Steroid Effects May Be in Part Mediated by Trophic Factors

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In addition to direct neuron to glia signaling mediated by adhesion molecules, soluble factors may also be involved in the effects of steroids on brain cells. Glial cells may release different growth factors that could alter neuronal function and that may be involved in the regulation of synaptic connectivity. For instance, it has been shown that estrogen receptors co-localize with low-affinity nerve growth factor (NGF) receptors in cholin-ergic neurons of the basal forebrain of developing rodents (46) and that estrogen modulates the expression of transforming growth factor-a (TGFa) in the hypothalamus (47) and the levels of NGF receptors in PC12 cells and dorsal root ganglion neurons of adult female rats (48,49). Furthermore, astroglia are a source of trophic factors, such as TGF-a and -p, and insulin-like growth factor I (IGF-I), substances that may mediate some of the neuroendocrine effects of gonadal hormones (47,50-52).

We have recently studied the interaction of gonadal hormones with IGF-I. This factor has paracrine trophic effects on neural cells and also acts as a hormonal signal involved in the regulation of hypothalamic hormone secretion. IGF-I is locally synthesized by glia and neurons of the hypothalamus and other brain areas (53,54) and has prominent trophic actions, including stimulation of survival, proliferation and differentiation of specific neural cell populations (55,56). IGF-I may also participate in neuroendocrine events at the level of the hypothalamus because it has been shown to be involved in the feed-beck regulation of growth hormone by affecting the synthesis or the release of growth hormone-releasing hormone and somatostatin by hypothalamic neurons (57,58). IGF-I may also affect the reproductive axis by modulating the secretion of gonadotrophin-releasing hormone by hypothalamic cells and, therefore, the release of gonadotrophins (50,59).

In several tissues, such as rodent uterus and pituitary, and in several cell types, such as human breast cancer cells, estrogen up-regulates IGF-I gene expression (60-65) and modulates IGF-I action by affecting the levels of IGF-I receptors (66) and IGF binding proteins (IGFBPs) (67-70). Likewise, IGF-I may regulate steroid hormone action by stimulating the synthesis of steroid hormones (71-73) and steroid hormone receptors (74-76). In addition, estrogen and anti-estrogens regulate several cellular responses induced by IGF-I (74,77-79). As in other cell types, IGF-I and estrogen may have interactive effects on neurons. The first evidence was provided by Toran-Allerand and coworkers (80), showing that in explant cultures of fetal rodent hypothalamus, estrogen, and insulin have synergistic effects on neurite growth, an effect probably mediated by IGF-I receptors. More recent data from our laboratory indicates that estrogen modulates IGF-I receptors and binding proteins in monolayer hypothalamic cultures (81).

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