Two Things to Understand First: Autoimmunity & Perimenopause
To understand why hormonal fluctuations in perimenopause affect autoimmunity, let’s start with a quick review of both.
Autoimmune conditions happen when the immune system loses its ability to distinguish between the body’s own tissue (self) and an antigen (non-self). There are anywhere from 80 to 120 or more autoimmune diseases, from Hashimoto’s thyroiditis to rheumatoid arthritis to lupus. What they all have in common is immune dysregulation and chronic inflammation, with most autoimmune diseases occurring more often in women than men (Fairweather et al, 2024). We’re not exactly sure why autoimmunity mainly affects women, however we do know that sex hormones like estrogen and progesterone are involved in regulating the immune system and inflammation signaling in the body (Klein et al, 2016).
Perimenopause is the transition leading up to menopause where hormone production and ovulation becomes inconsistent. It can start as early as a woman’s mid-30s, and it can last anywhere from four to over ten years. During that time, there is often a decline in estrogen and progesterone, but these same hormones are also swinging wildly up and down as the brain works harder to tell the ovaries to release the hormones needed for ovulation. Some months hormones may look more normal, and other months they may look very low. Those swings affect nearly every system in the body, including the immune system.
Estrogen, Progesterone, and the Immune System: More Connected Than You Think
When you think of estrogen, you think of it as a reproductive hormone, but it also plays an important role in regulating the immune system and inflammation.
Estrogen, particularly estradiol, plays a complex role in immune regulation. At higher levels it tends to calm inflammatory responses, while at lower levels it can actually amplify them. This helps explain why declining estradiol is often associated with increased inflammation and changes in how the immune system behaves (Klein et al, 2016).
This is exactly what happens in perimenopause. As estrogen levels start to fluctuate erratically, immune regulation can become more erratic. Inflammation that was previously low can start to increase, which can contribute to new or worsening autoimmune activity. Clients struggling with inflammation often complain about feeling “puffy,” having joint pain, or getting sick often.
These immune system shifts, with more inflammation and less immune regulation, mirror patterns seen in autoimmune conditions. For example, the peak onset of rheumatoid arthritis in women lines up with menopause, when estrogen drops and the immune system shifts toward a more inflammatory state. The relationship between hormones and other autoimmune conditions like multiple sclerosis is less straightforward, but the general pattern of hormonal transitions creating conditions where the immune system is primed to overreact still holds (Desai & Brinton, 2019).
To be clear, perimenopause doesn’t cause autoimmunity on its own. But the resulting increase in inflammation and shift in immune imbalance during this hormonal transition can raise the risk of developing autoimmune conditions, and for those who already have one, it can make symptoms worse.
This relationship can also work in the other direction. The same inflammation that drives autoimmunity can affect ovarian function, potentially accelerating hormonal decline and making the perimenopause transition harder than it needs to be. (Desai & Brinton, 2019) The relationship between the two is something we need to consider and be mindful of when supporting our clients.
It’s also not just estrogen, we need to be thinking about progesterone as well. Progesterone is usually the first hormone to shift during perimenopause, often years before estrogen. This can present as trouble sleeping or irritability, especially towards the end of the menstrual cycle. As progesterone drops relative to estrogen, it can create a state of estrogen dominance where the ratio between the two hormones negatively shifts. Since progesterone normally keeps inflammation in check, that shift may contribute to immune system imbalances. Progesterone also has a generally calming effect on immune responses (Klein et al, 2016) and plays an important role in supporting gut health, which as we’re about to discuss, you’ll find is at the center of everything.
The Gut Connection
This is where it gets really interesting, because the gut is one of the places we always support to make the biggest impact.
In our digestive system, certain gut bacteria carry genes, which are collectively known as the estrobolome, that produce enzymes capable of reactivating estrogen. The liver processes estrogen for removal by attaching a chemical tag to it and sending it to the gut through the bile. But before that estrogen can be eliminated, estrobolome bacteria can remove that tag, reactivating the estrogen so it gets resorbed back into the body. When the gut is healthy and diverse, this recycling process helps maintain more stable estrogen levels. When gut health is compromised, whether from dysbiosis, food sensitivities, pathogens, or suboptimal breakdown of food, the estrobolome gets disrupted, and hormonal imbalance can get worse (Peters et al 2022).
This relationship between the gut and estrogen also runs in both directions. As estrogen declines during perimenopause, it can also disrupt the gut microbiome, shifting bacterial populations and weakening the gut lining itself (Braniste et al, 2009; Peters et al, 2022). When the gut lining is compromised, it can allow more inflammatory triggers to pass into the body, leading to more inflammation, more immune activation, and more potential for increases in autoimmune symptoms like fatigue, aching joints, trouble sleeping, or anxiety.
At this point you have a loop: hormonal changes affecting gut health, and poor gut health affecting hormonal imbalance, which drives more inflammation, and in turn, drives more autoimmune activity.
This is one reason why a woman with autoimmunity can experience a symptom flare even when nothing obvious in her life has changed. Her gut may have shifted along with her hormones, and her immune system can respond to those changes.
Fortunately, there is significant overlap when we are supporting both hormones and the immune system for our clients.
The Good News: The Same Supports Help Both
What makes this so effective for client application is that you don’t have to choose between supporting her hormones or supporting her immune system. Many of the same supports will address both, and this streamlined approach helps the client stay motivated to continue the protocol. Here are the key things you always want to keep in mind when working with clients in perimenopause who also have autoimmunity.
Gut health. Supporting the digestive system, the gut microbiome, and the gut lining is foundational for both hormones and a balanced immune system. A healthy, diverse microbiome helps regulate estrogen levels through the estrobolome, reduces inflammation, and reinforces tight junctions to help prevent intestinal permeability that can drive immune reactivity. This is why comprehensive stool testing, like a GI-MAP, is so valuable. You’re not guessing at what’s happening in the gut, rather you’re actually seeing what specifically needs to be addressed.
Reducing inflammation. Both perimenopause and autoimmunity are, at their core, prone to elevations in inflammation. Identifying and removing the specific foods that trigger inflammation for her is one of the most powerful ways to reduce inflammation and immune reactions. In addition, a comprehensive stool test can reveal additional drivers of inflammation like pathogens or opportunistic bacteria that often go undetected and add to her overall inflammation levels.
Blood sugar balance. Blood sugar dysregulation drives inflammation and disrupts cortisol patterns, adding to hormonal fluctuations. Most clients won’t realize their blood sugar is an issue, but they will complain about afternoon fatigue or trouble sleeping, both of which can be related to blood sugar. Utilizing CGMs (continuous glucose monitors) and a comprehensive blood chemistry panel will not only help keep your client accountable, but also let you know what level of support your client needs to balance her blood sugar.
Stress reduction. Chronic stress is a significant driver of both hormonal dysregulation and immune dysregulation. Cortisol, when chronically elevated, disrupts immune regulation, disrupts gastrointestinal function, spikes blood sugar, and increases inflammation. It also directly interferes with the balance of estrogen and progesterone, which is already challenged during perimenopause. Women in this season of life are often at peak career and caregiving years. Their time and attention is stretched in many different directions, and stress is a major component. Many women in this season have been running on fumes or doing “all the things” for years as they juggle everything for everyone. They tend to prioritize care for their loved ones, but forget to provide that same level of care for themselves. Good sleep hygiene, nervous system regulation, creating a new mindset around self care, and realistic conversations about managing responsibilities are all part of the clinical picture.
What This Looks Like in Practice
When a woman in her 40s or early 50s comes in with worsening or newly emerging autoimmune symptoms, add perimenopause to your thinking right away. You don’t need to wait for menopause to help her. Irregular cycles, new sleep disruption, mood changes, and increased PMS are all early signals that hormones are shifting, and the immune system may be shifting with them.
From there, look at the gut, identify inflammatory triggers, support blood sugar and stress physiology, and reduce the total inflammatory burden. A comprehensive stool test, food sensitivity testing, and functional blood chemistry panel can tell you a lot about what’s driving her picture specifically, so you’re not applying a generic protocol, you’re building one customized to her unique needs.
What this woman needs is a practitioner who understands that her hormones and her immune system don’t operate separately, and who knows how to support both at the same time. When you approach her with that understanding and the right tools to support both, you stop chasing symptoms and start addressing what’s actually driving them. That’s when she starts to feel like herself again.
If this is the kind of clinical thinking you want to bring into your practice, we’d love to have you learn alongside us.
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FAQ
The following frequently asked questions expand on key clinical concepts discussed in this article and provide additional context for practitioners supporting women with autoimmunity during perimenopause.
Can perimenopause make autoimmune symptoms worse?
Yes, perimenopause can contribute to worsening autoimmune symptoms by increasing inflammation and altering immune regulation. Hormonal fluctuations during this transition may create conditions that make autoimmune symptoms more noticeable or difficult to manage. Perimenopause itself does not cause autoimmunity, but it can influence disease activity.
Why should practitioners consider perimenopause when evaluating autoimmune flares in women?
Perimenopause should be considered because hormonal changes can influence immune function and inflammation. Women may present with worsening fatigue, sleep disturbances, joint pain, digestive changes, mood shifts, or irregular cycles that coincide with hormonal transition rather than a new autoimmune condition.
What is the relationship between perimenopause and the immune system?
Perimenopause affects the immune system through fluctuating estrogen and progesterone levels. These hormonal shifts can alter inflammatory signaling and immune regulation, creating a more reactive immune environment in some women.
How does estrogen influence immune regulation and inflammation?
Estrogen helps regulate immune activity and inflammation. Higher levels tend to support a more controlled inflammatory response, while lower levels may be associated with increased inflammation and changes in immune behavior. During perimenopause, fluctuating estrogen levels can contribute to immune instability.
What role does progesterone play in immune balance during perimenopause?
Progesterone generally has a calming effect on immune responses and helps keep inflammation in check. Because progesterone is often one of the first hormones to decline during perimenopause, reduced progesterone may contribute to immune imbalance, sleep disruption, and irritability.
What early signs may indicate that perimenopause is contributing to autoimmune symptoms?
Early signs can include irregular menstrual cycles, increased PMS symptoms, sleep disruption, mood changes, fatigue, digestive complaints, and worsening autoimmune symptoms. These changes may signal that hormonal and immune shifts are occurring simultaneously.
How are gut health, hormones, and autoimmunity connected?
Gut health influences both hormone regulation and immune function. Changes in the gut microbiome can affect estrogen metabolism, while hormonal changes during perimenopause can also alter the microbiome and gut barrier function. This bidirectional relationship may contribute to inflammation and autoimmune symptom flares.
What is the estrobolome and why does it matter during perimenopause?
The estrobolome is a collection of gut bacteria that help regulate estrogen metabolism. These bacteria can reactivate estrogen in the digestive tract before it is eliminated. When gut health is compromised, disruption of the estrobolome may contribute to hormonal imbalance.
How can changes in gut barrier function affect autoimmune symptoms?
A compromised gut lining may allow more inflammatory triggers to interact with the immune system. This can contribute to increased immune activation, inflammation, and symptoms such as fatigue, joint discomfort, sleep disturbances, or anxiety.
Why is reducing inflammation important for women experiencing both perimenopause and autoimmunity?
Inflammation is a common feature of both perimenopause-related hormonal shifts and autoimmune conditions. Identifying and addressing sources of inflammation may help reduce immune reactivity and support overall symptom management.
How does blood sugar balance affect autoimmune and hormonal health during perimenopause?
Blood sugar dysregulation can contribute to inflammation and disrupt cortisol patterns. These effects may add to hormonal fluctuations and symptom burden during perimenopause. Clients may notice signs such as afternoon fatigue or difficulty sleeping.
What role does chronic stress play in autoimmune symptoms during perimenopause?
Chronic stress can affect both hormonal regulation and immune function. Elevated cortisol may increase inflammation, disrupt gastrointestinal function, influence blood sugar regulation, and interfere with the balance between estrogen and progesterone.
What assessments can help practitioners evaluate women with autoimmune symptoms during perimenopause?
The article highlights several tools that may help practitioners better understand individual drivers of symptoms, including:
- Comprehensive stool testing
- Food sensitivity testing
- Functional blood chemistry panels
- Continuous glucose monitoring (CGM)
These assessments can provide insight into gut health, inflammatory triggers, blood sugar patterns, and other factors contributing to a client’s presentation.
What clinical approach is recommended for women experiencing autoimmune flares during perimenopause?
A comprehensive approach should consider both hormonal and immune factors. The article recommends evaluating hormonal shifts, supporting gut health, identifying inflammatory triggers, addressing blood sugar balance, supporting stress physiology, and reducing overall inflammatory burden.
References
Baker, J. M., Al-Nakkash, L., & Herbst-Kralovetz, M. M. (2017). Estrogen–gut microbiome axis: Physiological and clinical implications. Maturitas, 103, 45–53. https://doi.org/10.1016/j.maturitas.2017.06.025
Braniste, V., Leveque, M., Buisson-Brenac, C., Bueno, L., Fioramonti, J., & Houdeau, E. (2009). Oestradiol decreases colonic permeability through oestrogen receptor beta-mediated up-regulation of occludin and junctional adhesion molecule-A in epithelial cells. The Journal of Physiology, 587(Pt 13), 3317–3328. https://doi.org/10.1113/jphysiol.2009.169300
Desai, M. K., & Brinton, R. D. (2019). Autoimmune disease in women: Endocrine transition and risk across the lifespan. Frontiers in Endocrinology, 10, 265. https://doi.org/10.3389/fendo.2019.00265
Fairweather, D., Beetler, D. J., McCabe, E. J., & Lieberman, S. M. (2024). Mechanisms underlying sex differences in autoimmunity. Journal of Clinical Investigation, 134(18), e180076. https://doi.org/10.1172/JCI180076
Klein, S. L., & Flanagan, K. L. (2016). Sex differences in immune responses. Nature Reviews Immunology, 16(10), 626–638. https://doi.org/10.1038/nri.2016.90
Peters, B. A., Lin, J., Qi, Q., et al (2022). Menopause is associated with an altered gut microbiome and estrobolome with implications for adverse cardiometabolic risk in the Hispanic Community Health Study/Study of Latinos. mSystems, 7(3), e0027322. https://doi.org/10.1128/msystems.00273-22
ABOUT THE AUTHOR:
Jaimee Kimmel
RHP, NTP
Jaimee earned her Nutritional Therapy Practitioner (NTP) certification in 2022 and became a Restorative Health Practitioner (RHP) in 2023. She specializes in working with busy professional women navigating autoimmunity and chronic illness, helping them to regain energy and mental clarity so they can thrive in work and home.
