Pituitary Prolactin-Secreting Tumor Formation: Recent Developments

Abstract

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 F₃₄₄ rat to be the most sensitive strain of rats to estrogen (E₂)-induced prolactinoma formation. Nonetheless, E₂ 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 E₂ 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 E₂-induced rat prolactinomas, prolactin mRNA contents and the expression of some proto-oncogenes, e.g. c-myc and c-ras, TGFα and TGFβ1 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 E₂-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 sug...

Prolactinoma induced by estrogen and cyproterone acetate in a male-to-female transsexual

“…In rats, fetal exposure to this drug results in an increase of prolactin in the lactotrope cells of the pituitary gland. In 20 women with advanced breast cancer, a phase 2 study in which patients were administered 400 mg/ day of cyproterone acetate produced an increment of prolactin levels (10). Moreover, in men with prostatic carcinoma, treatment with cyproterone acetate causes prolactin levels to rise.…”

Fear of novelty in infant rats predicts adult corticosterone dynamics and an early death

“…The elevated glucocorticoid response may itself mediate the shortened lifespan by altering apoptosis rates (47)(48)(49); altering immune function (11) and, thus, susceptibility to tumor development (50); or inducing oxidative stress (47). Alternatively, the glucocorticoid profile may be associated with other physiological systems (e.g., sympathetic nervous system activation, amygdala, or dopaminergic activity) that may either enhance pituitary tumorgenesis (51) or, more generally, reduce the ability to handle a tumor load in neophobic individuals (e.g., increased heart rate, blood pressure, etc.). The animal model that we have developed provides an ideal system in which to conduct longitudinal and experimental studies to identify the neuroendocrine, molecular, and genetic mechanisms underlying early death in neophobic individuals.…”

Aromatase cytochrome P450 enzyme expression in human pituitary

“…In experimental animal studies it has been demonstrated, that prolonged administration of estradiol (E 2 ) induces prolactinomas [8][9][10]. On the other hand lactotrophs are known to proliferate during pregnancy and up to 30% of macroadenomas may grow during gestation [11].…”