Estradiol, progesterone, obesity and decreased dopaminergic tone contribute to the development of prolactinomas in transgenic female mice overexpressing hCGbeta subunit.

AHTIAINEN P, RULLI SB, ROYTTA M, HUHTANIEMI I.

Boston, USA

Congreso; 88th Annual Meeting of The Endocrine Society; 2006

The Endocrine Society

Prolactinomas are the most common tumors in pituitary gland, but still their etiology is poorly known. Female sex and estradiol are known risk factors. We used a recently developed transgenic (TG) mouse model, expressing ubiquitously the human chorionic gonadotropin ß-subunit and developing lactotroph adenomas without overt hyperestrogenism but with elevated progesterone secretion, to dissect out the hormonal mechanisms inducing the prolactinomas. TG females were treated with bromocriptine, tamoxifen or mifepristone (between 8-24 wks of life). Tamoxifen totally blocked lactotroph hyperplasia and adenomas, in line with the known role of estrogens in this process. Bromocriptine partially blocked the lactotroph hyperplasia, and mifepristone treatment was equally effective, indicating that both progesterone and disturbed dopamine synthesis contribute to the pituitary phenotype of the TG females. In another approach, we gonadectomized 8-wk-old TG and wild type (WT) females and replaced them with estradiol (E), progesterone (P) or both for a 10-wk period. E+P treatment increased significantly pituitary size in comparison to E and P alone (smaller and no effect, respectively), indicating additive effect of the two hormones. Furthermore, we showed that cyclin D1 (Ccnd1) mRNA was upregulated in the TG female pituitaries, but not in the any of the treatment groups. Ccnd1 expression was higher at 6 mo than at 2 and 4.5 mo in relation to age-matched WT controls, suggesting that Ccnd1 is upregulated only in the adenomatous pituitaries. Body weights of the TG females were significantly higher than in any other treatment group, and we found a positive correlation between body weights and those of the pituitary adenomas (P<0.001), suggesting that obesity contributes to the adenomatous transformation, possibly through elevated leptin levels. Leptin induced MAPK signaling may be responsible for the increased Ccnd1 expression. Also in man, obesity has been associated with prolactinomas, though with unproven causality. Fasting experiments in the TG females will elucidate the role of obesity and leptins in the pathogenesis of prolactinomas.