Sex and adrenal hormones interact with immune cells during acute and chronic inflammation. They provide the marching orders for coordinated events like tissue repair, humoral system engagement, and even allergic response. Hormones like estradiol and DHEA play roles in tissue repair, act as inflammatory mediators, stimulate cell differentiation, and generally stimulate the immune response. Progesterone, testosterone, and cortisol damper a strong immune response. It’s no wonder immune disruption is so common considering the changing hormone landscape of menstrual cycling, perimenopause, menopause, and otherwise age-related hormonal decline in both males and females.   

To understand how the immune system can affect adrenal and sex hormones and vice versa, let’s segue into a quick review of how the immune system is laid out. Immune cells originate in the bone marrow and mature at different sites in the body – lymph tissue along barriers like the skin and gut lining, thymus, and spleen.  

• The innate immune system functions as first line defense, acting without any real specificity to the challenger a little bit like Pac Men. Neutrophils, monocytes, eosinophils, basophils, mast cells, macrophages, dendritic and natural killer cells fall under the ‘innate’ distinction. When activated, they also release inflammatory messengers called cytokines that draw the attention of the cell-mediated adaptive immune system.  
• The adaptive immune system programs itself to recognize a challenger it’s seen before. Its T cells finish the job the innate immune system has started through T helper 1’s (Th1) and 17’s (Th17) “cell-mediated” cytotoxic mechanisms and through the T helper 2’s (Th2) induction of B cells. That “humoral” system made up of B cells and plasma cells remains ready with finger on the trigger to mount a massive response to a challenger if it ever breaches again thanks to its antibody production long after the original challenge is resolved. And finally, T regulatory (Treg) cells make sure an immune response stays within a magnitude that ensures the safety of the body tissues involved.[6]  

The immune system, residing within different sites in circulation and the gut and skin barrier lining, communicates distress to the body by producing characteristic patterns of inflammatory cytokines and mediators. Inflammation is a crucial aspect of immune function. Sex and adrenal hormones like estradiol, progesterone, testosterone, DHEA, and cortisol shift immune cell expression and influence inflammatory cytokine signatures by directly binding to immune cells and by shifting the gut microbiome diversity, gene expression, and activities.  

Hormones facilitate communication between the gut and systemic immune systems so that they function as a unit. Not only do circulating sex hormones modify the gut microbiome, the gut microbiome modifies levels of circulating hormones as well. Commensal resident bacteria in the gut such as Bacteroides fragilis express genes like CYP3A4 and 17BHSD that can both synthesize estrogens and break them down to form phase one metabolites like 16-OHE1 (a phase one metabolite of estrogen which selectively binds ERα (estrogen receptor) covalently and irreversibly).[3] Others like Klebsiella spp can form androgens.[3] Microbiome-produced B-glucuronidase creates the mechanism that encourages systemic re-uptake of hormones back across the gut lining and into systemic circulation.[3] Gut production of sex hormones and cortisol contribute to hormonal signaling that represent the gas or the brakes on the gut and systemic immune systems. 

5 Key Hormones Affect Immune Function 

Cortisol: Master of Suppression

The glucocorticoid, cortisol is probably the most important immune suppressor in this hormone lineup. Signals from the hypothalamus/pituitary act on the adrenal gland (together termed the HPA axis) to increase cortisol production during immune stress. Adrenal cortisol output is tightly controlled by negative feedback to return levels to normal once a stressor is resolved. However, other tissues including the skin and the gut synthesize their own cortisol outside the negative feedback of the HPA axis.[1] The gut may be a significant source of ongoing extra-adrenal glucocorticoid production in the face of chronic gut inflammation that can influence HPA axis activity. Cortisol binds GRα receptors and response elements in immune cells with such force that it is used as a swift, first line agent to quench inflammatory and allergic presentations. In functional medicine, proper HPA axis modulation under stress is a cornerstone of health.  

DHEA: Goldilocks

DHEA, like cortisol, is produced by the adrenal glands under HPA axis control and similarly inhibits cytokines that drive inflammation; however, unlike cortisol, its actions on the immune system are overall “anti-glucocorticoid” and thus immune supportive through multiple mechanisms including interfering with GRα activity, upregulating ERα, and converting to both immune-tempering androgens and immune-stimulating estrogens in tissues. DHEA is an important immune support in males and in females around/after menopause once sex hormones settle to their lows. Adrenal DHEA production decreases with aging but total cortisol production rises and diurnal variation flattens [5]. As these changes in DHEA and cortisol coincide with the age-related decline of sex hormones as well, immune system function shifts toward immune suppression, termed immunosenescence.  

Estradiol/Estrogens: Stimulating

Estradiol (through its ERα receptor) signals action. It stimulates the immune system and cell proliferation overall. It increases the innate immune response including mast cell activity. Estradiol particularly stimulates the adaptive system’s T cells, shifting T helper balance to favor Th2 and pouring gas on the humoral system’s B cells, plasma cells, and antibody production. Estradiol also acts through ERβ receptors in a more “tempering” capacity, increasing Treg cell function to modulate all that activity it stimulated via ERα.[4] And in the gut, the push/pull between the more pro-stimulatory ERα and the pro-suppressive ERβ/GPER1 receptor binding by estradiol leads to positive shifts in gut microbiome health, gut integrity, and hopefully an overall anti-inflammatory environment if everything is working correctly. Microbial dysbiosis, on the other hand, can lead to variations in the way estrogens are locally formed and metabolized, continuously reinforcing an estrogen-driven agenda throughout the immune system.[3] 16-OHE1 and Indican elevations on a DUTCH test are important indicators of this phenomenon. 

The increased immune activity associated with estradiol along with higher B cell antibody production makes those with ‘estrogen dominance’ less susceptible to acute infections but kicks the door open to autoimmune diseases and to allergic responses due to that heightened activity especially when other key immunosuppressive hormones like cortisol, testosterone, and progesterone are out of balance. Estradiol, when within proper physiologic levels and in balance with androgens and progesterone, performs an anti-inflammatory role when inflammation is acute. As estrogen levels constantly shift, especially in females, so does the potential for inflammation. 

Estrogen flux is a key hormonal driver of the monthly menstrual cycle. As estradiol production rises during follicle development, inflammatory markers in the serum decrease; menses-associated lows result in low grade inflammation [4]. Perimenopause, because of its erratic estradiol production and declining progesterone and testosterone levels, is a time of potential inflammatory load and a ripe opportunity for monitoring hormone levels and symptoms in an effort to stay ahead of inflammatory changes. At menopause, monumental estrogen decline causes a shift to a more Th1 pro-inflammatory signature.[4] Females carry a significantly higher risk burden for autoimmune diseases in large part due to the inflammatory landscape of hormone flux plus estradiol’s stimulating effect on mast cells and the antibody-producing humoral immune system. When inflammation becomes chronic, estrogen can increase pro-inflammatory cytokines making high or low estrogens on hormone testing a critical smoking gun of inflammation.

Progesterone: Suppressive

Progesterone can have a similar influence through Tregs and Th2-like effects on the adaptive immune system as estradiol when in follicular phase concentrations. In contrast, partially due to its ability to bind GRα receptors when it’s high in luteal phase, it also suppresses innate, cell-mediated, and humoral immune activity including stopping mast cell degranulation and halting B cell expansion.[7,8] In males and postmenopausal females, progesterone levels remain fairly static but in cycling females, progesterone rises significantly after ovulation while estrogen drops to its luteal plateau. In the luteal phase, when progesterone is dominant, progesterone-induced immune suppression is significant enough that females carry a generally higher propensity to experiencing pain, illness, and even develop PTSD particularly if the PG/E2 ratio gets too high.[8] On the flip side, this luteal immune quiescence each month may offer an important temporary break from estrogen and protection from autoimmune disease development. Those who treat chronic autoimmune diseases and mast cell activation syndrome (MCAS) in women often find micronized progesterone therapy an invaluable part of an immune-balancing treatment plan, though some may experience paradoxical symptoms with progesterone. 

Testosterone: Suppressive

Androgens like testosterone and DHT (through ARs) generally suppress the innate and humoral systems but support Treg cell function, altogether decreasing autoimmune risk. Like DHEA, testosterone is anti-inflammatory.[2] High testosterone’s downregulation of immune function in men and in women can leave them more susceptible to infections especially when estradiol and/or DHEA are concurrently low. On the flip side, males with low testosterone plus estrogen dominance or deficiency may well have an adaptive immune system on overdrive more like females with increased risk of autoimmune diseases like lupus and rheumatoid arthritis.[6] This underscores the importance of testing and treating hormonal imbalances in males as well as females in an effort to prevent morbidity from autoimmune and even mast cell-driven allergic presentations.  

Balance is Key 

Sex hormone and functional adrenal testing (DUTCH) as a routine part of patient care can identify adaptive changes in the HPA axis and point to downstream effects in the hypothalamic-pituitary-gonadal (HPG) axis and gut function that can affect the immune system, sensitivity to allergens, and autoimmune disease susceptibility. Early and preventive interventions should start with the gut microbiome and create a basis of intestinal health from which to work. Examples of gut therapeutics with positive impact on immune function are acidifying the upper GI, increasing fiber, and introducing pre- and probiotics. With healthy gut function established, ensure proper levels and diurnal rhythms (as applicable) of immune-modulating hormones like cortisol, DHEA, testosterone, and progesterone before addressing the more immune-stimulating estradiol. Assess, test, restore balance, prevent disease. 

References: 

1 Ahmed, A, et al. Extra-adrenal glucocorticoid synthesis in the intestinal mucosa: Between immune homeostasis and immune escape. Front Immunol, 2019. 

2 Buendía-González FO, et al. The similarities and differences between the effects of testosterone and DHEA on the innate and adaptive immune response. Biomolecules, 2022. 

3 Cross, TL, et al. Gut microbiome responds to alteration in female sex hormone status and e exacerbates metabolic dysfunction. Gut Microbes, 2024. 

4 Harding, AT, et al. The impact of estrogens and their receptors on immunity and inflammation during infection, Cancers (Basel), 2022. 

5 Stamou, MI, et al. Adrenal aging and its effects on the stress response and immunosenescence. Maturitas, 2023. 

6 Taneja, V. Sex hormones determine immune response. Front Immunol, 2018. 

7 Vasiadi M, et al. Progesterone inhibits mast cell secretion. Int J Immunopathol Pharmacol, 2006. 

8 Zwahlen, M., et al. Impact of progesterone on the immune system in women: a systematic literature review. Arch Gynecol Obstet. 2024.