Functional and molecular neuroimaging of menopause and hormone replacement therapy

Abstract

The level of gonadal hormones to which the female brain is exposed considerably changes across the menopausal transition, which in turn, is likely to be of great relevance for neurodegenerative diseases and psychiatric disorders. However, the neurobiological consequences of these hormone fluctuations and of hormone replacement therapy in the menopause have only begun to be understood. The present review summarizes the findings of thirty-five studies of human brain function, including functional magnetic resonance imaging, positron and single-photon computed emission tomography studies, in peri- and postmenopausal women treated with estrogen, or estrogen-progestagen replacement therapy. Seven studies using gonadotropin-releasing hormone agonist intervention as a model of hormonal withdrawal are also included. Cognitive paradigms are employed by the majority of studies evaluating the effect of unopposed estrogen or estrogen-progestagen treatment on peri- and postmenopausal women's brain. In randomized-controlled trials, estrogen treatment enhances activation of fronto-cingulate regions during cognitive functioning, though in many cases no difference in cognitive performance was present. Progestagens seems to counteract the effects of estrogens. Findings on cognitive functioning during acute ovarian hormone withdrawal suggest a decrease in activation of the left inferior frontal gyrus, thus essentially corroborating the findings in postmenopausal women. Studies of the cholinergic and serotonergic systems indicate these systems as biological mediators of hormonal influences on the brain. More, hormonal replacement appears to increase cerebral blood flow in several cortical regions. On the other hand, studies on emotion processing in postmenopausal women are lacking. These results call for well-powered randomized-controlled multi-modal prospective neuroimaging studies as well as investigation on the related molecular mechanisms of effects of menopausal hormonal variations on the brain.

Neuroimaging the Menstrual Cycle and Premenstrual Dysphoric Disorder

“…Volumetric differences in within-subject study designs indicate gray matter volume to be increased in the hippocampus in the late follicular relative to the early follicular and mid-luteal phases [31••], in the right fusiform/ parahippocampal gyrus during early follicular compared to the mid-luteal phase [32], or in the right anterior hippocampus during the late follicular compared to late luteal phase [33]. These findings are in keeping with the commonly reported association between estrogen treatment and larger hippocampal volume, along with enhanced hippocampus function, in postmenopausal women (see review [34]). …”

“…While hormone replacement during menopause appears to increase cerebral blood flow in several cortical regions (review [34]), these measures have not really yet been employed to investigate hormonal influences in fertile women. The one and only existing resting-state PET-rCBF study indicates heightened local neuronal activity, measured as glucose metabolism, in the cingulate, insular, temporal, occipital, and cerebellar regions during the mid-luteal phase, and in prefrontal and temporal regions during the early follicular phase [43].…”

“…Research in support of this include findings of symptom relief during gonadotropin releasing hormone agonist-induced anovulatory cycles [101], the reinstatement of symptoms when add-back progesterone is administered together with GnRH agonists [102], and findings of progestagen-induced mood symptoms in postmenopausal women [103][104][105]. While the neural correlates of GnRH agonist treatment have been evaluated in healthy women [34], they remain to be established in women with PMDD.…”

“…The altered brain activation patterns by estrogenonly or estrogen-progestagen treatment in therapeutic doses in postmenopausal women are quite scattered (see review [34]). Generally, though in many cases no difference in cognitive performance is present, estrogen treatment enhances activation of frontocingulate regions during cognitive functioning, and progestins seem to counteract these effects.…”

“…In contrast, studies on emotion processing in postmenopausal women are lacking. Hormonal replacement appears to increase cerebral blood flow at rest in several cortical regions, and the cholinergic and serotonergic systems seem to act as biological mediators of hormonal influences on the brain [34]. On the other hand, findings of exogenous hormone exposure in studies of women in childbearing ages suggest various sex hormone effects on brain function [2••] and structure [32,38,42,106].…”