Pituitary prolactin-secreting tumor formation: recent developments.

Prolactinoma is the most common type of primary pituitary tumors. It occurs more frequently in women than in men. Dopaminergic agonists are effective in the shrinkage of prolactin-secreting pituitary tumor and are preferred in some patients. However, pituitary radiotherapy may enable the long-term removal of prolactin-secreting tumor cells. Recent evidence suggests that prolactinoma is a heterogeneous disorder with complicated and multifactorial etiology and pathogenesis. Apparently, a thorough understanding of prolactinoma tumorigenesis would be important. To facilitate investigations on tumorigenesis of prolactinoma, animal models for prolactinomas have been developed. These models have expedited our progress in the recent years. Many researchers consider the F(344) rat to be the most sensitive strain of rats to estrogen (E(2))-induced prolactinoma formation. Nonetheless, E(2) treatment for 60 days also induces the formation of pituitary prolactin-secreting adenoma in male Sprague-Dawley (SD) rats. Evidently, the SD rat is also a good animal for prolactinoma investigations. Following E(2) implantation, prolactinomas developed in the eutopic adenohypophysis in situ and/or ectopic pituitary grafted under the renal capsule in SD rats. These observations favor the hypothesis that prolactinoma growth is the result of pathological changes in the adenohypophysis and/or hypothalamus. In the latter case, abnormal release of hypothalamic dopamine, GABA, or brain-gut peptides (such as cholecystokinin, vasoactive intestinal polypeptide, galanin, angiotensin, opioid peptide, gastrin, gastrin-releasing peptide, pancreatic polypeptide, and adrenocorticotropic hormone) results in some of the pathological changes that may lead to hyperprolactinemia and/or prolactinoma development. Dysregulation of prolactin synthesis and secretion may be the result of prolactin gene modulation. In E(2)-induced rat prolactinomas, prolactin mRNA contents and the expression of some proto-oncogenes, e.g. c-myc and c-ras, TGFalpha and TGFbeta1 mRNA were significantly changed. The above findings are consistent with results in human prolactinoma development. In addition, in rats abnormal expression of the prolactin gene was correlated with hypomethylated status of CpG sites in exons 1, 2 and 4 of the prolactin gene, as well as the increase in hypersensitive sites to DNase 1 in the encoding region of the prolactin gene. In E(2)-treated rats, a point mutation with a base substitution from cytidine (C) to adenine (A) was found at the -36-bp site of the proximal promoter of the prolactin gene in eutopic pituitary prolactinomas, but no change was observed in the same sequence of the prolactin gene in ectopic prolactinoma. The association of a base substitution with the hyperexpression of the prolactin gene in eutopic prolactinomas suggests that different mechanisms may mediate the formation of eutopic and ectopic prolactin-secreting tumors. Melatonin decreases the expression of the prolactin gene in vitro suggesting that this pineal hormone may be a potential anticarcinogen in vivo. It has also been shown that MT(2) (Mel(1b)) melatonin receptors are expressed in anterior pituitary cells. The use of melatonin as a preventive or therapeutic drug for prolactinomas should be further investigated. In summary, improved knowledge on tumorigenesis of prolactinomas, especially in the rat model, was noted. These E(2)-induced rat prolactinoma models would facilitate future investigations, and expected results shall be fruitful and exciting for the development of future drug designs for the prevention and/or treatment of prolactin-secreting pituitary tumors.

[The effects of gastrin-releasing peptide (GRP) and vasoactive intestinal polypeptide (VIP) on the prolactin (PRL) gene transcription of pitutitary PRL releasing tumor of rat].

The effects of gastrin-releasing peptide (GRP) and vasoactive intestinal polypeptide (VIP) on the prolactin gene transcription of cultured pituitary of male Sprague-Dawley (SD) rats PRL releasing tumor (PPRT) (induced by estradiol) cells were studied. The PRL mRNA levels were determined by in situ hybridization of cytoplasmic RNA with a DIG-labeled PRL cDNA probe. PRL mRNA levels didn't change when the PPRT cells were incubated with 10(-8) mol/L or 10(-7) mol/L GRP for 24 h, but decreased by 20% when GRP was increased to 10(-6) mol/L (P < 0.05). The PRL mRNA level increased to 1.60, 2.10, 2.21 times of the control group when the PPRT cells were respectively incubated with 10(-8), 10(-7), 10(-6) mol/L VIP for 24 h (P < 0.05). The PRL mRNA level didn't change when the PPRT tumor cells were incubated with 10(-8) mol/L E2 for 48 h, but did increase to 2.80 and 2.92 times of the control group respectively when 10(-7) mol/L and 10(-6) mol/L E2 were used. The results above indicated that GRP and VIP exert an inhibitory and a stimulatory effect on RPL gene transcription respectively, while the stimulatory action of E2 on PRL secretion is a direct one.

[Effect of U-50, 488H administered centrally in rats on urination and activity of TH-IR neurons in PVH].

The effect of a kappa-receptor agonist U-50, 488H on urine flow and the activity of TH-IR (tyrosine hydroxylase-immunoreactivity) neurons in PVH (Paraventricular neucleus of the hypothalamus) was studied in ethanol-anesthetized rats. U-50, 488H (5 micrograms/1 microliter) injected into PVH induced a potent diuretic response with no significant action on mean arterial pressure and heart rate. The diuretic response began within 20 min after injection, reached a peak value 41-60 min later and subsided at about 100 min. This diuretic response could be blocked by pretreatment with kappa-receptor antagonist NBT (Nor-Binaltorphimine Tetrahydrate). Both the number of neurons and staining density of TH-IR in the PVH tended to decrease at 20 min after the injection of U-50, 488H (10 micrograms/10 microliters) into the third cerebroventricle. The effect was most evident at 50 min and recovered at about 100 min after injection.