Summary and Conclusions of the Extramural Working Group on "Bench to Bedside: Estrogen as a Case Study"

There is considerable evidence from both pre-clinical and human studies that ovarian steroids have widespread neuroregulatory potential. These hormones mediate effects within the CNS relevant to the pathophysiology, course, and treatment response characteristics of several brain disorders. However, critical gaps exist in our knowledge of both the effects on brain function of declining ovarian steroid secretion during reproductive aging, and the role of ovarian steroid hormone therapy in the prevention or treatment of brain diseases. Ovarian steroids exert a wide range of physiologic effects within the body. Their signaling pathways are extremely complex; involve many different organ systems, and interact with a variety of other hormonal systems. Thus the manifold nature of their regulatory capacity is accompanied by a wide range of potential actions – some beneficial to the individual, others not. Indeed, one observation emerging from the literature is that the effects of ovarian steroids on brain function are not uniform, and several potential sources of variability have been identified that may explain these otherwise discordant results. First, both the chronological and reproductive age as well as the health status of the individual influence the observed response to administered ovarian steroids. Thus the timing of administering hormone therapy is an important determinant of both the health benefits and risks to the individual. Second, the type of steroid preparation could mediate a range of diverse effects within the same organ system resulting in benefits accrued with one hormonal preparation and either no benefits or adverse health events caused by another preparation. Finally, the schedules of administration of estrogen and progestin (i.e., cyclic or continuous combined) are important to consider with respect to effects on brain.

Future efforts should focus on developing the following: improved understanding of the variables that predict those women in whom the menopause transition adversely alters the course of specific brain diseases and those women who will benefit from the introduction of ovarian hormone therapy; novel therapeutics, such as selective ovarian steroid (i.e., estrogen, progesterone, and androgen) modulators, that enhance the potential therapeutic benefits of these steroids in the CNS but have more acceptable long-term safety profiles; and clinically relevant assessment tools of both brain function and disease progression.

As a final caveat, the committee membership was concerned about two trends in prior studies that have examined the role of ovarian steroids (both endogenous and exogenous forms) in human brain function: the majority of these studies were neither designed to specifically measure brain function as the primary endpoint nor were they adequately informed by the extant knowledge derived from pre-clinical studies.