Impact of clinically relevant progestins on the neural effects of estradiol and the signaling pathways involved

The natural ovarian hormone progesterone functions as an effective neuroprotective agent. However, in its native state it is not an efficient therapeutic compound because of its poor bioavailability. Thus, for practical therapeutic usage it became necessary to develop orally active progestogens for use in hormone therapy. We have shown that not all progestogens are equal in their ability to modulate neuronal survival and markers of neuronal plasticity. Thus, one cannot assume that all hormone therapies will perform the same, and it is crucial to determine the neural effects and interactions with estradiol of synthetic progestins used in place of natural progesterone. We have analyzed a number of clinically relevant progestins for neuroprotective efficacy. These in vitro analyses of neuroprotective efficacy could serve as a predictive index of clinical efficacy for progestins to protect against degenerative insults that lead to Alzheimer's disease. To aid in such therapeutic development, we determined the chemical structural features that predict progestin efficacy in the brain and showed that binding affinity does not predict neuroprotective efficacy or the direction of effect and thus cannot be used as an indicator of neurological benefit. In contrast, there was a set of common features of ligand-receptor interactions that are correlative and hopefully predictive of neuroprotective efficacy. Elucidation of the sites and targets of progestogen action should have a clear impact on both the use of hormone therapy for the prevention of neurodegenerative disease and the future design of target-specific hormone therapy formulations.