Vol 4 n° 2 - Cerebral aspects of reproductive endocrinology
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For many years, beliefs about sex differences in brain and behavior   were   part   of   the   province   of   myth   and sterotype, and the reproductive steroids—estradiol, prog- esterone, and testosterone—appeared largely irrelevant to psychiatrists. The possible role of gender and repro- ductive steroids in mood regulation has recently been transformed, however, into a critical locus of research in clinical neuroscience. This transformation largely reflects the explosive advances in molecular biology, which have convincingly  demonstrated  the  enormous  impact  of reproductive  steroids  on  neuroregulation  and  brain ontogeny. Sex, it turns out, does make a difference—in the formation, functioning, and fate of the brain and its constituents. The clinical implications of these effects not only encompass gender-related differences in suscepti- bility to psychiatric illness, symptom expression, and response to treatment, but also predict entirely new addi- tions to our therapeutic armamentarium. As suggested in the State of the art  article by David R. Rubinow and Peter J. Schmidt (page 123), not only do reproductive steroids provide a context in which the brain develops, but their effects on the brain are also highly context-dependent. As such, two fundamental principles of reproductive psychiatry have widespread implications for many psychiatric disorders: (i) normal  levels of repro- ductive steroids can trigger affective dysregulation in those with preexisting vulnerability  (which presumably has its own biological mediators and antecedents); and (ii) a variety of factors—past history, environment, meta- bolic capacity, and gender—create a context that can alter the response to a given stimulus. This differential sensitivity may help explain a central conundrum in psy- chiatry: why do different persons respond differently to the same stimulus? Three Basic research  papers provide insights into the molecular mechanisms underlying cognitive and neuro- protective effects of reproductive steroids (particularly estradiol) as well as sex differences in stress responsivity. Bruce S. McEwen (page 163) describes the genomic and nongenomic mechanisms by which estradiol regulates synapse formation, signal transduction, and neural/glial survival. He details the interactions between estradiol, signaling  proteins  (eg,  cyclic  adenosine  monophos- phate–responsive binding protein [CREB] and protein kinase B [Akt]), and neurotransmitters and receptors (eg, the g-aminobutyric acid [GABA] and N-methyl-D-aspar- tate [NMDA] receptors) in the hippocampus to provide a model for how estradiol may impact a variety of central nervous system (CNS) disorders, including dementia, seizure disorders, cognitive dysfunction, and affective ill- ness. One of the contextual factors that alters the nature of the effects and impact of estrogen is aging. Not only does estrogen have different effects on the old versus the young brain, but the prolonged hypoestrogenism of the postmenopause may critically influence neural systems mediating cognitive function as well as intracellular sys- tems determining neuronal survival and death. Dena B. Dubal  and  Phyllis  M.  Wise  (page  149)  review  these effects and summarize the emerging literature support- ing the neuroprotective actions of estradiol as well as its potential therapeutic role in the prevention of neurode- generation. Finally, Tracey J. Shors (page 139) reviews sex differences in learning and response to stress, as well as the organizational and activational impact of reproduc- tive steroids on these processes. Of particular note in her studies of classical conditioned learning is the impairment of  performance  seen  in  females  compared  with  the enhanced performance in males in response to stress. In the Pharmacological aspects  article, Ellen W. Free- man (page 177) distills an extensive literature on repro- ductive endocrine–related mood disorders to present the information that is critical to the successful evaluation and treatment of women with premenstrual syndrome (PMS),  postpartum  depression,  and  perimenopausal depression. While treatment of these disorders must be individualized, the likelihood of success is high. Two Clinical research articles examine the treatment of mood disorders in women. Peter J. Schmidt and David R. Rubinow (page 211) review the history of the use of hor- mones as psychotropic agents and then describe the use of reproductive hormones in both reproductive endo- crine–related mood disorders (PMS, postpartum depres- sion, and perimenopausal depression) and major (and minor) depressive disorder. The emerging role of estradiol in the psychiatric therapeutic armamentarium is dis- cussed, particularly with reference to perimenopausal depression. Raquel E. Gur and Ruben C. Gur (page 197) extend the effects of aging and gender described in the basic papers to human studies. They employ the imaging tools (magnetic resonance imaging [MRI], positron emis- sion tomography [PET], and functional MRI [fMRI]) to investigate gender differences in the effects of aging on 1 2 1 I n   t h i s   i s s u e . . .