Modulation of cognition-specific cortical activity by gonadal steroids: A positron-emission tomography study in women

Abstract

There is considerable evidence from animal studies that gonadal steroid hormones modulate neuronal activity and affect behavior. To study this in humans directly, we used H 2 15 O positron-emission tomography to measure regional cerebral blood f low (rCBF) in young women during three pharmacologically controlled hormonal conditions spanning 4-5 months: ovarian suppression induced by the gonadotropin-releasing hormone agonist leuprolide acetate (Lupron), Lupron plus estradiol replacement, and Lupron plus progesterone replacement. Estradiol and progesterone were administered in a double-blind cross-over design. On each occasion positron-emission tomography scans were performed during (i) the Wisconsin Card Sorting Test, a neuropsychological test that physiologically activates prefrontal cortex (PFC) and an associated cortical network including inferior parietal lobule and posterior inferolateral temporal gyrus, and (ii) a no-delay matching-to-sample sensorimotor control task. During treatment with Lupron alone (i.e., with virtual absence of gonadal steroid hormones), there was marked attenuation of the typical Wisconsin Card Sorting Test activation pattern even though task performance did not change. Most strikingly, there was no rCBF increase in PFC. When either progesterone or estrogen was added to the Lupron regimen, there was normalization of the rCBF activation pattern with augmentation of the parietal and temporal foci and return of the dorsolateral PFC activation. These data directly demonstrate that the hormonal milieu modulates cognition-related neural activity in humans.An extensive body of data from animal studies indicates that gonadal steroid hormones modulate neuronal activity and affect behavior. In humans, however, the behavioral and cognitive evidence has not been conclusive, and direct neurophysiological data are scant. Effects of gonadal steroids in the human central nervous system have been inferred largely from behavioral changes during the menstrual cycle, during administration of ovarian hormones, or in a gender-specific context. These inferences are, by definition, indirect and associational and, further, are incapable of disentangling the effects of hormones, such as estrogen and progesterone, which are simultaneously present in women of reproductive age. We directly tested the central nervous system effects of gonadal steroid hormones in young women by measuring regional cerebral blood flow (rCBF) as a marker of local neuronal activity and by controlling their hormonal states with the gonadotropin-releasing hormone (GnRH) agonist leuprolide acetate (Lupron).GnRH is produced by the hypothalamus and causes the anterior pituitary to release follicle-stimulating hormone and leuteinizing hormone. Lupron is a synthetic nonapeptide used clinically when suppression and͞or control of gonadal steroid secretion is the goal, such as in infertility and endometriosis in women and prostate cancer in men. It is some 80-100 times more potent than native GnRH at anterior pituitary receptors (1), an...

Risk for Premenstrual Dysphoric Disorder Is Associated with Genetic Variation in ESR1, the Estrogen Receptor Alpha Gene

“…Estradiol regulates PFC blood flow in humans (Berman et al 1997), and Korol (2002;2004) has demonstrated that E2 biases toward or against the activation of circuits mediating different forms of cognition: high estrogen favoring place-activated learning and low estrogen levels response-dependent learning. It is tempting to speculate, therefore, that disturbed ER alpha signaling in the luteal phase may interact with decreased PFC efficiency in those with the Val/ Val genotype so as to permit the expression of a dysphoric state suggestive of disinhibited subcortical (e.g., amygdala) activity.…”

“…As such, we were interested in examining the significantly associated variants in ESR1 (multi-SNP association) against the background of gene polymorphisms that do not appear associated with the diagnosis of PMDD but may nevertheless be involved. The Val158Met polymorphism in the COMT gene was selected for the following reasons: 1) COMT is involved in estrogen metabolism, performing O-methylation of 2-and 4-hydroxy estrogen metabolites (catecholestrogens); 2) the COMT gene contains estrogen response elements (Xie et al 1999), consistent with its regulation (decrease) by estradiol in vitro (Jiang et al 2003), an effect that is presumed to be mediated by ER alpha (Jiang et al 2003); 3) COMT is implicated in sex steroid associated cancers (Tanaka et al 2006;Sazci et al 2004); 4) COMT is responsible for regulating dopamine levels in the PFC, which are critical for modulation of cognitive function and "tuning" of the PFC (the ratio of task-related to task-unrelated neuronal firing), and the PFC is a brain region in which estradiol has been shown to regulate cerebral blood flow and function in humans (Berman et al 1997;Keenan et al 2001); 5) the COMT Val/Met polymorphism has been linked to the predisposition to several psychiatric disorders, including schizophrenia and OCD (Tunbridge et al in press;Karayiorgou et al 1997) and has been shown to moderate the effects of environmental factors in determining disease expression (Caspi et al 2005). The manifold interactions of COMT and estradiol and their convergence in areas of the brain critical in regulating mood and hypothesized as dysfunctional in PMDD (Rubinow et al in press) provided compelling justification for investigation of possible epistasis (gene-gene interactions).…”

Neuropsychological dysfunction associated with cancer and cancer therapies: a conceptual review of an emerging target

“…antioestrogens) have been examined with both neuroimaging (Berman et al, 1997) and neurocognitive probes (Varney et al, 1993, Rich andMaki, 1999). In summary, a pattern of relative hypometabolism in prefrontal cortex has been demonstrated with PET, and neurocognitive impairments in memory, executive function, and motor coordination have been reported.…”

Changes in estrogen receptor-alpha mRNA in the mouse cortex during development

“…The absence of such a hormone milieu results in a shift in development towards a phenotypic female brain [20]. In addition to generating sex differences in structural changes in the brain, estrogen is also responsible for the generation of sex differences in cognition and emotion [2,6,13,21].…”