Non-Genomic Actions of Sex Steroids

Thomas M. Price, M.D.

Traditionally, actions of sex steroids have involved the regulation of nuclear gene transcription. Sex steroid receptors (SR), including estrogen receptors (ER) α and ERβ, progesterone receptors (PR) -B and PR-A, and the androgen receptor (AR), have common protein domains, including an amino-terminus transactivation domain, a DNA binding domain, a hinge region, and a hormone- or ligand-binding domain. Transcriptional regulation by these receptors typically involves nuclear localization, homo and heterodimerization with ligand binding, DNA binding and autophosphorylation in responsive tissues.

A more recent area of study involves sex steroid actions not involving nuclear DNA interactions. These actions are typically rapid and referred to as non-genomic or extranuclear. Many different pathways may be involved in these actions. Our first article by Boonyaratanakornkit and Edwards reviews these pathways, including non-genomic interactions of typical SRs with cytoplasmic signaling peptides, membrane-mediated actions of typical SRs, and membrane-mediated actions of novel SRs not physically similar to the traditional receptors.

Our second article, by Gavrilova-Jordan and Price, examines actions of steroids in the power-house of the cell, the mitochondria. In the mitochondria, steroids may function to regulate mitochondrial DNA transcription and/or have a direct affect on mitochondrial cation membrane flux. Modulation of processes, including oxidative phosphorylation and apoptosis by sex steroids, is discussed with reference to physiological processes.

Subsequent articles in this issue deal with observations of non-genomic sex steroid actions in particular organs or tissues. Dr. Rønnekleiv et al review the actions of estradiol in the brain, including neuroprotection, modulation of gonadotropin-releasing hormone activity, and the control of feeding. Mechanisms such as membrane-controlled changes in calcium flux and interactions with cytoplasmic signaling peptides are considered.

Next, Drs. Fu and Simoncini review the effects of estrogen, progesterone, and androgens on the vascular system. The role of rapid interaction of estrogen with the nitric oxide system in vasodilatation is reviewed, along with less well-known data regarding the control of vascular cell migration and the cytoskeleton.

Dr. Song provides a concise review of the extensive literature regarding non-genomic effects of estrogen and breast cancer. Receptor-mediated interactions with the mitogen-activate protein kinase and Akt signaling pathways and calcium modulation by a novel estrogen-binding G protein-coupled receptor (GPR30) are discussed. In addition, new models of non-genomic estrogen action, such as the long-term estrogen deprivation cell line, are examined.

We conclude our issue with a discussion of sex steroids in the reproductive tissues of the ovary and spermatozoa. Dr. Peluso presents the current data regarding the role of progesterone in the control of mitosis of granulosa and luteal cells, and the antineoplastic mechanisms of progestins in ovarian surface cells.

Dr. Kirkman-Brown et al review the abundant information regarding progesterone and estrogen action in spermatozoa. The induction of the acrosome reaction by progesterone represents one of the first examples of non-genomic actions of a sex steroid. Spermatozoa are one of the best models for non-genomic steroid actions, given the general lack of active protein synthesis in these cells.

In conclusion, this issue of Seminars in Reproductive Medicine reveals to the reader the very latest information of non-genomic sex steroid actions, provided by the world leaders in this area of research. The complexity of these pathways, including interactions with cation fluxes, interactions with cytosolic signaling peptides, and cross-talk with traditional genomic actions becomes readily apparent. This emerging area of study continues to provide insight into pathophysiological processes.