Genetic variability in estrogen disposition: Potential clinical implications for neuropsychiatric disorders

Variability in the physiological levels of neuroactive estrogens is widely believed to play a role in predisposition to several disorders of the central nervous system. Local biosynthesis of estrogens in the brain as well as their circulating serum levels are known to contribute to this pool of neuroactive steroids. It has been well accepted that estrogens modulate neuronal functions by affecting genesis, differentiation, excitability, and degeneration of nerve cells. These actions of estrogens appear to be more prominent in females with higher concentrations and marked variability of circulating serum levels occurring over a woman's lifetime. However, our knowledge regarding the variability of neuroactive steroid levels is very limited. Furthermore, several studies have recently reported differences in the synchronization of circulating and neuronal levels of estradiol. In the absence of reliable circulating steroid levels, knowledge of genetic variability in estrogen disposition may play a determining factor in predicting altered susceptibility or severity of neuropsychiatric disorders in women. Over the past decade, several genetic variants have been linked to both differential serum estrogen levels and predisposition to diverse types of neuropsychiatric disorders in women. Polymorphisms in genes encoding estrogen-metabolizing enzymes as well as estrogen receptors may account for this phenotypic variability. In this review, we attempt to show the contribution of genetics in determining estrogenicity in females with a particular emphasis on the central nervous system. This knowledge will further provide a driving force for unearthing the novel field of "Estrogen Pharmacogenomics." © 2010 Wiley-Liss, Inc.