one operation, including 84% of patients with microadenomas and 64% of patients with macroadenomas. Seventy-three percent of patients with macroadenomas 11 to 20 mm in size achieved remission, as compared with a 20% remission rate for patients with adenomas larger than 20 mm. Patients with preoperative random GH levels lower than 50 ng/ml had a better outcome (85% remission), whereas GH greater than 50 ng/ml was associated with remission in 30% of the patients. Only one of the patients (8%) with postoperative active disease who underwent a second operation achieved remission. Recurrence was rare (one patient), and all failed surgical attempts could be detected during the immediate postoperative evaluation. CONCLUSION: On the basis of strict postoperative GH and insulin-like growth factor I criteria to define remission, our series demonstrates the efficacy of transsphenoidal surgery for acromegalic patients with microadenomas and noninvasive macroadenomas. However, patients with large adenomas (>20 mm) and preoperative GH greater than 50 ng/ml have a poor prognosis and require adjunctive medical or radiation therapy to control GH hypersecretion.

Acromegaly↗
PubMed2001

Prolactin (PRL)-releasing peptide stimulates PRL secretion from human fetal pituitary cultures and growth hormone release from cultured pituitary adenomas.

The hypothalamic peptide PRL-releasing peptide (PrRP) has recently been cloned and identified as a ligand of an orphan pituitary receptor that stimulates in vitro PRL secretion. PrRP also induces PRL release in rats in vivo, especially in normal cycling females. However, no information on the effects of PrRP in the human is available. To elucidate the role of PrRP in regulating human anterior pituitary hormones, we used human PrRP-31 in primary cultures of human pituitary tissues, including fetal (20--27 weeks gestation) and normal adult pituitaries, as well as PRL- and GH-secreting adenomas. PrRP increased PRL secretion from human fetal pituitary cultures in a dose-dependent manner by up to 35% (maximal effect achieved with 10 nM), whereas TRH was slightly more potent for PRL release. Coincubation with estradiol resulted in enhanced fetal PRL response to PrRP, and GH release was only increased in the presence of estradiol. Although PRL secretion from PRL-cell adenomas was not affected by PrRP, PrRP induced PRL release from cultures of a GH-cell adenoma that cosecreted PRL. PrRP enhanced GH release in several GH-secreting adenomas studied by 25--27%, including GH stimulation in a mixed PRL-GH-cell tumor. These results show for the first time direct in vitro effects of PrRP-31 on human pituitary cells. PrRP is less potent than TRH in releasing PRL from human fetal lactotrophs and is unable to release PRL from PRL-cell adenomas in culture, but stimulated GH from several somatotroph adenomas. Thus, PrRP may participate in regulating GH, in addition to PRL, in the human pituitary.

Adenoma↗
PubMed2001

Ovarian hyperstimulation without elevated serum estradiol associated with pure follicle-stimulating hormone-secreting pituitary adenoma.

We report a unique case of a 28-yr-old woman with a gonadotroph adenoma secreting FSH, presented with ovarian hyperstimulation, without elevation of serum estradiol. She presented with abdominal pain and large ovaries (both 10 cm in diameter) with multiple follicular cysts shortly after discontinuing oral contraceptive pills. She had a supranormal PRL level of 71 microg/liter (normal, <20), FSH of 8.4-9.2 IU/liter (normal for follicular phase, 2.4-10), LH of 0.01 IU/liter (normal, 1.6-9.3), estradiol of 108 pmol/liter (normal for follicular phase, 80-790), and free alpha-subunit level of 0.11 microg/liter (normal, <1.8). A nuclear magnetic resonance study revealed invasive pituitary macroadenoma, 30 mm in diameter. Dopamine agonist (cabergoline) treatment normalized serum PRL but had no affect on FSH levels. A transsphenoidal surgery was performed, and most of the adenoma was resected. One month after surgery the patient resumed menstruation, and the hormonal profile included serum FSH of 6.3 IU/liter, LH of 2.1 IU/liter, estradiol of 156 pmol/liter, and PRL of 10 microg/liter. The excised adenoma tissue exhibited intense immunostaining for FSH and secreted this hormone to culture medium. Stimulation with TRH (both in vivo preoperatively and in vitro study of the excised tumor) had no effect on FSH secretion from the adenoma. Estradiol did not suppress FSH release from cultured adenoma cells. Patient serum samples showed significant FSH bioactivity when tested in a human granulosa cell line. This case is remarkable because the ovarian hyperstimulation related to the FSH-secreting adenoma was not associated with high levels of serum estradiol, probably due to insufficient LH production by the normal pituitary. Thus, it supports the two-cell, two-gonadotropin theory, that both FSH and LH are necessary for normal ovarian estrogen production.

Abdominal Pain↗
PubMed2000

Acromegaly with normal growth hormone levels: response to Sandostatin-LAR treatment.

We report a case of acromegaly with relatively low GH secretion in a patient with GH-secreting pituitary macroadenoma. The 44-year-old male patient presented with left temporal hemianopsia and characteristic acromegalic face, but had relatively low baseline and post-glucose GH levels. IGF-1 and IGFBP-1 were elevated. Transsphenoidal surgery did not achieve clinical or biochemiacl remission, and the patient still had elevated IGF-1 levels with low GH. Histological examination of the resected tumor revealed a pituitary adenoma stained weakly for GH. The patient was treated then with monthly injections of Sandostatin-LAR, with clinical improvement and suppression of IGF-I to the normal range. This is a rare case of acromegaly without elevated GH levels, and good response to treatment with somatostatin analog, as expected in classical GH-secreting pituitary adenomas.

Acromegaly↗
PubMed2000

Hypopituitarism following closed head injury.

We describe four young patients (age 19-34 years) with hypopituitarism following closed head injury. The diagnosis was made by demonstration of low basal pituitary hormone levels and dynamic tests showing low pituitary reserve. The time interval between the injury and diagnosis of hypopituitarism was between three weeks and two months demonstrating the difficulty and complexity of making this diagnosis. Three of our patients (all patients suffering from anterior pituitary hormone deficiency) had ACTH deficiency, a condition which may be life threatening if left undiagnosed; these patients also demonstrated central hypothyroidism. Hypogonadotrophic hypogonadism occurred in three of the patients and was treated with hormonal replacement. Diabetes insipidus was the only insult in one of our patients, accompanied other hormonal deficits in two, and did not appear at all in another patient. Information about skull damage was available for three of the patients, and included skull base and facial bone fractures, probably reflecting the extent of injury necessary to cause hypopituitarism. All patients regained normal lives with adequate hormonal replacement therapy.

Adrenocorticotropic Hormone↗
PubMed1999

Leukaemia inhibitory factor enhances tissue factor expression in human monocyte-derived macrophages: a gp130-mediated mechanism.

Leukaemia inhibitory factor (LIF) and interleukin (IL)-6 are members of a cytokine group that share a common signal transducer gp130 and induce pleiotropic biological effects in cells of diverse lineage. In monocytes, LIF facilitates differentiation, which may stimulate the biosynthesis of tissue factor (TF) that initiates the coagulation cascade. We tested the hypothesis that LIF would enhance TF expression in human monocyte-derived macrophages (MDMs). Human peripheral blood mononuclear cells separated from whole blood by density centrifugation were allowed to differentiate into MDMs in primary culture, and were then exposed to LIF, IL-6 and oncostatin M (OSM) for 24 h. LIF and IL-6 receptors, and gp130 were demonstrated in MDMs by immunocytochemistry and RT-PCR. TF procoagulant activity (TF-PCA) was measured by recalcification clotting time and TF protein by Western blotting. The results show that both TF procoagulant activity and TF protein increased significantly in response to LIF over the concentration range of 1-100 nM (P < 0.03). Although OSM and IL-6 tended to enhance TF expression by MDMs, the increase did not reach statistical significance. Anti-LIF receptor and anti-gp130 antibodies attenuated the effect of LIF on TF expression as assayed by both bioassay and flow-cytometry. In conclusion, LIF increases TF-PCA and TF protein in MDMs, and specific anti-LIF receptor antibodies attenuate this effect. Thus, LIF may regulate by a gp130-dependent pathway macrophage-mediated procoagulant function in diverse pathological states involving inflammation and thrombosis and seems to serve as an important mediator at the interface between these processes.

Antigens, CD↗
PubMed1998

Management of pituitary tumors.

Management of pituitary tumors has improved in the past decade since the introduction of novel therapeutic agents. As a result, several treatment options are now available. Dopamine agonists are the preferred treatment for both symptomatic microprolactinomas and macroprolactinomas; these drugs result in normalization of hormone levels and tumor shrinkage in most treated patients. New formulations (such as cabergoline and parenteral bromocriptine) with prolonged duration of action offer improved compliance with treatment and cure rates. For acromegaly and adrenocorticotropin hormone (ACTH)-secreting, thyroid-stimulating hormone (TSH)-secreting, and nonfunctional adenomas, surgery often results in cure. Octreotide and the long-acting, slow-release somatostatin analogues are effective medical alternatives to or adjuvants for transsphenoidal surgery in patients with growth hormone-secreting and TSH-secreting tumors. No drug treatment is available for symptomatic nonfunctional tumors, and patients with ACTH-secreting adenomas may benefit from cortisol-lowering drugs after surgical failure. Pituitary irradiation may be required after surgery for ACTH-secreting, TSH-secreting, and nonfunctioning tumors; it is less commonly required for acromegaly. Although many pituitary tumors are successfully resected, functional adenomas may not be cured by surgery. As more-effective drugs are introduced for the management of pituitary tumors, more patients with hormone-secreting adenomas are being successfully treated medically.

Adenoma↗
PubMed1998

Prolactinomas express human heparin-binding secretory transforming gene (hst) protein product: marker of tumour invasiveness.

BACKGROUND AND OBJECTIVE: We have shown previously that heparin-binding secretory transforming gene (hst) overexpression in rat pituitary cells mediates lactotroph tumour growth and stimulates PRL transcription, and that transforming sequences of the gene, which encode fibroblast growth factor-4 (FGF-4), are expressed in human prolactinomas. To further determine the role of hst in human PRL-secreting adenoma pathogenesis we studied the presence of hst protein in these tumours and other types of human pituitary adenoma. PATIENTS AND DESIGN: Pituitary adenoma tissue samples were obtained at surgery from 14 patients with PRL-secreting adenomas, 5 patients with GH-secreting tumours, 3 with ACTH-secreting, and 13 patients with nonfunctioning tumours. Two normal pituitary tissue specimens were also studied. Clinical data, including tumour invasiveness assessed by preoperative MRI studies, were available. For hst protein immunolocalization, tumour frozen sections were immunostained with antihuman FGF-4 antibody. Immunoperoxidase staining for the proliferation-related nuclear antigen Ki-67 was performed using MIB-1 monoclonal antibody. RESULTS: Normal anterior pituitary cells did not contain immunoreactive hst protein. Lactotrophs in five of 14 prolactinomas (36%) stained strongly for hst compared with immunoreactive pituicytes in only one of 21 nonfunctioning, GH-, and ACTH-secreting adenomas (P = 0.05). Immunoreactive hst in adenoma cells was detected in 3 of 5 invasive prolactinomas, and in 2 of 9 noninvasive PRL-cell adenomas. Immunostaining for the proliferation-related antigen Ki-67 showed a higher proliferation index in hst-positive adenomas (3.94 + 0.85%) as compared with those immunonegative for hst (1.98 + 0.7%; P = 0.05). CONCLUSIONS: hst protein may be directly involved in prolactinoma development or progression, particularly in invasive tumours, probably due to the growth promoting effects of FGF-4.

Adrenocorticotropic Hormone↗
PubMed1998

Diagnosis and treatment of pituitary disease.

Critical issues in diagnosis and treatment of pituitary disease are surveyed. The most relevant clinical aspects of hyperprolactinemia, acromegaly, Cushing's disease, secondary hyperthyroidism, syndrome of inappropriate ADH secretion, panhypopituitarism, growth hormone deficiency, gonadotropin deficiency, ACTH deficiency, TSH deficiency, and diabetes insipidus are discussed. Diagnostic and therapeutic issues in the approach to pituitary adenomas, craniopharyngiomas and pituitary apoplexy are analyzed.

Diagnosis, Differential↗
PubMed1998

Human fetal pituitary expresses functional growth hormone-releasing peptide receptors.

The synthetic hexapeptide GH-releasing peptide (GHRP) stimulates a dose-dependent release of GH in humans in vivo and in animals both in vitro and in vivo via a specific receptor in the hypothalamus and pituitary. To determine the action of GHRP in the human fetal pituitary, reverse transcription-PCR was performed, and GHRP receptor messenger ribonucleic acid expression was detected in fetal pituitaries of 18- and 31-week gestation. Therefore, primary human fetal pituitary cultures (second and third trimesters) were treated with GHRP-6. GHRP-6 dose-dependently increased GH secretion from human fetal pituitary cultures by up to 80% (P < 0.001; maximal effect achieved with 100 nmol/L), whereas GHRH (10 nmol/L) stimulated GH by up to 120% (P < 0.001). However, GHRP together with GHRH was additive (up to 2.8-fold GH induction) with no evidence of further positive synergy. In contrast to GHRH, GHRP-6 did not alter human ACTH and PRL levels. A treatment time of 2 h was required for maximal GH stimulation. GHRP-6 reversed suppressed GH levels in cultures cotreated with either insulin-like growth factor I (P < 0.0001) or somatostatin (P < 0.05). GHRP-6 and GHRP-2 (100 nmol/L) had similar effects in stimulating human GH release. These results show a direct in vitro action of GHRP on human pituitary cells. GHRP is less potent than GHRH in directly releasing GH from human somatotrophs, and only additive effects of these two peptides occur at the level of the human fetal pituitary.

Adrenocorticotropic Hormone↗
PubMed1998

Intact leptin receptor is selectively expressed in human fetal pituitary and pituitary adenomas and signals human fetal pituitary growth hormone secretion.

Leptin, a circulating hormone secreted by adipocytes, communicates peripheral nutritional status to hypothalamic centers affecting satiety, energy expenditure, and body weight. The intact leptin receptor (OB-R), a single membrane-spanning peptide containing an approximately 300-amino acid intracellular domain, is highly expressed in the hypothalamus, whereas shorter OB-R isoforms with truncated cytoplasmic regions resulting from alternative splicing have also been identified. We studied expression of OB-R isoforms in human fetal pituitaries, adult anterior pituitaries, and human pituitary adenomas. Using RT-PCR, messenger ribonucleic acid expression of the OB-R intact isoform was detected in fetal anterior pituitary tissues, but not in adult anterior pituitary glands, whereas both fetal and adult tissues expressed the short forms. Messenger ribonucleic acid of both intact and short OB-R isoforms were expressed in 4 of 5 GH-secreting, all 9 PRL-secreting, and 26 of 29 nonfunctioning pituitary adenomas. Recombinant human leptin (3-6 nmol/L) specifically stimulated GH secretion from primary human fetal pituitary cultures by 40-90% (P < 0.05) without altering fetal ACTH, PRL, or gonadotropin secretion. Thus, the intact OB-R is selectively expressed in human fetal and adult pituitary tumor tissues, but not in normal adult pituitary. Leptin specifically stimulates GH release from normal fetal somatotrophs, substantiating the functionality of its intact receptor in the fetal pituitary. Thus, pituitary adenomas appear to revert to a fetal phenotype of leptin receptor expression.

Adenoma↗
PubMed1998

Mutation and expression analysis of the cyclin-dependent kinase inhibitor gene p27/Kip1 in pituitary tumors.

By regulating cyclin-cyclin-dependent kinase (CDK) complex activity, individual CDK inhibitors (CDKIs) are potential tumor suppressors. One of the CDKIs, p27/Kip1, binds to a variety of CDK-cyclin complexes. A link between loss of p27/Kip1 function and development of pituitary tumors was suggested by the formation of pituitary tumors in almost all mice with germline deletion of the p27/Kip1 gene. However, genetic aberrations in the p27/Kip1 locus have not been analyzed in human pituitary tumors. We investigated eighteen non-functioning and GH-secreting pituitary tumor samples for p27/Kip1 mutations by single-strand conformational polymorphism (SSCP) following PCR. We found five abnormally migrating samples on the PCR-SSCP analysis. The sequence of these samples revealed a polymorphism of codon 109 (Val-->Gly), which has been previously described. No other structural changes of p27/Kip1 were found in these pituitary tumors within the coding region. In addition, no difference in p27/Kip1 protein levels in pituitary tumor tissues compared with normal pituitary tissues was demonstrated by immunostaining. These data suggest that both p27/Kip1 mutations and decreases in p27/Kip1 protein levels are infrequent in the development of pituitary tumors.

Cell Cycle Proteins↗
PubMed1997

Somatostatin receptor (SSTR) subtype-selective analogues differentially suppress in vitro growth hormone and prolactin in human pituitary adenomas. Novel potential therapy for functional pituitary tumors.

Previously, we have shown somatostatin receptor (SSTR) subtype-specific regulation of growth hormone (GH), thyroid-stimulating hormone, and prolactin (PRL) secretion in human fetal pituitary cultures, where GH and thyroid-stimulating hormone are mediated by both SSTR2 and SSTR5, whereas SSTR2 preferentially mediates PRL secretion. We now tested SSTR subtype-selective analogues in primary human GH- and PRL-secreting pituitary adenoma cultures. Analogue affinities determined by membrane radioligand binding in cells stably expressing human SSTR forms were either SSTR2 or SSTR5-selective. Analogues preferential either for SSTR2, including octreotide, lanreotide, and novel compounds with improved affinity for SSTR2, or new SSTR5-selective compounds suppressed GH in tumor cell cultures (up to 44% of control; P < 0.0005). However, novel analogues from both groups were 30-40% more potent than octreotide and lanreotide in suppressing GH (P < 0.05). Heterologous analogue combinations containing both SSTR2- and SSTR5-selective compounds were more potent in decreasing GH than analogues used alone (P < 0.05), or than combinations of compounds specific for the same receptor subtype (P < 0.005). In contrast, SSTR2-selective analogues did not suppress PRL release from six cultured prolactinomas studied. However, new SSTR5-selective analogues suppressed in vitro PRL secretion (30-40%; P < 0.05) in four of six prolactinomas. These results suggest that both SSTR2 and SSTR5 are involved in GH regulation in somatotroph adenoma cells, whereas SSTR5 exclusively regulates PRL secretion from prolactinoma cells. Thus, somatostatin analogues with improved selective binding affinity for these receptor subtypes may be effective in the treatment of either GH- or PRL-secreting adenomas.

Adenoma↗
PubMed1997

Cytokine-dependent gp130 receptor subunit regulates human fetal pituitary adrenocorticotropin hormone and growth hormone secretion.

We have shown recently that leukemia inhibitory factor (LIF) and oncostatin M (OSM), two members of the gp130-dependent cytokine family, stimulate murine proopiomelanocortin (POMC) transcription and adrenocorticotropin hormone (ACTH) secretion. LIF and corticotropin-releasing hormone (CRH) also synergistically induced in vivo ACTH secretion in fetal nonhuman primates. To elucidate the role of the gp130-related cytokines in human pituitary hormone regulation, we tested expression of gp130-related cytokine receptors in human fetal pituitaries. Using RT-PCR, mRNA expression of receptors for LIF, IL-6, and CRH, and the gp130 subunit, were all detected in fetal pituitaries of 18- and 31-wk gestation. Recombinant human IL-6, LIF, and OSM treatments of primary human fetal pituitary cultures (16-31 wk) increased ACTH secretion by up to 48% (P < 0.05) using doses of 1 nM, and when fetal cultures were cotreated with CRH, ACTH was induced five- to sixfold as compared to CRH alone (three- to fourfold; P = 0.01). Incubation with gp130-specific antibody suppressed basal and cytokine-stimulated ACTH secretion (alone or with CRH) from human fetal cells. Human POMC promoter -879/+6 fused to the luciferase reporter gene and transfected into AtT-20 cells, was stimulated by LIF (7-fold), which also exerted strong (22-fold) synergy with CRH on POMC transcription. Growth hormone (GH) release from fetal cultures was modestly stimulated (15-31%, P < 0.05), while other anterior pituitary hormones were not altered by these cytokines. Thus, physiologic concentrations of the gp130-related cytokines have direct effects on ACTH and GH regulation in the human pituitary, indicating that gp130-dependent signals serve as a paracrine system controlling early human pituitary function.

Adrenocorticotropic Hormone↗
PubMed1997

Somatostatin receptor subtype specificity in human fetal pituitary cultures. Differential role of SSTR2 and SSTR5 for growth hormone, thyroid-stimulating hormone, and prolactin regulation.

Somatostatin (SRIF), a hypothalamic inhibitor of pituitary growth hormone (GH) and thyroid-stimulating hormone (TSH) secretion, binds to five distinct receptor (SSTR) subtypes. We therefore tested SSTR subtype-specific SRIF analogs in primary human fetal pituitary cultures (23-25-wk gestation) to elucidate their role in regulating human pituitary function. Using reverse transcription-PCR, mRNA expression of SSTR2 and SSTR5 were detected in fetal pituitary by 25 wk. SRIF analog affinities were determined by membrane radioligand binding in cells stably expressing the human SSTR forms. GH secretion was suppressed equally (40-60%, P < 0.005) by analogs preferential for either SSTR2 (IC50 for receptor binding affinity, 0.19-0.42 nM) or SSTR5 (IC50, 0.37 nM), and compounds with enhanced affinity for SSTR2 were more potent (EC50 for GH suppression, 0.05-0.09 nM) than Lanreotide (EC50, 2.30 nM) and SRIF (EC50, 0.19 nM). Similarly, analogs with high affinity for SSTR2 or SSTR5 decreased TSH secretion (30-40%, P < 0.005). However, prolactin was effectively inhibited only by compounds preferentially bound to SSTR2 (20-30%, P < 0.05). Luteinizing hormone was modestly decreased (15-20%) by SSTR2- or SSTR5-specific analogs. An SSTR5-specific analog also exclusively inhibited GH in acromegalic tumor cells. Thus, SRIF regulation of GH and TSH in primary human fetal pituitary cells is mediated by both SSTR2 and SSTR5, both of which are abundantly expressed by 25 wk. In contrast, suppression of prolactin is mediated mainly by SSTR2. These results indicate that SSTR5 is critical for physiologic regulation of GH and TSH. SRIF analogs with selective affinity for this receptor may therefore be more effective in the treatment of hormone-secreting pituitary adenomas.

Adrenocorticotropic Hormone↗
PubMed1997

A pituitary mass and hypopituitarism: improvement after corticosteroid therapy.

Lymphocytic hypophysitis of the anterior pituitary is a rare autoimmune disease, invariably diagnosed either by surgical biopsy of the adenohypophysis or at autopsy. The current report describes the rapid development of hypopituitarism in a 42-year-old nulliparous woman with a large sellar mass, who did not undergo pituitary surgery. Transient regression of the sellar mass and partial improvement of the hypopituitarism was induced by treatment with corticoids. We suggest that the diagnosis of lymphocytic hypophysitis can be established clinically and that conservative treatment with corticoids should be considered prior to surgical intervention.

Adult↗