Sex steroids and the brain

Abstract

Although it still remains relatively inaccessible, intrepid explorers are scaling the heights and swarming the forests of the human brain. Among the most pregnant returns of these ventures is information indicating the formation of steroid hormones, their metabolism and receptor-based and non-receptor-based actions in the brain. The sex steroids are presently receiving the most attention, but the corticosteroids should not be forgotten. Brain sex steroids, their precursors, receptors and metabolizing enzymes are present from the earliest periods studied. They are known to regulate brain development, sexual dimorphism, inflammatory responses and the physical barriers of the brain. Neural conduction, ordinary and special behavior, cognition, mood, appetite and many other functions of the brain are controlled, or at least informed by brain sex steroids. While some brain activities are certainly independent of sex steroids, even these are impacted by the effects of estrogen, progestins, corticoids and androgens on associated neuronal and glial systems. The latter, referred to as the second communication system of the brain, is also sex steroid-sensitive and well worth attention. These matters are ever-more widely appreciated. They include gender issues, developmental activities, cognition, mood, motor function and higher brain activities. They are subject to perturbation by administered drugs, some of which are steroids and some of which ‐ though not composed as steroids ‐ may act as steroids do; examples include phenatoin, DDT, DES, etc. In dramatic examples, sport has been drastically affected by sex steroids’ effects on mood. Of course, the first and often the last signs of estrogen deficiency are most often acted out with the brain as the prima donna. The conquest of ‘the brain and sex steroids’ began with clinical observations; history is strewn with them. Progress lagged as other, more accessible organs took center stage. But, now the signatures of autism, cognition, memory and the excessive mood swings of premenstrual syndrome have appeared on the imager’s small screen and are being embraced by clinicians, described in context, cataloged, prevented and treated. In some cases, clinical application is running ahead of science. These will be very exciting times for those who have always considered the human brain as the last frontier. But they will be difficulties as we move from planned observation and perturbation over workday-long observation periods to the wild and wooly adventure of following the effects of sex steroids during the lightening events of stroke and the snail’s pace of progress on cerebrovascular disease. The study of multiple sclerosis, depression, posttraumatic shock, perversity and mental illness will also involve sex steroids; at present the issue is whether there are useful generalities involved or if there are specific steroid-specific actions to be defined and addressed. Interest in esoteric and physically striking diseases has thus far separated the efforts of clinicians from the more basic investigations of laboratory scientists. However, this is changing as basic patterns of sex steroid formation and action become clear. This will include the understanding of the breadth of sex steroid action in mood disorders and cognition, the for-once-andfor-all grasp of the extent of estrogens’ action on the brain represented by menopausal symptoms, and the understanding of the power of the agents hurled out of the tornado that is the inflammatory cascade in brain. Then will we see the most fascinating sights, as the remaining loose pieces of the puzzle are inserted