Xenoestrogen-induced ERK-1 and ERK-2 activation via multiple membrane-initiated signaling pathways.
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Xenoestrogens can mimic or antagonize the activity of physiological estrogens, and the suggested mechanism of xenoestrogen action involves binding to estrogen receptors (ERs). However, the failure of various in vitro or in vivo assays to show strong genomic activity of xenoestrogens compared with estradiol (E2) makes it difficult to explain their ability to cause abnormalities in animal (and perhaps human) reproductive functions via this pathway of steroid action. E2 has also been shown to initiate rapid intracellular signaling, such as changes in levels of intracellular calcium, cAMP, and nitric oxide, and activations of a variety of kinases, via action at the membrane. In this study, we demonstrate that several xenoestrogens can rapidly activate extracellular-regulated kinases (ERKs) in the pituitary tumor cell line GH3/B6/F10, which expresses high levels of the membrane receptor for ER-alpha (mER). We tested a phytoestrogen (coumestrol), organochlorine pesticides or their metabolites (endosulfan, dieldrin, and DDE), and detergent by-products of plastics manufacturing (p-nonylphenol and bisphenol A). These xenoestrogens (except bisphenolA) produced rapid (3-30 min after application), concentration (10(-14)-10(-8) M)-dependent ERK-1/2 phosphorylation but with distinctly different activation patterns. To identify signaling pathways involved in ERK activation, we used specific inhibitors of ERs, epidermal growth factor receptors, Ca2+ signaling, Src and phosphoinositide-3 kinases, and a membrane structure disruption agent. Multiple inhibitors blocked ERK activation, suggesting simultaneous use of multiple pathways and complex signaling web interactions. However, inhibitors differentially affected each xenoestrogen response examined. These actions may help to explain the distinct abilities of xenoestrogens to disrupt reproductive functions at low concentrations. (+info)
Gynaecomastia: is one cause enough?
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Gynaecomastia can be detected in between one-third and two-thirds of men. A wide variety of causes of gynaecomastia, some physiological, some very serious, have been identified. We present a case in which the cause of the gynaecomastia seemed obvious after history taking and physical examination but we finally ended up with a more complex combination of diagnoses. This case stresses the importance of combining history taking and physical examination with additional laboratory testing for the assessment of gynaecomastia. (+info)
Spontaneous remission of functioning pituitary adenomas without hypopituitarism following infarctive apoplexy: two case reports.
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Functioning pituitary adenomas may exhibit spontaneous remission after pituitary apoplexy usually in association with hypopituitarism. We report two patients who presented with sudden headache and double vision, showed a ring-enhanced sellar tumor on MRI, underwent transsphenoidal surgery that revealed a coagulation necrotic adenoma without massive hemorrhage, and showed normal pituitary function after the surgery. Definitive diagnoses were made based on immunohistochemistry of the necrotic cells. The findings were consistent with the presence of selective infarct of a GH adenoma and a prolactinoma that had led to remission of acromegaly and menstrual disturbance, respectively, without pituitary insufficiency. In contrast to hemorrhagic apoplexy, infarctive apoplexy tends to affect only the tumor and thus presents with mild symptoms and lack pituitary deficiencies. (+info)
Acute tumor response to ZD6126 assessed by intrinsic susceptibility magnetic resonance imaging.
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The effective magnetic resonance imaging (MRI) transverse relaxation rate R(2)* was investigated as an early acute marker of the response of rat GH3 prolactinomas to the vascular-targeting agent, ZD6126. Multigradient echo (MGRE) MRI was used to quantify R(2)*, which is sensitive to tissue deoxyhemoglobin levels. Tumor R(2)* was measured prior to, and either immediately for up to 35 minutes, or 24 hours following administration of 50 mg/kg ZD6126. Following MRI, tumor perfusion was assessed by Hoechst 33342 uptake. Tumor R(2)* significantly increased to 116 +/- 4% of baseline 35 minutes after challenge, consistent with an ischemic insult induced by vascular collapse. A strong positive correlation between baseline R(2)* and the subsequent increase in R(2)* measured 35 minutes after treatment was obtained, suggesting that the baseline R(2)* is prognostic for the subsequent tumor response to ZD6126. In contrast, a significant decrease in tumor R(2)* was found 24 hours after administration of ZD6126. Both the 35-minute and 24-hour R(2)* responses to ZD6126 were associated with a decrease in Hoechst 33342 uptake. Interpretation of the R(2)* response is complex, yet changes in tumor R(2)* may provide a convenient and early MRI biomarker for detecting the antitumor activity of vascular-targeting agents. (+info)
Efficacy of chimeric molecules directed towards multiple somatostatin and dopamine receptors on inhibition of GH and prolactin secretion from GH-secreting pituitary adenomas classified as partially responsive to somatostatin analog therapy.
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OBJECTIVE: This study compared the potency of a somatostatin receptor (sstr)2-sstr5 analog, BIM-23244, of an sstr2-dopamine D2 receptor (sstr2-DAD2) molecule, BIM-23A387 and of new somatostatin-dopamine chimeric molecules with differing, enhanced affinities for sstr2, sstr5 and DAD2, BIM-23A758, BIM-23A760 and BIM-23A761, to suppress GH and prolactin (PRL) from 18 human GH adenomas that are partially responsive to octreotide or lanreotide. MATERIALS AND METHODS: The sstr2, sstr5 and DAD2 mRNA levels were determined by RT-PCR. The effect of drugs was tested in cell cultures at various concentrations. RESULTS: In all tumors, the sstr2, sstr5 and DAD2 mRNA levels were coexpressed (mean levels+/-s.e.m. 0.4+/-0.1, 5.3+/-1.9 and 2.0+/-0.4 copy/copy beta-glucuronidase). In 13 tumors, the maximal suppression of GH secretion produced by BIM-23A387 (30+/-3%) and BIM-23244 (28+/-3%) was greater than that produced by octreotide (23+/-3%). In six out of 13 tumors, BIM-23A758, BIM-23A760 and BIM- 23A761 produced greater maximal suppression of GH secretion than octreotide (33+/-5, 38+/-2 and 41+/-2 vs 24+/-2%). Their EC(50) values were 10, 2 and 4 pmol/l. BIM-23A761 was more effective than BIM-23A387 in GH suppression (41+/-2 vs 32+/-4%). The new chimeric molecules produced maximal PRL suppression greater than octreotide (62+/-8 to 74+/-5 vs 46+/-11%). CONCLUSIONS: Novel dopamine-somatostatin chimeric molecules with differing, enhanced activity at sstr2, sstr5 and DAD2, consistently produced significatly greater suppression of GH and PRL than either octreotide or single-receptor-interacting ligands in tumors from patients classified as only partially responsive to octreotide therapy. The higher efficacy of the chimeric compounds was, at least partially, linked to their high affinity for sstr2 (IC50 1-10 pmol/l). The other mechanisms by which such molecules produce an enhanced inhibition of GH remain to be elucidated. (+info)
A combined case of macroprolactinoma, growth hormone excess and Graves' disease.
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Thyrotoxicosis due to Graves disease is a relatively common endocrine disorder. The occurrence of a prolactinoma with co-secretion of growth hormone (GH) is on the other hand, rare. We report the rare co-existence of Graves' disease in a patient with macroprolactinoma and GH hypersecretion and describe the successful response to medical therapy with dopamine agonist and antithyroid therapy. We hypothesize that hyperprolactinaemia played a role in promoting autoimmune thyroid disease in our patient and that treatment of hyperprolactinaemia may have been important in suppressing autoimmune disease activity in Graves' disease. This case also reflects on the close and complex interactions between thyroid hormones, prolactin (PRL), GH and testosterone (T). (+info)
Metastatic renal cell carcinoma mimicking pituitary adenoma: case report.
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A 54-year-old man, with a past history of renal cell carcinoma, presented with bitemporal visual field defect, hyponatremia, and diabetes insipidus. Endocrinological examination revealed panhypopituitarism. Computed tomography and magnetic resonance imaging showed an intrasellar mass with suprasellar extension. The initial radiological impression was pituitary adenoma. The tumor was decompressed via the transsphenoidal route. Histological examination revealed metastatic renal cell carcinoma. The clinical characteristics of metastatic pituitary carcinoma appear to be panhypopituitarism, and neuroimaging findings of strong enhancement of the tumor and bony destruction without marked sellar enlargement. (+info)
Endonasal endoscopic transsphenoidal chiasmapexy with silicone plates for empty sella syndrome: technical note.
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Silicone plates sutured together to form blocks were used for extradural elevation of the sella floor in two patients who underwent chiasmapexy for visual disturbance associated with empty sella syndrome. A 36-year-old woman had been treated for prolactinoma for about 19 years with bromocriptine and then presented with left visual disturbance. A 79-year-old man presented with right blurred vision of unknown cause other than empty sella. The sella turcica was accessed via the endonasal transsphenoidal approach under endoscopic guidance. The bony sellar floor was opened with a drill. Two or three pieces of 1-mm-thick silicone plate were sutured to make a block. Two or three blocks were inserted into the epidural space to elevate the sellar contents. Visual symptoms improved in both patients. Silicone is biocompatible and not absorbable. Silicone plates are elastic and easy to handle during insertion, but firm enough to support the sella. The elevation can be adjusted by changing the number of plates in the block. The endonasal endoscopic approach is minimally invasive and particularly suitable for transsphenoidal extradural chiasmapexy for empty sella syndrome. (+info)