Estrogen and insulin synergism in neurite growth enhancement in vitro: mediation of steroid effects by interactions with growth factors?

Addition of estradiol to organotypic cultures of the fetal murine hypothalamus, preoptic area and cerebral cortex has been shown to elicit a striking enhancement of neurite growth which appears restricted to estrogen receptor-containing explant regions. The mechanisms underlying this response are unknown. An important question is whether the neurite enhancement which follows exposure to estradiol is due directly to the interaction of estrogen with the cell that was stimulated (the receptor-containing cell) or whether intermediate steps involving the possible interaction of estrogen and the endogenous polypeptide neurite-promoting growth factors or their receptors may play an important role. Recent findings in the cultures suggest that the effect of estrogen on neurite growth may involve synergistic interactions between estradiol and insulin-related peptides and may be important in regulating estrogen-responsive neurite growth in the central nervous system. Concurrent addition of estradiol and high levels of insulin (10 micrograms/ml or 50 micrograms/ml) to cultures of the olfactory bulb, hypothalamus, preoptic area and cerebral cortex of the fetal rat and mouse results in a dramatic acceleration and increase of neurite outgrowth which appears localized to estrogen receptor-containing explant regions. The supraphysiological concentrations of insulin required to elicit this response suggest that the factor(s) involved is unlikely to be insulin per se. Insulin may activate the receptor of different but closely related molecules such as the insulin-like growth factors (IGF)-I or -II to which it exhibits a relatively low affinity. Interactions between hormones and endogenous growth factors have been implicated in the modulation or mediation of an increasing number of endocrine-dependent, differentiative processes in vivo and in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)