Longitudinal 7T MRI reveals volumetric changes in subregions of human medial temporal lobe to sex hormone fluctuations

Abstract

The hippocampus and surrounding medial temporal lobe (MTL) are critical for memory processes, with local atrophy linked to memory deficits. Animal work shows that MTL subregions densely express sex hormone receptors and exhibit rapid structural changes synchronized with hormone fluctuations. Such transient effects in humans have thus far not been shown. By combining a dense-sampling protocol, ultra-high field neuroimaging and individually-derived segmentation analysis, we demonstrate how estradiol and progesterone fluctuations affect MTL subregion volumes across the human menstrual cycle. Twenty-seven healthy women (19-34 years) underwent 7T MRI at six timepoints to acquire T1-weighted and T2-weighted images. Linear mixed-effects modeling showed positive associations between estradiol and parahippocampal cortex volume, progesterone and subiculum and perirhinal Area 35 volumes, and an estradiol*progesterone interaction with CA1 volume. We confirmed volumetric changes were not driven by hormone-related water (cerebral spinal fluid) or blood-flow (pulsed arterial spin labeling) changes. These findings suggest that sex hormones alter structural brain plasticity in subregions that are differentially sensitive to hormones. Mapping how endogenous endocrine factors shape adult brain structure has critical implications for women's health during the reproductive years as well as later in life, such as increased dementia risk following perimenopause, a period of pronounced sex hormone fluctuations.

Heritability of hippocampal functional and microstructural organisation

“…Nevertheless, it is still possible that the captured variability in hippocampal functional organisation may reflect more state-like features, also taking into account that the hippocampus is a region that is considered particularly plastic ( Cooper et al, 2018 ). Next to effects on cognitive state on hippocampal function, hippocampal structure and function have been reported to be susceptible to variation hormonal status ( Barth et al, 2016 , Zsido, et al ) and stress ( Kim et al, 2015 , McEwen, 1999 ), factors that likely differ between twins at a given time point. In line with these observations, we found subtle co-variations between age and sex and hippocampal functional and structural organisation ( Kim et al, 2015 , McEwen, 1999 ), possibly suggestive of long-term hormonal plasticity effects as well as experience-driven plasticity effects.…”

“…For example, the unique plasticity of hippocampal formation is associated with its different subfields and, amongst others, affected by the hormonal levels and stress responses ( McEwen, 1999 , Bannerman et al, 2014 ). Such environmentally-induced plasticity has also been shown in humans, such as variation in hippocampal structure due to variation hormonal status ( Barth et al, 2016 , Zsido, et al ) and stress levels ( Kim et al 2015 ). A second way to reconcile the notion of plasticity and stability reported in the hippocampus is by means of the structural model ( Barbas, 2015 ).…”

Diurnal fluctuations in steroid hormones tied to variation in intrinsic functional connectivity in a densely sampled male

“…At the cellular level, steroid hormones regulate synaptic plasticity in the hippocampus and prefrontal cortex (PFC) (Galea et al, 2017; Taxier et al, 2020). At the behavioral level, hormonal transitions such as puberty (Brouwer et al, 2015; McDermott et al, 2012; Pattwell et al, 2013), the menstrual cycle (Pritschet et al, 2020; Taylor et al, 2020; Zsido et al, 2022), pregnancy (Carmona et al, 2019; Hoekzema et al, 2017), menopause (Jacobs et al, 2017), and andropause (Janowsky, 2006) are tied to changes in brain function and structure. Fluctuations in hormone concentrations across shorter timescales, like diurnal rhythms, may also influence brain function.…”

“…Neuroimaging studies that densely sample individuals over timescales of days, weeks, or even months (Fedorenko, 2021; Gordon et al, 2017; Poldrack et al, 2015) are now being leveraged to provide unique insights into the role our endocrine system plays in regulating the dynamic nature of the human brain over time (Jacobs, 2023; Pritschet et al, 2021). Precision imaging of the human brain across neuroendocrine transitions adds a novel methodological approach for understanding the influence of biological rhythms on the brain (Jacobs, 2023; Pritschet et al, 2020, 2021; Taylor et al, 2020; Fitzgerald et al, 2020; Mueller et al, 2021; Zsido et al, 2022; de Filippe et al, 2021).…”

Menopause status- and sex-related differences in age associations with spatial context memory and white matter microstructure at midlife

“…First, our premenopausal females were not scanned during a specific phase of their menstrual cycle, as done in some related studies (e.g., Jacobs et al, 2016). It is possible, therefore, that menstrual cycle-related variability in the structure and/or function of regions involved in episodic memory (Dubol et al, 2021;Zsido et al, 2023) may have contributed to the lack of age effects among this group. However, recent research showing that verbal and spatial cognition remain relatively stable across the menstrual cycle casts some doubt on this, instead suggesting that such variability -if present -is adaptive and may not necessarily influence cognitive function (Pletzer et al, 2024).…”