Ethanol alters production and secretion of estrogen-regulated growth factors that control prolactin-secreting tumors in the pituitary

Abstract

Background: Chronic administration of ethanol increases plasma prolactin levels and enhances estradiol's mitogenic action on the lactotropes of the pituitary gland. The present study was conducted to determine whether ethanol's lactotropic cell-proliferating action, like estradiol's, is associated with alteration in the production of 3 peptides that regulate cell growth: transforming growth factor beta 1 (TGF-beta1), TGF-beta3 and basic fibroblast growth factor (bFGF).

Methods: Using ovariectomized Fischer-344 female rats, we determined ethanol's and estradiol's actions on lactotropic cell proliferation and growth-regulatory peptide production and release in the pituitary gland during tumorigenesis.

Results: Ethanol increased basal and estradiol-enhanced mitosis of lactotropes in the pituitary glands of ovariectomized rats. The level of growth-inhibitory TGF-beta1 was reduced in the pituitary following ethanol and/or estradiol treatment for 2 and 4 weeks. In contrast, ethanol and estradiol alone as well as together increased levels of growth-stimulatory TGF-beta3 and bFGF in the pituitary at 2 and 4 weeks. In primary cultures of pituitary cells, both ethanol and estradiol reduced TGF-beta1 release and increased TGF-beta3 and bFGF release at 24 hours. Ethanol's effect on growth factor levels in the pituitary or growth factor release from the pituitary cells was less than that of estradiol. When ethanol and estradiol were applied together, their individual effects on these growth factors were amplified.

Conclusions: These results confirm estradiol's modulation of pituitary growth factor production and release, and provide evidence that ethanol, like estradiol, alters the production and secretion of growth-regulatory peptides controlling lactotropic cell proliferation.

Fig. 1

Ethanol increases basal and estradiol-altered lactotropic cell proliferation and growth factor production in the pituitary. The changes in lactotropic growth and growth-regulatory polypeptides in the anterior pituitary were determined in ovariectomized rats sc implanted with an empty capsule (No E, 2 and 4 weeks combined) or estradiol-treated capsule (E) and fed rat chow ad libitum (Ad lib-fed) or given ethanol-containing liquid diet (Alcohol-fed) or pair-fed isocaloric diet (pair-fed) for 2 and 4 weeks. (A) The changes in the percentage of mitotic lactotropes as determined by the percentage of prolactin-stained lactotropes that are double stained with BrdU. B-D. Showing the changes in pituitary levels of TGF-β1 (B), TGF-β3 (C), and bFGF (D) in ovariectomized and estradiol-treated ovariectomized rats fed with control diet or ethanol diet for 2 and 4 weeks. Data are means ± SE obtained from 6 rats. ^ap < 0.05 compared with the similarly treated ovariectomy groups. ^bp < 0.05 compared with pair-fed group in similar steroid treatment.

Fig. 2

Ethanol increases basal and estradiol-altered secretion of growth factors from the pituitary cells in primary cultures. Effect of ethanol, estradiol and ethanol + estradiol on TGF-β1 (A), TGF-β3 (B), and bFGF (C) release from mixed pituitary cells (5 × 10⁴) in primary cultures. TGF-β1, TGF-β3, and bFGF levels in media samples were measured by ELISA. Treatment time was 24 hours. Data are means ± SE of 6 cultures. ^ap < 0.001, significantly different from the rest of the group.