An estimated 50 million Americans are diagnosed with an autoimmune disease, a staggering 80% of whom are women. Autoimmunity is the leading cause of morbidity and among the top 10 causes of death in women in the United States. Hormonal fluctuations and imbalances significantly influence development of autoimmune diseases, particularly in women. Functional medicine adopts a holistic approach to addressing autoimmune diseases, considering the interconnectedness of body systems, such as the immune and endocrine systems, and acknowledging the influence of lifestyle, nutrition, and environmental factors on both immune and hormonal health.

[signup]

Understanding the Connection Between Hormones and Autoimmune Diseases

The immune system serves as the body’s defense against foreign invaders, such as bacteria and viruses. Under normal circumstances, it exhibits self-tolerance, meaning it can differentiate between our own cells and external threats. In autoimmune diseases, this tolerance is lost causing the immune system to mistakenly attack healthy cells and tissues. More than 80 different autoimmune conditions have been identified that vary in several ways including the specific types of tissues or organs they target, the types of immune responses involved, and their overall clinical manifestations. In addition to the breakdown of tolerance, a common characteristic shared by many autoimmune diseases is their higher prevalence among women. Particularly notable gender disparities occur in conditions such as Sjogren’s syndrome, systemic lupus erythematosus (SLE), primary biliary cholangitis (PBC), autoimmune thyroid disease (including Graves’ disease and Hashimoto thyroiditis), and systemic sclerosis (SSc). Listed below are commonly diagnosed autoimmune conditions in women and their female-to-male prevalence ratios (89): 

• Primary biliary cirrhosis 10:1 
• Sjogren’s syndrome 9:1 
• Systemic lupus erythematosus 9:1
• Hashimoto thyroiditis 5-18:1
• Grave’s disease 7:1
• Systemic sclerosis 5:1
• Myasthenia gravis 3:1 
• Rheumatoid arthritis 3:1
• Multiple sclerosis 2:1 

The development of autoimmune diseases is a multifactorial process. Genetic predisposition plays a significant role, as certain individuals may inherit a susceptibility to autoimmune conditions. Environmental triggers, such as infections and exposure to toxins, lifestyle factors, the composition of the gut microbiome, and hormones, particularly in women, have also been linked to autoimmune conditions. 

Women experience substantial endocrinological shifts at least twice in their lives - during puberty and menopause. Additionally, many undergo an extra change during pregnancy. Beyond their role in reproductive functions, sex hormones wield influence over various aspects of the immune system’s development and function. The interplay between women’s fluctuating sex hormone levels and the immune system is considered a key factor in their heightened susceptibility to autoimmune diseases. Indeed, the onset, aggravation or amelioration of autoimmune conditions in women often aligns with these significant endocrine transitions (55).

Key Hormonal Imbalances in Autoimmune Conditions

Bidirectional communication exists between the endocrine and immune systems to keep both systems working optimally. This harmonious relationship can be disrupted by environmental triggers like stress and infections. Hormone imbalances are frequently observed in women who develop autoimmune diseases, some of which are discussed in more detail below (55).

HPA Axis Dysregulation

The stress response involves the intricate activation of two key systems: the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis. In the face of a stressor, the SNS initiates the "fight or flight" response, releasing catecholamines like norepinephrine and epinephrine. Simultaneously, the HPA axis is activated, ultimately resulting in the release of cortisol from the adrenal glands. While this acute stress response is adaptive, chronic activation of these systems, as seen in prolonged or recurrent stress, can cause dysregulation of the HPA axis and have detrimental effects on health. Glucocorticoids, including cortisol, can influence the balance of pro-inflammatory and anti-inflammatory cytokines, impacting immune cell function. Dysregulated glucocorticoid signaling may disrupt this delicate balance, contributing to chronic inflammation and immune dysregulation characteristic of autoimmune diseases. In fact, stress-related disorders have been associated with an increased risk of developing autoimmune diseases and retrospective studies show that 80% of individuals report high levels of stress prior to the onset of an autoimmune disease. Furthermore, HPA axis dysregulation, quantified through salivary and hair cortisol levels, has been identified in autoimmune disorders.

Estrogen

Estrogen plays a complex role in the immune system, with both low and high levels influencing immune responses. Estrogen exerts diverse effects on different components of the immune system. As a result, the influence of estrogen on autoimmune diseases varies, occasionally offering protective effects and, in other instances, contributing to disease progression. The effects are influenced by the specific immune pathways involved and the stage of the autoimmune condition. In MS, for example, estrogen seems to be protective. On the other hand, it seems to exacerbate symptoms of SLE (60). Potential imbalances in estrogen include estrogen deficiency, estrogen excess, and estrogen dominance, a state in which estrogen levels are elevated in relation to progesterone.

Thyroid Disorders

Autoimmune thyroid diseases are the most prevalent organ-specific autoimmune diseases. Graves’ disease is the most common cause of hyperthyroidism and Hashimoto thyroiditis is the most common cause of hypothyroidism in developed countries. Individuals with other forms of autoimmune disease are also at a higher risk of developing thyroid dysfunction, particularly hypothyroidism (64, 81).

Insulin Resistance

Insulin, a critical hormone in blood sugar regulation, can impact overall hormone balance. Elevated insulin levels, often seen in conditions like insulin resistance and metabolic syndrome, disrupt metabolism and cause sex hormone imbalances (99). Inflammation is a driving force behind the development of both insulin resistance as well as autoimmune diseases. Research shows that people with autoimmune diseases, such as rheumatoid arthritis (RA) or SLE, are more likely to have insulin resistance or type 2 diabetes than the general population (76, 94, 100).

Functional Medicine Assessment of Hormonal Health

The functional medicine approach to assessing hormonal health in women with autoimmunity, extends beyond traditional hormone level assessments.This approach recognizes the interconnectedness of various systems within the body and their impact on hormonal balance. Through personalized assessments based on individual health histories and specific autoimmune conditions, practitioners aim to identify potential triggers and contributors to hormonal imbalances. This may involve evaluating the impact of factors such as stress, exposure to toxins, and the health of the gut microbiome on endocrine function.

Hormone Testing

Various testing methods can be used to assess hormone levels including blood, saliva, and urine. Traditionally, blood testing has served as the standard for diagnosing hormone imbalances. However, noninvasive alternatives, such as saliva and urine testing, offer distinct benefits. Saliva testing provides insights about free, bioavailable hormone levels and urine testing allows for the additional measurement of hormone metabolites. Hormone levels can vary throughout the day and month. Both saliva and urine testing provide the opportunity to easily collect multiple samples at home. This enables patients to monitor daily or monthly patterns, offering a more comprehensive understanding of hormonal fluctuations.

Blood tests are utilized to evaluate thyroid function. Although thyroid stimulating hormone (TSH) is traditionally used to diagnose hypothyroidism or hyperthyroidism, a complete thyroid panel can provide additional insight. It measures thyroxine (T4), triiodothyronine (T3), free T4, free T3 and thyroid antibodies in addition to TSH. The inclusion of these markers facilitates a thorough assessment of various aspects of thyroid health, including total thyroid hormone production, the efficiency of T4 conversion into T3, the availability of free or bioavailable hormones, and the potential presence of an autoimmune thyroid condition. Reproductive and adrenal hormones can also be measured using blood samples. ZRT Laboratory’s Female Blood Profile II combines a thyroid panel with measurements of adrenal hormones, such as DHEA and cortisol, and reproductive hormones, such as estrogen, progesterone, and testosterone. The Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) test by Boston Heart Diagnostics uses fasting insulin and blood glucose levels to approximate an individual’s level of insulin resistance.

Pathological conditions of the adrenal glands exist such as Addison’s disease or Cushing’s syndrome, in which too much or too little cortisol is produced. These conditions can be diagnosed using blood tests.  In other cases, changes to the normal daily rhythm of cortisol production can be seen in response to stress. Genova’s Adrenal Stress Profile with Cortisol Awakening Response measures the diurnal pattern of cortisol with 4 salivary measurements throughout the day. It also measures the Cortisol Awakening Response (CAR), which provides additional information on how well the body is adapting to stress. The Saliva Profile III by ZRT Laboratory provides a picture of the daily cortisol pattern, as well as salivary measurements of reproductive hormones. For women experiencing irregular menstrual cycles, relying on single-day collections may overlook potential hormone imbalances. Genova's Rhythm test presents an excellent solution in such cases as it conducts multiple measurements of estrogen and progesterone throughout the monthly cycle.

The DUTCH Complete by Precision Analytical is a dried urine test that not only assesses adrenal and reproductive hormones, but also their metabolites. Similar to the salivary hormone profile, it evaluates cortisol levels at various intervals throughout the day, revealing any deviations from the typical circadian rhythm. Additionally, it incorporates melatonin, a hormone crucial for regulating the sleep-wake cycle, a component not covered by the other testing options.

Gut Health

The gastrointestinal system plays a part in hormone metabolism, and disruptions in the composition of the gut microbiome can impact hormone levels. Additionally, the gut wields significant influence over the development and regulation of the immune system. Genova’s GI Effects Comprehensive Profile not only analyzes the composition of the microbiome, but also measures markers linked to inflammation, barrier integrity, and hormone metabolism. This multifaceted approach allows for the identification of potential triggers that may contribute to immune system dysregulation and hormone imbalances.

Environmental Exposures

Exposure to pollutants, heavy metals, pesticides, and other environmental toxins has been associated with an increased risk of autoimmune diseases by promoting immune system dysregulation. Simultaneously, many environmental toxins, known as endocrine disrupting chemicals (EDCs) have the potential to interfere with normal hormone function, including the synthesis, secretion, transport, binding, action, or elimination of hormones. The Environmental Pollutants Profile (EPP) by Us Biotek assesses exposure to eight common environmental chemicals, including common EDCs such as parabens and phthalates, by measuring 14 metabolites in the urine. The Metals Urine Test by Mosaic Diagnostics assesses exposure to heavy metals such as lead, mercury, and cadmium.

[signup]

Nutritional Strategies for Hormonal Balance

Dietary choices play a crucial role in influencing both the immune and endocrine systems, with micronutrient and macronutrient balance influencing processes such as inflammation, metabolic dysfunction, and hormone balance (87). The Western style diet, characterized by increased caloric intake with lower intake of essential nutrients and fiber, has been associated with the increased risk of many types of chronic diseases in recent decades (1, 62, 103).

Employing whole-food, anti-inflammatory dietary strategies ensures individuals are provided with a rich source of vitamins and minerals that play crucial roles in immune and endocrine function. The Mediterranean diet is an example of one such strategy. It is an eating pattern inspired by the culinary traditions of the Mediterranean region, prioritizing a diverse range of colorful fruits and vegetables rich in phytonutrients and polyphenols, whole grains and legumes, and healthy fats such as olive oil and omega-3-fatty acids. Lean proteins are preferred over red meat.  It is a well-researched therapeutic diet for supporting hormones, metabolism, and immune system function (10, 79, 93).

Phytoestrogens, such as isoflavones, stilbene, coumestan, and lignan, are plant compounds with a similar structure to estrogen that allows them to interact with estrogen receptors. Food sources of phytoestrogens include legumes, such as soy and beans, and seeds, such as flaxseeds. Research shows that phytoestrogens can be used to treat symptoms of low estrogen, such as hot flashes. Omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found in fatty fish, promote anti-inflammatory responses in the body and can regulate steroid hormone production (2). Vitamin D is essential for immune regulation and vitamin D receptors are found in reproductive tissues, influencing women’s hormones (13). Food sources of vitamin D include fatty fish (such as trout, salmon, tuna, and mackerel) and fish liver oils as well as beef liver, egg yolks, and some dairy products. Minerals like selenium, found in seafood, organ meats, and Brazil nuts, and zinc, found in meat, fish, seafood, legumes, nuts and seeds, are cofactors for antioxidant enzymes and play important roles in thyroid hormone function and immune system activity.

Addressing Stress and Lifestyle Factors

Unhealthy lifestyle behaviors are accepted as factors contributing to the inflammation that drives chronic diseases. Sleep deprivation is associated with changes to immune system function and hormone imbalances. The National Sleep Foundation recommends 7-9 hours of sleep for adults, but one-third of US adults do not hit this goal. Some good sleep hygiene practices to implement for improved sleep quality include: stick to a consistent sleep schedule, get daytime natural light exposure, make sure the bedroom is cool, dark and quiet, limit screen exposure in the evenings, and avoid heavy meals and caffeine too close to bedtime.

Mind-body practices, like meditation and breathing exercises, are used to manage stress. These techniques promote relaxation through regulation of the SNS and HPA axis. In addition to promoting feelings of relaxation, they can reduce inflammation and balance various hormones. 

Sedentary behavior is associated with increased inflammation and metabolic dysfunction. Regular physical activity enhances sleep quality, reduces inflammation, strengthens the immune system, and regulates hormone production and function (32, 42, 75). The World Health Organization (WHO) recommends that adults should do at least 150 minutes of moderate-intensity aerobic activity or 75 minutes of vigorous-intensity aerobic activity with at least 2 days of muscle-strengthening exercise each week.

Herbal and Nutritional Supplements for Hormonal Support

Herbs and nutritional supplements can be used as complements to dietary and lifestyle interventions, offering additional support when needed for managing hormone imbalances and autoimmune diseases.

Omega-3 Fatty Acids

Omega-3 and omega-6 fatty acids are two types of polyunsaturated fats. Maintaining a balanced ratio between the two is important for optimal health. Unfortunately, the typical American diet often results in an underconsumption of omega-3 fatty acids. Among the omega-3 fatty acids EPA and DHA are considered the most bioactive forms and are recommended for optimal immune function and inflammatory balance. For individuals who do not get adequate amounts of EPA and DHA through diet, supplementation can be considered (109).

Probiotics

Probiotic supplementation improves the composition of the gut microbiome, influencing immune system regulation and hormone metabolism. One mechanism through which probiotics impact immune regulation involves the modulation of cytokine production and the enhancement of regulatory T cell activity. This helps maintain a balanced immune response, preventing excessive inflammation or inappropriate immune reactions. Through their regulation of beta-glucuronidase in the gut, probiotics can improve hormone metabolism. Beta-glucuronidase is an enzyme involved in the deconjugation of glucuronidated compounds in the gut. High levels of beta-glucuronidase activity can lead to the reabsorption of certain hormones, interfering with their proper elimination.

Vitamin D

Vitamin D supplementation may be necessary for individuals who have limited sun exposure, reside in regions with little sunlight, or have difficulty absorbing vitamin D from dietary sources. This vitamin plays a crucial role in modulating immune responses and helps maintain immune tolerance, mitigating the risk of autoimmune conditions. Furthermore, vitamin D has been implicated in blood sugar metabolism and hormone regulation, especially in women's reproductive health. Adequate levels of vitamin D are associated with improved fertility, hormone balance, and reduced risks of certain hormonal disorders (44, 78).

Adaptogens

Adaptogens are a class of herbs that help the body adapt to stressors and maintain homeostasis. Commonly used adaptogens include ashwagandha, rhodiola, and holy basil. Through their regulation of the HPA axis and cortisol, they are able to positively impact both immune and hormonal function.

Integrating Conventional and Functional Approaches

Integrative medicine (IM) is a patient-centric, evidence-based, approach that aims to incorporate both conventional and complementary approaches to achieve optimal patient outcomes. Conventional treatments often focus on symptom management, but functional medicine delves deeper, seeking to identify and address the root causes of immune and endocrine dysfunction. Each individual’s unique genetic makeup, environment, and lifestyle are considered in order to personalize testing and treatment options. The rise in noncommunicable, chronic diseases can be attributed, at least in part, to behavior and lifestyle practices. Functional medicine providers prioritize lifestyle medicine principles, such as optimizing nutrition, promoting physical activity, managing stress, and improving sleep. This holistic, patient-centered approach helps to optimize health outcomes and increase patient satisfaction (56, 88).

[signup]

Hormonal Health for Women with Autoimmune Diseases: Final Thoughts

Navigating the complexities of autoimmune diseases in women requires a multifaceted approach that acknowledges the intricate relationship between hormonal health and immune function. Through advanced assessments of hormone levels as well as additional factors such as stress, gut health, and toxin exposure, functional medicine allows for the creation of comprehensive, individualized treatment plans that address the root causes of immune and endocrine dysfunction.