Participation of Growth Factor Signal Transduction Pathways in Estradiol Facilitation of Female Reproductive Behavior

Abstract

Estradiol (E(2)) regulates female reproductive behavior (lordosis) by acting on estrogen-sensitive neurons. We recently showed that E(2) facilitation of lordosis behavior requires concurrent activation of brain IGF-I receptors. The present study confirmed this finding and sought to identify the downstream signaling pathways involved in estrogen/IGF-I priming of lordosis. Intracerebroventricular infusions of a selective IGF-I receptor antagonist were administered to ovariectomized rats every 12 h beginning 1 h before the first of two daily E(2) injections. IGF-I receptor blockade partially inhibits lordosis if the antagonist is infused throughout the 2-d estrogen treatment period but not if it is administered only during the first or last 12 h of estrogen treatment. Because E(2) and IGF-I can activate phosphatidylinositol-3-kinase (PI3K) and MAPK, we infused agents that block PI3K and/or MAPK activity as described above. Both PI3K inhibitors (wortmannin and LY294002) and MAPK inhibitors (PD98059 and U0126) partially attenuate lordosis when administered during estrogen priming. None of these drugs modifies lordosis if they are infused only once, during the last 12 h of estrogen treatment. When both wortmannin and PD98059 are infused during E(2) priming, lordosis behavior is completely abolished. These data suggest that activation of both PI3K and MAPK by E(2) and IGF-I mediates hormonal facilitation of lordosis behavior.

Regulation of the phosphoinositide‐3 kinase and mitogen‐activated protein kinase signaling pathways by progesterone and its reduced metabolites in the rat brain

“…In addition, progesterone and its metabolites may interact with other regulators of growth factor signaling, including the ovarian hormone estradiol. Estradiol is known to regulate the activity of MAPK and PI3K signaling pathways in the brain (Etgen and Acosta-Martinez, 2003;Marin et al, 2005;Mannella and Brinton, 2006) and to affect the actions of different growth factors, such as nerve growth factor, basic fibroblast growth factor, glial cell line-derived neurotrophic factor, BDNF, and IGF-I (Etgen and Garcia-Segura, 2008). Therefore, acting on MAPK and PI3K, progesterone and estradiol may potentially interact in the regulation of growth factor signaling in the brain, and this may be part of the mechanisms involved in the coordinated regulation of brain function, brain plasticity, and neuroendocrine and behavioral events by ovarian hormones.…”

Setting the Pace for Retinal Development: Environmental Enrichment Acts Through Insulin-Like Growth Factor 1 and Brain-Derived Neurotrophic Factor

“…IGF-1 concentration in the injected solution was changed between P1 and P7 according to the increasing size of the eye globe to maintain a final intraocular concentration of the factor equal to 100 ng/l (Sale et al, 2007). Analogously, JB1 concentration was varied according to the increasing size of the eye globe to maintain a final intraocular concentration of the factor equal to 1 ng/l, demonstrated to be effective for at least 3 d in vitro (Elmlinger et al, 1998;Pozios et al, 2001;Etgen and Acosta-Martinez, 2003). The volume injected was 250, 500, and 750 nl at P1, P4, and P7, respectively, both for IGF-1 and JB1.…”

Membrane-initiated estrogen signaling in hypothalamic neurons

“…In addition, co-administration (i.c.v.) of blockers of PI3 kinase (wortmannin) and MAPK (PD98059) inhibit the long-term (48 h) effects of E2 to induce the LH surge and facilitate lordosis behavior (Etgen and Acosta-Martinez, 2003). Therefore, facilitation of female sexual behavior by E2 appears to involve activation of both PI3 kinase and MAPK signal transduction pathways.…”