Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Of 210 women with galactorrhea 66.2% had normal prolactin serum levels. Only in 33.4% elevated prolactin levels could be found, 0.4% were hypoprolactinemic. The TRH-stimulation test detected latent hyperprolactinemia in 13.5% of the cases, showed a normal thyroid function in 81.5%, hypothyroidism in 13.9% and hyperthyroidism in 4.6% and this is considered to be a more valuable diagnostic tool than the MCP-test. Galactorrhea was associated with the following conditions: hyperprolactinemia (34.8%), menstrual disturbances (67.4%), post-pill amenorrhea (30.2%), mastalgia (30.2%), prolactinoma (18.6%), fibrocystic disease (11.6%), hirsutism (4.6%), diabetes mellitus (2.3%).
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PMID:[The value of hyperprolactinemia determination within the scope of galactorrhea]. 249 8

Pre- and postoperative hypothalamic-pituitary-thyroid axis function was studied in 38 patients with pituitary adenomas (PRL, GH and ACTH tumours), of whom 35 were surgically confirmed and three diagnosed by clinical signs, CT scanning and hormone assessments. About ten days after operation, the same study was repeated in 10 patients with prolactinoma and 7 with growth hormone (GH) tumour. The preoperative abnormal serum TSH response to TRH was found in 8/20 patients with prolactinoma, 9/16 with GH tumour, and 2/2 with Cushing's disease due to ACTH microadenoma. The incidence of abnormal TSH response to TRH was not significantly increased in patients with larger adenoma in either PRL or GH tumour group. In 8 cases of prolactinoma, metoclopramide (MCP, 10 mg, P.O.) test was also performed and there was a significant positive correlation between TSH responses to TRH and to MCP. Serum TT3 in the GH tumour group was within normal ranges, but significantly higher than that of the normal and prolactinoma groups. After operation, TT3 was significantly decreased as compared with that before operation and there were marked changes in TSH response to TRH. In conclusion, there were some abnormalities in TSH control in patients with non-TSH pituitary tumour, and in serum TT3 control in patients with GH tumour. The surgical treatment of pituitary adenoma can lead to transient decrease in TSH reserve and serum TT3 level probably resulting from both stress and/or destruction of thyro-trophs by the operation.
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PMID:Pre- and post-operative hypothalamic-pituitary-thyroidal axis function in patients with prolactinoma, growth hormone tumour and ACTH tumour. 255 2

This study was carried out using a dopaminergic agonist (carbidopa plus levodopa, CD + LD) and antagonist (metoclopramide, MCP) respectively for dynamic tests to observe the variations of serum prolactin (PRL), thyrotropin (TSH) and luteinizing hormone (LH) levels in 7 normal women and 11 women with pituitary prolactinoma. It was shown that CD + LD resulted in minimal suppression of serum PRL (18.4 +/- 3.4%) in tumor patients, with this being significantly less than that in normal women (80.7 +/- 4.6%). However, similar degrees of TSH and LH suppression were observed after CD + LD in patients (23.8 +/- 4.2% and 28.2 +/- 2.1%, respectively) and in normal women (27.9 +/- 2.4% and 34.7 +/- 9.0%, respectively). MCP greatly increased PRL levels in the normal women as compared with the patients (892.1 +/- 195.3%, 16.4 +/- 6.5%), but increased TSH and LH levels were much higher in the patients than in the normal women (291.4 +/- 36.1% vs 19.9 +/- 3.3% and 96.9 +/- 7.4% vs 24.9 +/- 5.5%, respectively). It was also found that the levels of TSH or LH after MCP strongly correlated with basal PRL levels in the patients (r = 0.858, P less than 0.001 and r = 0.737, P less than 0.01, respectively). These results indicate that synthesis, turnover and release of hypothalamic dopamine are normal and the hypothalamic tone is relatively high in patients with PRL-secreting pituitary tumors.
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PMID:Evaluation of hypothalamic dopaminergic function in patients with pituitary prolactinoma. 259 32

It has been previously demonstrated that patients with hyperprolactinemia have impaired PRL response to dopaminergic blockade and increased TSH response. Since inhibitory dopaminergic modulation of aldosterone is well established, we have examined whether prolactinoma patients have an altered aldosterone response to dopaminergic blockade. To investigate this possibility we compared the plasma PRL, TSH and aldosterone responses to the dopamine (DA) antagonist metoclopramide (MCP; 10 mg i.v.) in 10 women with prolactinomas and 7 healthy female controls. Basal PRL levels in prolactinoma patients were elevated and showed a blunted rise following MCP. Although basal TSH levels were similar in the 2 groups of subjects, they significantly increased (p = 0.017) in prolactinoma patients while in contrast they did not significantly change in control subjects. Basal supine plasma aldosterone was similar in patients with prolactinomas (0.23 +/- 0.03 nmol/l) and in healthy subjects (0.25 +/- 0.04 nmol/l) and the increased aldosterone concentrations from 15 to 120 min following MCP were not significantly different in prolactinoma patients and in control subjects. It is concluded that in patients with prolactinomas, the alteration in the dopaminergic regulation is specifically related to the lactotroph.
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PMID:Plasma aldosterone response to metoclopramide is unmodified by hyperprolactinemia. 362 28

Pituitary adenoma (PA) is one of the most common intracranial tumors, and approximately 40% of all PAs are prolactinomas. Dopamine agonists (DAs), such as cabergoline (CAB), have been successfully used in the treatment of prolactinomas. The expression of dopamine type 2 receptor (DRD2) determines the therapeutic effect of DAs, but the molecular mechanisms of DRD2 regulation are not fully understood. In this study, we first demonstrated that DRD2 underwent proteasome-mediated degradation. We further employed the yeast two-hybrid system and identified kelch repeat and BTB (POZ) domain containing 7 (KBTBD7), a substrate adaptor for the CUL3-RING ubiquitin (Ub) ligase complex, as a DRD2-interacting protein. KBTBD6/7 directly interacted with, and ubiquitinated DRD2 at five ubiquitination sites (K221, K226, K241, K251, and K258). CAB, a high-affinity DRD2 agonist, induced DRD2 internalization, and cytoplasmic DRD2 was degraded via ubiquitination under the control of KBTBD6/7, the activity of which attenuated CAB-mediated inhibition of the AKT/mTOR pathway. KBTBD7 knockout (KO) mice were generated using the CRISPR-Cas9 technique, in which the static level of DRD2 protein was elevated in the pituitary gland, thalamus, and heart, compared to that of WT mice. Consistently, the expression of KBTBD6/7 was negatively correlated with that of DRD2 in human pituitary tumors. Moreover, KBTBD7 was highly expressed in dopamine-resistant prolactinomas, but at low levels in dopamine-sensitive prolactinomas. Knockdown of KBTBD6/7 sensitized MMQ cells and primary pituitary tumor cells to CAB treatment. Conversely, KBTBD7 overexpression increased CAB resistance of estrogen-induced in situ rat prolactinoma model. Together, our findings have uncovered the novel mechanism of DRD2 protein degradation and shown that the KBTBD6/7-DRD2 axis regulates PA sensitivity to DA treatment. KBTBD6/7 may thus become a promising therapeutic target for pituitary tumors.
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PMID:The KBTBD6/7-DRD2 axis regulates pituitary adenoma sensitivity to dopamine agonist treatment. 3257 97