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.