Non-Reproductive Actions of Sex Hormones

Ovarian steroids have numerous effects on the brain throughout the lifespan, beginning during gestation and continuing on into senescence. These hormones affect areas of the brain that are not primarily involved in reproduction, such as the basal forebrain, hippocampus, caudate-putamen, midbrain raphe and brainstem locus coeruleus. The mechanisms for these effects involve not only classical genomic actions but also non-genomic forms of classical genomic steroid receptors that activate signaling pathways that cause neurotransmitter release, actin polymerization, protein synthesis. We study four classes of actions of estrogens and progestins that are especially relevant to memory processes and their alterations during aging and neurodegenerative diseases:

First, estrogens and progestins regulate synaptogenesis in the CA1 region of the hippocampus during the 4-5d estrus cycle of the female rat. Formation of new excitatory synapses is induced by estradiol and involves NMDA receptors, whereas down-regulation of these synapses involves intracellular progestin receptors.

Second, there are developmentally-programmed sex differences in hippocampal structure that may help to explain differences in the strategies which male and female rats use to solve spatial navigation problems. During the period of development when testosterone is elevated in the male, aromatase and estrogen receptors are transiently expressed in hippocampus, and recent data on behavior and synapse induction strongly suggest that this pathway is involved in the masculinization or defeminization of hippocampal structure and function.

Third, ovarian steroids have widespread effects throughout the brain, including brainstem and midbrain catecholaminergic neurons, midbrain serotonergic pathways and the basal forebrain cholinergic system. Regulation of the serotonergic system appears to be linked to the presence of estrogen and progestin sensitive neurons in the midbrain raphe, whereas the ovarian steroid influence upon cholinergic function involves induction of choline acetyltransferase and acetylcholinesterase according to a sexually dimorphic pattern. Because of the widespread influences of these various neuronal systems, it is not so surprising that ovarian steroids have measurable effects on cognition that are evident after ovariectomy and during aging.

Fourth, ovarian steroids influence repair processes and exert neuroprotective effects on brain cells via the regulation of the production of inflammatory cyokines that are activated in microglial cells in aging and by damage and in diseases such as Alzheimer's.

Relevant Publications

  • Woolley, C. and McEwen, B.S. Estradiol regulates hippocampal dendritic spine density via an N-methyl-D-aspartate receptor dependent mechanism. J. Neurosci. 14:7680-7687 (1994).
  • McEwen, B.S. and Alves, S.E. Estrogen actions in the central nervous system. Endocrine Rev. 20:279-307 (1999).
  • Akama, K.T. and McEwen, B.S. Estrogen stimulates postsynaptic density-95 rapid protein synthesis via the Akt/protein kinase B pathway. J. Neurosci. 23:2333-2339 (2003).
  • Znamensky, V., Akama, K.T., McEwen, B.S., and Milner, T.A. Estrogen levels regulate the subcellular distribution of phosphorylated Akt in hippocampal CA1 dendrites. J. Neurosci. 23:2340-2347 (2003).
  • McEwen, B.S. and Milner, T.A. Hippocampal formation: Shedding light on the influence of sex and stress on the brain. Brain Res. Rev. 55L 343-355 (2007).
  • Milner, T.A., Lubbers, L.S., Alves, S.E., and McEwen, B.S. Nuclear and extranuclear estrogen binding sites in the rat forebrain and autonomic medullary areas. Endocrinology 149:3306-3312 (2008).
  • Waters, E.M., Torres-Reveron, A.T., McEwen, B.S., and Milner, T.A. Ultrastructural localization of extranuclear progestin receptors in the rat hippocampal formation. J. Comp. Neurol. 511:34-46 (2008).
  • Yildirim, M., Janssen, W.G.M., Tabori, N.E., Adams, M.M., Yuen, G.S., Akama, K.T., McEwen, B.S., Milner, T.A., and Morrison, J.H. Estrogen and aging affect synaptic distribution of phosphorylated LIM kinase (pLIMK) in CA1 region of female rat hippocampus. Neuroscience 152: 360-370 (2008).
  • Spencer, J.L., Waters, E.M., Milner, T.A., Lee, F.S., and McEwen, B.S. BDNF variant Val66Met interacts with estrous cycle in the control of hippocampal function. Proc. Natl. Acad. Sci. 107:4395-4400 (2010).
  • Yuen, G.S., McEwen, B.S. and Akama, K.T. LIM kinase mediates estrogen action on the actin depolymerization factor Cofilin. Brain Res. (2010).

Current Grant Support:

Gene Expression in Nervous Tissue (NIH/NINDS)
Estrogen and the Aging Brain (NIH/NIA)