Shaping of the Female Human Brain by Sex Hormones: A Review

Abstract

Traditionally sex hormones have been associated with reproductive and developmental processes only. Since the 1950s we know that hormones can have organizational effects on the developing brain and initiate hormonal transition periods such as puberty. However, recent evidence shows that sex hormones additionally structure the brain during important hormonal transition periods across a woman’s life including short-term fluctuations during the menstrual cycle. However, a comprehensive review focusing on structural changes during all hormonal transition phases of women is still missing. Therefore, in this review structural changes across hormonal transition periods (i.e., puberty, menstrual cycle, oral contraceptive intake, pregnancy and menopause) were investigated in a structured way and correlations with sex hormones evaluated. Results show an overall reduction in grey matter and region-specific decreases in prefrontal, parietal and middle temporal areas during puberty. Across the menstrual cycle grey matter plasticity in the hippocampus, the amygdala as well as temporal and parietal regions were most consistently reported. Studies reporting on pre- and post-pregnancy measurements revealed volume reductions in midline structures as well as prefrontal and temporal cortices. During perimenopause, the decline in sex hormones was paralleled with a reduction in hippocampal and parietal cortex volume. Brain volume changes were significantly correlated with estradiol, testosterone and progesterone levels in some studies, but directionality remains inconclusive between studies. These results indicate that sex hormones play an important role in shaping women’s brain structure during different transition periods and are not restricted to specific developmental periods.

Differences in Total Brain Volume between Sexes in a Cognitively Unimpaired Elderly Population

“…Another possible hypothesis, according to the findings of Ryan et al ( 2 ), would be linked to sexual hormones. It is known that humans have estrogen receptors (ESR1 and ESR2) distributed throughout the brain, especially in limbic areas, which contribute to cognitive functioning ( 1 , 2 , 32 ) and emotional processing ( 1 , 33 ). Ryan et al ( 2 ) has suggested that estrogen has a possible neuroprotective effect due to its influence on synaptic plasticity and its interaction with other neurotrophins.…”

“…This type of effect could contribute to the larger GM volumes seen in women ( 2 , 34 , 35 ). Nevertheless, regarding the evaluation of the direct effect of estrogen on the human brain, the literature presents conflicting results, with data suggesting a detrimental effect of estrogen on brain volume in some studies ( 2 ), while a beneficial effect of hormonal therapy has been reported in other studies ( 1 , 34 , 36 ). On the other hand, specifically regarding the aging process, there are theories stating that the brain volume loss due to aging is not only greater but also starts earlier in men than in women ( 14 , 25 , 37 - 39 ).…”

“…Several studies have documented the brain’s anatomical differences across various age groups and sexes and multiple theories aim to explain the cause of these disparities. An example is to attribute these differences to hormones, for instance, the action of estrogen on synaptogenesis and the effects of the absence of this hormone during menopause ( 1 , 2 ). There is no consensus, however, regarding whether the differences between sexes are due to an actual disparity in the size of the brain structures or if this is merely a reflection of the varied cranial volumes among individuals ( 3 ).…”

Relapsing and progressive MS: the sex-specific perspective

“…This could indicate that, in addition to the disease course, other factors, such as genetics or hormones, 19 , 24 , 25 could be relevant and have an influence on the development and pathophysiology of the disease (e.g. inflammation, 14 , 26 regeneration, 27 , 28 including brain plasticity, 29 – 31 and neurodegeneration). 32 Pathophysiological differences between relapsing and progressive MS have been described.…”

Friend vs. Foe: Cognitive and Affective Empathy in Women With Different Hormonal States

“…It has been suggested that menstrual cycle dependent as well as OC-induced changes in mental states and behavior may be explained by a differential binding of endogenous (i.e., due to changing concentrations) as well as synthetic sex steroids (i.e., due to slightly different binding properties) to receptor sites of brain regions involved in socio-emotional processing (e.g., limbic areas and frontal cortex; Toffoletto et al, 2014;Barth et al, 2015;Louw-du Toit et al, 2017). This differential binding and the resulting changes in transcription cascades can lead to hormone-induced changes of neural activity as well as brain morphology (Toffoletto et al, 2014;Barth et al, 2015;Rehbein et al, 2021). Due to these modulatory effects of hormonal status on brain regions relevant for socio-emotional processing, it would not be surprising if next to influences on mood, fear processing and sexual desire (Montoya and Bos, 2017;Lundin et al, 2018;Lewis et al, 2019), hormonal status also affected empathy.…”