Distinct cognitive effects of estrogen and progesterone in menopausal women
Introduction
The cognitive effects of postmenopausal hormone treatment have remained controversial in recent years, and as a result, hormones are less commonly prescribed for complaints of memory loss. However, hormones are still commonly prescribed on and off-label for non-cognitive indications, and some hormone formulations may impart a cognitive benefit for some women. There is emerging evidence that progestins and progesterone do not equivalently influence neurobiological mechanisms of cognitive function, and that progesterone is likely to be more beneficial and carry fewer risks than its synthetic counterparts (Fischer et al., 2014, Jodhka et al., 2009, Maki, 2012, Singh and Su, 2013a). Despite this distinction, there is currently little evidence on the cognitive effects of progesterone in postmenopausal women.
Postmenopausal hormone use by women with intact uteri consists of a combined estrogen and progesterone regimen. Previously standard conjugated equine estrogen (CEE) + medroxyprogesterone acetate (MPA) has been associated with several health risks, such as increased risk of breast cancer and cardiovascular disease, and variable cognitive effects, including negative cognitive outcomes in women who began treatment well past menopause (Braden et al., 2011, Chlebowski et al., 2013, Coker et al., 2010, Resnick et al., 2006, Rossouw et al., 2002, Shumaker et al., 2003). Synthetic progestins have also been associated with reductions in verbal ability in all postmenopausal age groups (Coker et al., 2010, Maki et al., 2007, Resnick et al., 2004, Resnick et al., 2006), however verbal impact appears to be heavily influenced by progestin formulation. Progestins with less anti-estrogenic effects have been shown to have neutral or positive impact on verbal benefits conferred by estradiol treatment (Spark and Willis, 2012).
Recent studies of combined hormone formulations suggest that progesterone carries fewer somatic risks than synthetic progestins, and is not associated with increased risk for adverse cardiovascular outcomes, venous thromboembolism, or breast cancer (L’Hermite, 2013, Simon, 2012). Progesterone is also documented to have neuroprotective effects (De Nicola et al., 2013, Deutsch et al., 2013, Melcangi et al., 2014, Singh, 2006, Singh and Su, 2013b). Natural progesterone is associated with more positive and fewer negative cognitive outcomes than synthetic progestins, particularly MPA. In fact some evidence suggests that type of progestrogenic compound is more critical than type of estrogen in determining cognitive impact (Maki, 2012, Stanczyk et al., 2013, Warren et al., 2014).
Despite the significant distinctions between progesterone and synthetic progestins, there are very few studies that isolate the effects of progesterone on cognitive outcomes in postmenopausal women, and none using neuroimaging measures of cognitive processing. A single study of cognitive effects of postmenopausal progesterone administration found no effect on verbal or executive function performance, but did not test visual cognition (Schussler et al., 2008, Spark and Willis, 2012). The majority of evidence for cognitive effects of natural progesterone comes from studies of postmenopausal women using combined hormone formulations (estrogen + progestin versus progesterone), studies of circulating progesterone levels or fluctuations in endogenous progesterone levels across a menstrual cycle, and progesterone administration in animals. Evidence from these studies suggest an effect of progesterone in cognitive processing brain regions, distinct from the effects of estrogen, and indicate the need for closer investigation of progesterone effects in postmenopausal women (Acosta et al., 2013, Chisholm and Juraska, 2012, Drake et al., 2000, Farage et al., 2008, Gibbs, 2000, Nilsen and Brinton, 2002b, Rapp et al., 2003, Stanczyk et al., 2013).
While cognitive outcomes have been variable across studies of postmenopausal hormone use, in general there have been more positive cognitive effects associated with unopposed estrogen than with combined estrogen/progestin regimens, with progestin appearing to mitigate estrogenic effects in some cases(Rice et al., 2000, Sherwin and Grigorova, 2011, Silverman et al., 2011). This is particularly true for the verbal cognitive domain, which appears to be more influenced by hormone treatment than visual cognition (Carlson and Sherwin, 1999, Jacobs et al., 1998, Krug et al., 2003, Maki, 2005, Resnick et al., 2006, Shaywitz et al., 2003, Sherwin, 2012). It is possible that synthetic progestins reduce some neuroprotective effects of estrogen, as has been demonstrated in cell culture models, and these studies also suggest that natural progesterone may increase estrogenic neuroprotections (Nilsen and Brinton, 2002a, Nilsen and Brinton, 2002b).
In contrast to variable behavioral outcomes, a growing collection of imaging studies of menopausal estrogen use have almost uniformly found differing brain activation patterns between hormone users and non-users during both verbal and visual cognitive tasks (Berent-Spillson et al., 2010, Dumas et al., 2010, Joffe et al., 2006, Persad et al., 2009, Shaywitz et al., 1999, Smith et al., 2006). Despite significant differences in study design, including differences in length of treatment, hormone formulations, and cognitive tasks, functional MRI (fMRI) of estrogen use has routinely shown increased activation during cognitive processing in frontal and cingulate cortical regions of the working memory circuitry (Dumas et al., 2010, Joffe et al., 2006, Shaywitz et al., 1999). Results from fMRI studies of combined estrogen + progestin have been less unequivocal, with similar but less distinct differences in activation patterns compared to non-users during verbal and visual cognitive tasks (Persad et al., 2009, Smith et al., 2006). Despite the distinct differences in activation of cognitive association and working memory circuitry between hormone users and non-users, sample sizes of neuroimaging studies have largely precluded meaningful behavioral analyses. However increased activation was associated with better visual working memory task performance in long-term estrogen or estrogen + progestin users (Berent-Spillson et al., 2010), and hormone use was associated with differential hippocampal activation and better verbal working memory performance in early-initiation hormone users compared to non-users (Maki et al., 2011). PET studies of blood flow to cognitive processing circuitry have also indicated differences between hormone users and non-users, largely but not uniformly indicating increased blood flow to cognitive association regions in hormone users during verbal and visual tasks, and often correlated with better cognitive task performance (Maki and Resnick, 2000, Resnick et al., 1998). To date there have been no neuroimaging studies of cognitive effects of unopposed progestin or progesterone use during menopause, however a notable PET study of Lupron-induced ovarian suppression in young women found that estrogen and progesterone were each independently able to regulate cerebral blood flow and prefrontal cortical activation during a test of frontal executive function (Berman et al., 1997).
Because of the differential effects of hormone use on visual and verbal cognition, and because of the neuroprotective potential of progesterone, there is a need for further study of the effects of estrogen and progesterone independently on each of these cognitive domains. In the current randomized placebo-controlled pilot study of 29 recently postmenopausal women, we separately assessed the effects of estrogen or progesterone treatment on visual and verbal cognitive function, using both neuropsychological measures and functional MRI to examine neural pathways used while performing verbal processing and visual working memory cognitive tasks. We hypothesized that estrogen treatment would be associated with more robust changes in cognitive performance and regional brain activation compared to placebo than would progesterone treatment, particularly in the prefrontal cortex and hippocampus, and that progesterone might be associated with slightly worse verbal processing performance scores.
Section snippets
Subjects
Twenty-nine women (25 included in fMRI imaging analysis), aged 45–55 years were recruited from the community. Women were included with FSH values over 40 IU/L and serum estradiol less than 40 pg/ml, and between 6 and 38 months of amenorrhea, to include women close to their final menstrual period. Two women with hysterectomy and bilateral oophorectomy meeting all other criteria were included, one in each of the two hormone treatment groups. Women were excluded for left handedness, acute illness,
Demographics
Demographic and clinical characteristics are provided in Table 2, and were similar between women randomized to either estrogen or progesterone treatment groups.
Neuropsychological assessment of verbal and visual cognition
Neuropsychological measures of cognitive function indicate similar scores after estrogen or progesterone treatment compared to after placebo for both verbal and visual domains. While much larger sample sizes are typically required to detect subtle differences in cognitive function (Cohen, 1988), we found a statistically significant
Discussion
The effects of postmenopausal hormone treatment on cognitive outcomes are inconsistent in the literature. Emerging evidence suggests that cognitive effects are influenced by specific hormone formulations, and that progesterone is more likely to be associated with positive outcomes than its synthetic counterparts (L’Hermite, 2013, Simon, 2012). There are very few studies of unopposed progesterone in postmenopausal women, and none that use functional neuroimaging, a sensitive measure that can
Contributors
All authors have approved the final article, and include:
Alison Berent-Spillson: study design, data collection, preparation, analysis, interpretation, manuscript preparation
Emily Briceno: data analysis, interpretation, manuscript preparation
Alana Pinsky: data preparation, analysis, interpretation
Angela Simmen: data interpretation, manuscript preparation
Carol Persad: study design, data interpretation
Jon-Kar Zubieta: study design, data interpretation
Yolanda Smith: study design, data
Role of funding sources
This work was supported by NIH (grant nos. R21AG031951 and 5K01MH095920), the NIH CTSA (grant no. 2UL1TR000433-06) for MCRU services, and by the Phil F. Jenkins Foundation (JKZ).
Funding sources had no involvement in study design, data collection, analysis, or interpretation, in writing the report, or in the decision to submit the article for publication.
Conflict of interest
We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us.
We confirm that
Acknowledgments
We have not published this work previously and it is not under consideration for publication elsewhere. This publication as approved by all authors, and if accepted, it will not be published elsewhere in the same form in any language without the written consent of the copyright-holder.
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