Disclaimer: WiNUK acknowledges that the menstrual cycle is not a gender-specific experience. Throughout this blog, people who experience the hormone changes of the menstrual cycle are referred to as the ‘female sex’ or ‘female’, and those who were assigned female at birth.
What is the menstrual cycle?
The menstrual cycle is the ~28 day hormone cycle females have to regulate the shedding and build up of the uterus lining. The hormones that fluctuate are oestrogen, progesterone, follicle stimulating hormone and luteinizing hormone. Fluctuations in oestrogen and progesterone are the most prominent, lasting for the majority of the cycle, with oestrogen peaking during the follicular phase until ovulation and progesterone increasing during the luteal phase as the lining builds, and dropping when the lining sheds.
"Even in people without PMDD, peak progesterone levels during the menstrual cycle are associated with increases in negative mood"
How can these hormones affect the brain?
As these changes are so long-lasting and distinct, with oestrogen levels rising 8-fold and progesterone levels 80-fold during the ~28 day cycle (1), it has been hypothesised that people who experience these hormone changes will have marked differences in brain function and behaviour during these times. Indeed, many report emotional changes, increased irritability and decreased self-esteem during their cycle. Furthermore, people who take hormonal contraception may experience similar mood disturbances. But how do sex hormones have such a profound effect on our emotions? It is all down to the distribution of sex hormone receptors in the brain. Progesterone binds to receptors located in the amygdala, a brain region responsible for a range of emotional responses, such as anxiety, social understanding (interpreting social cues), and fear. Progesterone has been implicated in premenstrual dysphoric disorder (PMDD), a severe form of premenstrual syndrome (PMS) that is associated with emotional dysregulation during the luteal phase (when progesterone peaks) (2). Even in people without PMDD, peak progesterone levels during the menstrual cycle are associated with increases in negative mood (3). Progesterone can easily cross the blood brain barrier and can even accumulate in brain tissue to beyond levels found in the blood. Moreover, progesterone also has a role in stress regulation. During periods of stress, it can be converted to cortisol, the primary stress hormone (4) maintaining the actions of the sympathetic nervous system (the branch of the nervous system responsible for staying in high alert during situations of prolonged stress).
Other areas of the brain have sex hormone receptors too. The hippocampus is rich in sex hormone receptors and is also highly plastic, meaning it can be structurally altered in response to stimuli such as hormones. Indeed, oestrogen has been found to modulate structural plasticity in the hippocampus (5), having important implications in learning and memory. The hippocampus is also responsible for long term memory storage which can have significant implications on emotion - such as how a fond childhood memory might make us happy and reminiscent, or a negative one fearful and anxious.
"Only 0.5% of neuroimaging studies consider the effects of sex hormones and hormone transition phases on the brain"
Studies on the hippocampus have shown conflicting responses to sex hormones; some suggest there is a significant increase in grey matter in this region during the peak oestrogen portion of the menstrual cycle (6, 7), while others find no such result and lean towards the effect of progesterone on cycle stage-dependent changes in hippocampal volume (3).
The gap in research on female sex hormones and neuroimaging
Unfortunately, the scarcity and vagueness of research on the effect of female sex hormones in the brain is in part due to the long-standing bias towards males in neuroscientific research. In recent years, researchers have been encouraged to include both sexes in their experiments, whether it is on humans or rodents. Despite this leading to an increase in female representation in sample populations, the majority of research does not then analyse sex differences - as few as 5% of papers in neuroscience and psychiatry published in 2019 included ‘optimal analysis of possible sex differences’ (8). This emphasises a very pressing issue in neuroscience research. If we aren’t including females in our sample populations and are not analysing sex differences as a variable within research, we most certainly are not taking into account sex-dependent hormone cycles. This is evident in neuroimaging, with only 0.5% of neuroimaging studies considering the effects of sex hormones and hormone transition phases on the brain (9). It is even more alarming that this has only been flagged in the past couple years, when oral contraceptives have been readily prescribed since the 1960’s.
The future of sex hormone and neuroendocrine research
Current trends, largely driven by female neuroscientists, are to provide more clarity on the effect of the menstrual cycle on brain structure and behaviour. The overarching flaw of most neuroimaging studies evaluating the effect of the menstrual cycle on the brain is that they only observe a snapshot of the cycle. To improve our understanding of brain changes across the full 28 days, imaging experiments need to visualise the brain at a range of time points. When neuroimaging takes into account the day-to-day hormone fluctuations over the breadth of the menstrual cycle, we can begin to see just how the brain is altered over this period of time. A number of studies by the Jacobs Lab (University of California, Santa Barbara) have done just that, looking at how oestrogen and progesterone affect functional brain networks of an individual across a 30-day cycle (10).
Now that people are becoming more aware of the sex bias in research, attention is turning to the long-dismissed importance of sex differences in neuroscience. Soon we may uncover answers as to why females make up two thirds of people with Alzheimer’s, how to help those suffering from PMDD, and other interesting differences.
References:
Stricker, Reto, Raphael Eberhart, Marie-Christine Chevailler, Frank A. Quinn, Paul Bischof, and Rene Stricker. "Establishment of detailed reference values for luteinizing hormone, follicle stimulating hormone, estradiol, and progesterone during different phases of the menstrual cycle on the Abbott ARCHITECT® analyzer." (2006): 883-887.
Mind UK ‘What is PMDD?’ (2021) https://www.mind.org.uk/information-support/types-of-mental-health-problems/premenstrual-dysphoric-disorder-pmdd/about-pmdd/. Accessed: February 2024.
Taylor, C.M., Pritschet, L., Olsen, R.K., Layher, E., Santander, T., Grafton, S.T. and Jacobs, E.G., 2020. Progesterone shapes medial temporal lobe volume across the human menstrual cycle. NeuroImage, 220, p.117125.
Sundström-Poromaa, I., Comasco, E., Sumner, R. and Luders, E., 2020. Progesterone–Friend or foe?. Frontiers in Neuroendocrinology, 59, p.100856.
Sheppard, P.A., Choleris, E. and Galea, L.A., 2019. Structural plasticity of the hippocampus in response to estrogens in female rodents. Molecular brain, 12(1), pp.1-17.
Pletzer, B., Harris, T. and Hidalgo-Lopez, E., 2018. Subcortical structural changes along the menstrual cycle: beyond the hippocampus. Scientific reports, 8(1), p.16042.
Zsido, R.G., Williams, A.N., Barth, C., Serio, B., Kurth, L., Mildner, T., Trampel, R., Beyer, F., Witte, A.V., Villringer, A. and Sacher, J., 2023. Ultra-high-field 7T MRI reveals changes in human medial temporal lobe volume in female adults during menstrual cycle. Nature Mental Health, 1(10), pp.761-771.
Rechlin, R.K., Splinter, T.F., Hodges, T.E., Albert, A.Y. and Galea, L.A., 2022. An analysis of neuroscience and psychiatry papers published from 2009 and 2019 outlines opportunities for increasing discovery of sex differences. Nature communications, 13(1), p.2137.
Taylor, C.M., Pritschet, L. and Jacobs, E.G., 2021. The scientific body of knowledge–Whose body does it serve? A spotlight on oral contraceptives and women’s health factors in neuroimaging. Frontiers in neuroendocrinology, 60, p.100874.
Pritschet, L., Santander, T., Taylor, C.M., Layher, E., Yu, S., Miller, M.B., Grafton, S.T. and Jacobs, E.G., 2020. Functional reorganization of brain networks across the human menstrual cycle. Neuroimage, 220, p.117091.
This article was written by Katie Mortimer and edited by Julia Dabrowska. Interested in writing for WiNUK yourself? Contact us through the blog page and the editors will be in touch!
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