Decreased nuclear binding of estrogen receptors in the pituitary of mice: correlation with biological effects throughout aging.

We have determined the biological impact of our previously reported decreased activation of pituitary E2 receptors (PER) in mice. Young (4-8 months), middle-aged (10-14 months) and aged (15-18 months) female mice were studied either intact (metestrous) or gonadectomized (ovx) for 2 weeks prior to decapitation. Recombination studies using heat-treated cytosolic PER and enriched nuclear fractions of various age groups showed a markedly reduced ability for nuclear binding with advancing age, despite unchanged affinity of activated PER for nuclear acceptor sites. Cross incubation studies of heat-activated cytosolic PER with nuclei from mice of various age groups suggested that the activation defect followed the onset of anestrous whereas a reduced nuclear ability to support receptor binding preceded this manifestation. In parallel with these endocrine changes we observed a decrease in baseline cytosolic progesterone receptor (RcP) concentration and in the activity of the enzyme G6PDH in intact aging mice. Ovx induced a further decrease of both markers in young and middle-aged, but not in old mice, while E2 administration induced a decreased pituitary response in RcP but not in G6PDH in aged mice. Our results suggest functional changes in cytosolic nuclear interactions in the pituitary of aging female mice.