The need for novel therapeutics has fueled the burgeoning impetus to uncover biological mechanisms that contribute to sex and individual differences in the manifestations of neuropsychiatric disorders. Investigating interactions between sex hormones and genetic makeup holds promise for this quest.
Animal studies have clearly established that sex hormones impact brain organization and function at critical developmental periods, including gestation and puberty; the neuromodulatory effects of ovarian steroids are well documented across the lifespan. However, little is known about the genesis of individual differences in cognitive and behavioral response to these hormones in humans. For example, why do some women develop postpartum depression while others do not, even in the face of the same hormonal events? Because ovarian hormones are important transcriptional regulators, their actions on the brain may vary according to individual differences in genetic make-up, suggesting an important research direction that could provide information regarding this and similar clinical questions.
The potential importance of such investigations is supported by preclinical studies in female transgenic mice harboring the uniquely human BDNF Val66Met variant. The BDNF gene is of particular interest for investigating gene–hormone interaction because estradiol induces BDNF expression that mediates hippocampal function . Likely as a consequence, in female BDNFMet knock-in mice, the estrus cycle critically interacts with the Val66Met variant to modulate anxiety-related behaviors  as well as hippocampally dependent function and behavior .
Building on these preclinical experiments, we used two different but complementary neuroimaging modalities, the blood-oxygen-level depndent functional magnetic resonance imaging and positron emission tomography regional cerebral–blood flow techniques, to measure working memory-dependent brain function in healthy, regularly menstruating women during a 6-month hormone-manipulation protocol with three hormone conditions: ovarian suppression induced by the gonadotropin-releasing hormone agonist leuprolide acetate (Lupron), Lupron + estradiol replacement, and Lupron + progesterone replacement. We found a genotype–hormone interaction in the hippocampus, a region that is typically not recruited and is often even deactivated during working memory: in women carrying the BDNFMet variant, the hippocampus was atypically activated (i.e., abnormally recruited), but only in the presence of estradiol . The results were consistent between both imaging platforms, providing important confirmatory data. Our findings demonstrate an estrogen sensitivity in the context of the Met variant in women, and thus provide an important translational step by demonstrating that the BDNF genotype–ovarian steroid interaction impacts neural function.
These studies offer evidence that harboring a genetic predisposition regulated in part by sex hormones in the brain, such as the BDNFMet allele, may have clinical implications . Additionally, a recent preclinical study showing BDNFMet variant-specific elimination of hippocampal function during peri-adolescence  suggests the importance of future studies examining gene–hormone interactions during this critical period of brain development and hormonal change.
Delineating how the interplay between genes and sex hormones influences the brain has important relevance for women’s mental health, for understanding individual differences in hormonal effects on brain and behavior, and for revealing mechanisms that confer sex-related differential risk for neuropsychiatric disorders. Moreover, the potential importance of such gene–hormone interactions suggests a general strategy for further exploration that may inform individualized treatments.
Funding and disclosure
This work was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health. The authors declare no competing interests.
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Wei, SM., Berman, K.F. Ovarian hormones, genes, and the brain: the case of estradiol and the brain-derived neurotrophic factor (BDNF) gene. Neuropsychopharmacol 44, 223–224 (2019). https://doi.org/10.1038/s41386-018-0223-5
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