Functional role of estrogen in pituitary tumor pathogenesis
Anthony P. Heaney, … , Manory Fernando, Shlomo Melmed
Anthony P. Heaney, … , Manory Fernando, Shlomo Melmed
Published January 15, 2002
Citation Information: J Clin Invest. 2002;109(2):277-283. https://doi.org/10.1172/JCI14264.
View: Text | PDF
Article

Functional role of estrogen in pituitary tumor pathogenesis

Abstract

Pituitary hyperplasia and lactotroph replication are induced by estrogen. The product of the pituitary tumor transforming gene (PTTG) exhibits in vitro and in vivo transforming activity and induces basic bFGF secretion, thereby modulating pituitary angiogenesis and tumor formation. We demonstrated previously that pituitary pttg is induced by estrogen and bFGF, the latter being expressed in a concordant fashion with pttg in experimental and human pituitary adenomas. We now elucidate the role of estrogen in paracrine regulation of pituitary tumorigenesis by PTTG. Coincident with the circulating rat estradiol surge and maximal pituitary proliferation, pituitary pttg mRNA, bFGF, and VEGF expression increased approximately threefold during proestrus and estrus. Osmotic mini-pump coinfusion of estrogen and antiestrogen abrogated estrogen-induced pituitary pttg expression in vivo, suppressed serum PRL concentrations by 88%, and attenuated prolactin-secreting pituitary tumor growth by 41% in rats. Antiestrogen treatment of primary human pituitary tumor cultures reduced PTTG expression approximately 65%. Pituitary pttg, bFGF, and VEGF are cyclically expressed during the rat estrus cycle, concordantly with estrogen levels. Because anti-estrogens reduced PTTG expression in human pituitary tumors in vitro and suppressed experimental tumor growth in vivo, concomitantly with reduced PRL secretion, these results indicate a role for selective antiestrogens in treating pituitary tumors.

Authors

Anthony P. Heaney, Manory Fernando, Shlomo Melmed

×

Figure 3

Options: View larger image (or click on image) Download as PowerPoint
Regulation of pttg- and PRL-mRNA in vitro by DES and 2-OHE2. GH3 cells w...
Regulation of pttg- and PRL-mRNA in vitro by DES and 2-OHE2. GH3 cells were incubated (3 days) in medium containing serum pretreated with charcoal-stripped serum before addition of DES (10–8 M) or 2-OHE2 (10–6 M) with/without the antiestrogen (ICI-182780 10–6 M) (AE) for 48 hours. pttg mRNA expression relative to 18S (internal control) is depicted in lower panel. M, marker. Rat testis served as a positive control. Experiments were performed twice in triplicate wells for each data point. Each lane represents the mean of three dishes. ANOVA = 0.0003. Bonferroni multiple comparisons: *P < 0.01 compared with control; **P < 0.001 compared with DES; and ***P < 0.001 compared with 2-OHE2.