Physiological variation in estradiol and brain function: A functional magnetic resonance imaging study of verbal memory across the follicular phase of the menstrual cycle
Introduction
Women frequently complain of memory problems at times in their reproductive lives that are associated with changes in estrogen concentration (e.g. around the time of the menopause and childbirth) (Mitchell and Woods, 2001). Studies to clarify the possible biological basis of this have generally focussed on the differences between postmenopausal women on and off estrogen therapy (ET), or examined younger women following acute medical or surgical loss of ovarian function. Some of these prior studies reported that verbal, and less consistently visual, memory improved in postmenopausal women taking ET (Jacobs et al., 1998, Kampen and Sherwin, 1994, Maki et al., 2001, Sherwin, 1988, Sherwin and Phillips, 1990, Zec and Trivedi, 2002) (particularly parenteral 17-β estradiol (E2)). Verbal memory deficits have also been reported in women following acute loss of ovarian function, and these deficits have been reversed with estrogen ‘add-back’ therapy (Newton et al., 1996; Phillips and Sherwin, 1992; Sherwin and Tulandi, 1996; Sherwin and Phillips, 1990). Thus there is increasing evidence that in some women estrogen may affect verbal memory.
The biological basis of these effects remains poorly understood. However, brain imaging studies in postmenopausal women reported that ET modulates the metabolism and function of brain regions sub-serving memory (e.g. hippocampal, frontal, parietal, and temporal regions) (Maki and Resnick, 2000, Resnick et al., 1998, Shaywitz et al., 1999). Furthermore, we have recently reported that acute suppression of ovarian function (following administration of a Gonadotropin Hormone Releasing Hormone agonist (GnRHa)) in young healthy women is associated with decreased activation in left prefrontal cortex, and particularly the left inferior frontal gyrus (LIFG), during successful verbal memory encoding (Craig et al., 2007). This finding is consistent with reports of an association between LIFG activation at encoding with subsequent memory success (Buckner et al., 2000, Davachi et al., 2003, Jackson and Schacter, 2004, Ranganath et al., 2003, Staresina and Davachi, 2006). Also it suggests that modulation of LIFG function may be an important mechanism through which estrogen affects verbal memory formation.
Several previous studies have reported that hormonal variation across the menstrual cycle is associated with significant changes in brain activity during motor and language tasks (Dietrich et al., 2001, Fernandez et al., 2003, Goldstein et al., 2005) but we are unaware of any brain imaging studies to date that have analysed the relationship between the normal variation in estradiol levels across the menstrual cycle and brain function during a memory task. This is, however, an area of potential interest as behavioural studies suggest that memory performance may fluctuate across the menstrual cycle. For example, high estrogen levels are associated with improved performance on verbal tasks, whereas improved performance on visuo-spatial tasks is associated with lower estrogen levels (Hampson, 1990a, Hampson, 1990b, Hoff et al., 2001, Rosenberg and Park, 2002, Young-Hoon et al., 2006). We therefore carried out the first study to investigate whether physiological variation in plasma estradiol concentration is associated with differences in activity of the LIFG during successful verbal encoding. We hypothesised that higher plasma concentrations of estradiol would be associated with increased brain activity at the LIFG and improved recall performance. In order to avoid the potentially confounding effect of changes in progesterone levels, we limited our analysis to the follicular phase of the cycle (i.e. when progesterone levels are low (≤ 8 nmol/l) and estradiol levels are rising).
Section snippets
Subjects
We included 16 right-handed young (26–45 years) pre-menopausal women with regular menstrual cycles. All women signed informed consent as per the Ethics Committee Guidelines of the University of London.
Exclusion criteria
All the women were screened to exclude psychiatric disorders using the Structured Clinical Interview for DSM-IV Axis I and II Disorders (SCID-I and SCID-II) (First et al., 1997a, First et al., 1997b). Scores on the Beck Depression and Anxiety Inventories (BDI and BAI, respectively) (Beck et al.,
Baseline screening tests
The mean age of female volunteers was 39 (range 26 to 45) and all women were in the normal range (mean ± SEM) with respect to the mini Mental State Examination (29.46 ± 0.24), verbal IQ (98.50 ± 3.31), performance IQ (99.44 ± 3.30), and full scale IQ (99.88 ± 3.14). The Structured Clinical Interview for DSM-IV Axis I and II Disorders Scores, Beck Depression Inventory (8.38 ± 1.9), and Beck Anxiety Inventory (8.29 ± 2.24) confirmed that women included in the study did not have clinically significant mental
Discussion
Our aim was to explore the relationship between plasma estradiol concentration and brain function at the left inferior frontal cortex (LIFG) during verbal encoding. We hypothesised that brain function at the LIFG, and verbal memory performance, would be positively correlated with estradiol concentration. In support of this, we report a positive correlation between brain function and estradiol concentration at the LIFG. These preliminary findings are important as they suggest a biological
Acknowledgments
The authors wish to thank Dr. Roy Sherwood and the staff in the clinical biochemistry department at Kings College Hospital for analysing our blood samples, Professor Linda Cardozo for her help in facilitating recruitment at Kings College Hospital, Wyeth Pharmaceuticals for their financial support, and MRC (UK) who funded a Clinical Research Training Fellowship for Dr. Michael Craig.
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