Many women report changes in gut function when experiencing the transition into perimenopause and menopause (Triadafilopoulos 1998, Yang 2021), but only recently have researchers begun to report on the link between the changes in estrogen levels and gut function. There is still much to be learned about the specific effects of estrogen levels on the gut and effective ways to manage any problems.
Regardless of the lack of studies specifically addressing menopause and gut health, what do we know?
What is perimenopause?
As women move into middle age, estrogen levels begin to decline and menstrual periods can become less regular. Eventually, periods stop completely, and one year after the last period marks official menopause. Thus, perimenopause refers to the process, which can take years, of transition into menopause.
What are the consequences of declining estrogen?
Declining estrogen levels can affect every tissue of the body, but the most concerning consequences include hypertension and increased risk for heart attack and stroke, bone loss, increased risk for dementia, sleep difficulties, and mood symptoms (Vetrani 2022).
There are two main root causes of these consequences:
1. an imbalance in autonomic tone, such that there is overactivity in the sympathetic system (Klassen 202, Philbois 2024) and underactivity in the parasympathetic system (Lee 2022), interacting with
2. increased systemic inflammation as estrogen levels decline (McCarthy 2020).
What does declining levels of estrogen mean for the gut?
The increase in sympathetic nervous system activity that accompanies declining estrogen has important consequences for the gut. A key function of the sympathetic nervous system is the coordination of gut responses to bodily and environmental challenges, and the effects of both acute and chronic stress on the gut are carried out mostly by the sympathetic nervous system. Thus, if declining estrogen leads to increased sympathetic nervous system activity, the effects in the gut will mimic those of stress: increased gut barrier permeability, impaired gastrointestinal motility, and increased inflammation.
Conditions within the gut, such as inflammation, can have widespread effects on other tissues. This is due in large part to the gut’s prominent influence on the immune system. Consequently, changes in gut function starting in perimenopause can contribute importantly to deleterious symptoms that can be experienced with declining estrogen levels.
Implications of sympathetic over-activity
In the gut, overactive sympathetic activity corresponds to increased gut permeability (Schaper 2013). The term “gut barrier” refers to the interface between the outside world and inside our bodies (Schoults 2020). This interface must be able to both absorb nutrients and keep out pathogens. Gut barrier function is maintained by cells that line the intestine and are protected and supported by a mucous layer along the outside of the barrier, and immune and nervous system cells in the intestine. If the gut barrier becomes permeable, microbes and toxins can get across it and induce inflammation or disease. This, in turn, triggers the symptoms associated with “leaky gut”, including systemic inflammation and neurological consequences including mood symptoms, sleep problems, fatigue, and cognitive impairment (for more explanation see Goehler 2023). Thus, gut barrier permeability can contribute to some of the familiar symptoms that women experience during perimenopause and menopause.
In addition, sympathetic nerve fibers can exert dramatic effects on gut motility in the context of stress. Increased sympathetic activity, such as during acute stress tends to slow down gastrointestinal motility (Tache et al. 2021), which could contribute to symptoms of constipation. Indeed, in women with IBS-C, increased sympathetic activity impairs gut motility (Mazur 2012). On the other hand, acute stress stimulates the colon (Lundgren 2002), and this is a well enough known phenomenon it is the focus of many jokes and sayings (such as “It scared the shit out of me!). Gut symptoms that intensify during peri/menopause are likely to result at least in part from the increase in sympathetic activity with falling estrogen levels, which could enhance the deleterious effects of stress on IBS symptoms.
One key concern with menopause is the increased risk of hypertension as estrogen levels decline (Adams 2023). Interestingly, a link between gut function and hypertension is illustrated by studies showing that increased gut barrier permeability and dysbiosis (imbalances in gut microbes) have recently been linked to hypertension (Snelson 2024) and cardiovascular disease (Lewis 2020). Interestingly, treatments directed toward cardiovascular disease (angiotensin-targeted drugs) can improve gut barrier function, suggesting that there are bidirectional interactions between the gut and cardiovascular regulatory systems. Thus, the effects of lower estrogen on gut barrier permeability may contribute to the pathophysiology of cardiovascular disease after menopause in women. This implies that factors that can support gut barrier function, such as diet and stress resilience, could be important factors for reducing risks of hypertension and cardiovascular disease for peri- and postmenopausal women.
Inflammation, peri/menopause, and the gut
Estrogen regulates immune function in important but complex ways (Kovats 2015) that are still incompletely understood. Estrogen seems to support effective immune function, while at the same time exerting mostly anti-inflammatory, or regulatory effects.
Inflammation involves the release of substances called cytokines from certain immune cells, such as T cells and macrophages, that serve to coordinate responses to infection and tissue damage. Cytokines can make blood vessels leaky, causing swelling. Cytokines can also cause the gut barrier to become “leaky” by reducing the amount of proteins produced by the gut lining cells that hold them all closely together. This leakiness causes even more inflammation.
As noted above, declining estrogen is associated with increasing levels of systemic inflammation. The main consequences of inflammation in the gut are increased permeability or “leakiness” (see above) and increased pain and pain sensitivity. This happens because cytokines can activate neurons that signal pain. A leaky gut can drive systemic inflammation that can affect tissues throughout the body. Thus, increasing levels of inflammation can worsen symptoms associated with irritable bowel syndrome or inflammatory bowel disease.
Consistent with this, in women with IBS, pain symptoms differ across the menstrual cycle such that when estrogen and progesterone levels are low (during pre-menstrual and menstrual phases), pain is worsened. In addition, results from a study of women transitioning through peri/menopause, the combination of “tension” (stress?) and low estrogen were associated with more gut pain (Yang 2021). Hormone replacement therapy improves symptoms in women with inflammatory bowel disease (Freeman 2024).
Taken together, these findings support the idea that “withdrawal” from estrogen and progesterone, such as during menstruation and menopause, can drive gut-related symptoms of IBS (Heitkamper 2009) and IBD. Similarly, women with IBS reported more severe symptoms after menopause, but men with IBS reported no differences as they aged (Yang 2021), implying that the more dramatic changes in hormone levels women experience with aging, compared to men, contribute to the severity of symptoms (Lenhart 2020).
Finally, menopause also seems to change gut microbe populations (Liu 2022; Yang 2022) which can lead to a condition called dysbiosis. Dysbiosis can drive inflammation, including systemic inflammation with important consequences for pain conditions, such as osteoarthritis (Rahman 2023) and brain functions including mood, energy, and cognition, thereby worsening menopause symptoms. Because diet is the major influence on gut microbe populations, the good and the bad, women undergoing peri/menopause need to be very mindful of the quality and variety of foods they eat.
Can “phytoestrogens” improve menopause symptoms?
“Phytoestrogens” are substances found in plants that are chemically similar to estrogen, that can interact with estrogen receptors in our bodies. The idea is that these substances may be able to buffer the effects of declining estrogen (Ionescu 2021). Phytoestrogens can be found in beans/legumes (especially soy), flax and sesame seeds, intact grains, and many fruits and vegetables. Some phytoestrogens have both anti-inflammatory actions, with similar mechanisms to NSAIDs, and antioxidant activity (Ionescu 2021; Jang 2022). For instance, polyphenol resveratrol is famous as an anti-inflammatory and antioxidant agent, and it is also a phytoestrogen. Thus, a diet rich in phytoestrogens could be an important strategy to mitigate the increases in inflammation that can accompany menopause.
However, human studies investigating the effects of phytoestrogens are generally thin on the ground. A recent narrative review of the literature (Dominguez-Lopez 2020) reports that overall, there is very scant good quality evidence for either beneficial or deleterious effects of phytoestrogens in humans, but that the topic warrants a great deal more research attention.
A major concern regarding consuming phytoestrogens, especially soy, has been whether or not there is an increase in risk or recurrence of breast cancer due to activity at estrogen receptors. Recent studies have addressed the issue, and the findings indicate either no effect of phytoestrogens, including soy, on breast cancer risk or recurrence, or a decreased risk (Lalioti 2024, Ionescu 2021). Any mechanisms of the association between phytoestrogens and reduced breast cancer risk are not established, but the findings seem relatively robust.
Of particular relevance, any effects of phytoestrogens will depend on a person’s gender, age, dose, food matrix (how the phytoestrogens are consumed, e.g. as extracted supplements or in a complex food), and overall diet, as this determines gut microbial populations that produce phytoestrogens (Dominguez-Lopez 2020, Ionescu 2021). This makes interpreting research findings and making specific recommendations challenging.