In humans, excess alcohol intake often causes reproductive abnormalities including infertility and loss of libido. Some alcoholic men also shown evidence of gynecomastia. These pathological conditions in many human alcoholics are secondary to elevated levels of plasma prolactin (PRL), a condition known as hyperprolactinemia. Owe chronic alcohol intake induces hyperprolactinemia is not yet established. The present proposal will address this issue by studying the actions of ethanol on PRL secreting lactotropic cells in the pituitary gland of rats.
Three specific aims are proposed for addressing this interest.
Specific Aim 1 is to evaluate the action of ethanol on lactotropic cell proliferation and PRL secretion. Preliminary data indicated that ethanol administration using liquid diet for two weeks elevates blood ethanol levels to 0.1 mg/dl and promotes estrogen-induced lactotropic cell proliferation in Fischer 344 rats.
The aim of this study is to confirm these data and to further characterize the time-course of ethanol action on lactotropic cell's growth and secretion.
Specific Aim 2 is to determine the site of action of ethanol. Our working hypothesis is that ethanol effects lactotropic cell proliferation by acting at the level of pituitary. This possibility will be tested by determining the action of ethanol on PRL synthesis and secretion and cell proliferation in the primary cultures of enriched lactotropes.
Specific Aim 3 is to elucidate the mechanisms by which ethanol enhances lactotropic cell proliferation. The working hypothesis is that ethanol increases lactotropic cell proliferation and secretion by preventing expression of the growth-inhibitory peptide transforming growth factor B1 (TBF-B1) in the pituitary gland. This hypothesis will be tested by I) characterizing ethanol-induced changes of TGF-B1 and TGF-B type II receptor in the pituitary; ii) determining the effect of ethanol on TGF-B1 secretion from the lactotropic cells in primary cultures; iii) evaluating whether ethanol-induced lactotropic cell growth and secretion is altered following overexpression or repression of TGF-B1 and it's TGF-B type II receptor in these cells. The proposed research will yield an increased understanding of ethanol effects on prolactinomas and hyperprolactinemia. Such knowledge should help to better manage these neuroendocrine diseases in alcoholic patients.
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