HORMONES & IMMUNITY – MEN VS WOMEN
• Immunity is greatly influenced by hormones
• Men and women have different immune responses that are influenced by hormones
• Men’s immunity is generally stable through their lifetimes until the age of 60 with a gradual decline linked to the drop-in hormones. Men have a weaker immune response which reduces the risk of autoimmune conditions but increases their susceptibility to infections including the COVID-19 to date.
• Women’s immunity shifts with their menses cycle. Immunity and the inflammatory response is highest in the first half of the menses cycle, increasing the risk of autoimmune conditions. Conversely immunity and the inflammatory is the lowest in the second half of the menses cycle, reducing the risk of autoimmune conditions. Women are less at risk to infections such as COVID-19 to date due to an increased immune response vs men, which also increases their risk of autoimmune conditions.
• As women and men age, hormones decline with a corresponding reduction of overall immunity.
• General immune support is available including vitamin C, D, zinc etc.
• Tailored immune support is recommended by seeing your Naturopathic Doctor to support your individual variations in health. Imbalances in sleep, digestion, stress hormones or other require refinement for your comprehensive immune plan.
I used to wonder why I would get a sore throat when I was a teenager and feel like I was coming down with a cold right before my period. Then life got busy, my health improved after being tested for food intolerances and removing dairy from my diet. In Naturopathic school I was reminded of that question when we were taught about the connection between hormones and immunity. In clinic, I have observed the association many times of hormones influencing immunity, autoimmunity, and how women with autoimmune conditions often get better during pregnancy.
COVID-19 AND HORMONES
Now with the COVID-19 my curiosity is peaked again wondering how hormones are influencing men and women, their susceptibility and response to the virus. What we see to date is that men are more likely to contract the COVID-19 as compared to women. The trend was first seen in China, where one analysis found a fatality rate of 2.8% in men compared with 1.7% in women. Since then, the pattern has been mirrored in France, Germany, Iran, Italy, South Korea and Spain. In Italy, men have accounted for 71% of deaths and, in Spain, data released suggests twice as many men as women have died.
Why are men more at risk to the COVID-19 vs women?
There are several possible explanations which include:
- Smokers– Across the world, men are much more likely to smoke cigarettes. That damages their lungs and primes them for inflammation and further damage when they are battling an infection. In China, where cigarette smoking rates are among the highest in the world, 54% of men were current smokers in 2010, and 8.4% were ex-smokers. Yet only 3.4% of Chinese women had ever smoked, according to the same 2016 study.
- Estrogen– In a series of experiments in 2016 and 2017, researchers infected male and female mice with the coronaviruses that caused severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). At every age, male mice were more susceptible to infection than females. At the same time, the death rates of infected female mice shot up when their ovaries were removed, or when they got drugs that suppressed the activity of the hormone estrogen. Theories are that if the “innate” immune response tends to be stronger in females, infected women may be able to keep their viral loads low. Then women may not need to roll out the army of the immune system’s big guns — the T-cells and B-cells — for a major battle which increases the degree of damage.
- Genetics – women carry two X-chromosomes containing immune-related genes while men carry only one. Interestingly there is compensation by twofold up-regulation of genes on the active X to compensate for having two X chromosomes in female’s vs only one in males.
Relative to the coronavirus and hormones more research is needed to understand the detailed links that exist. There are many options for natural immune support which we recommend tailoring by working with your Naturopathic Doctor depending on your health predispositions. Digestive, stress and sleep imbalances all play a priority as add on support to your comprehensive immune plan.
To help understand how hormone influence immunity it’s helpful to get an overview of how the immune system functions. Your immune response is divided into two categories: nonspecific and specific.
- Nonspecific Immunity– is an innate response that acts as the first line of defense against infections. This includes immune cells like monocytes, macrophages, natural killer (NK) cells, dendritic cells, neutrophils, eosinophils and basophils.
- Specific Immunity – is acquired immunity that is developed when exposed to bacteria, viruses, and other substances. Acquired immunity includes B and T lymphocytes, and antibodies that have developed in response to infection and vaccination.1-3 Specific immunity can be divided into two types:
- a. Cell Mediated – immune response does not include antibodies but active immune cells such as phagocytes, antigen specific T lymphocytes, and various cytokines.
- b. Humoral – immune response includes antibodies. T lymphocytes are divided into cytotoxic (Tc cells) that kill foreign or infected cells, helper cells (Th1 & Th2 cells) that provide help to other immune cells by producing cytokines and regulatory T cell (Treg) that is the centre of immune-regulation.
HORMONES & IMMUNITY
How do hormones affect immunity?
Cortisol a glucocorticoid (GC) steroid hormone produced by the adrenal gland can boost your immunity by limiting inflammation initially during times of acute stress.4 In the long-term, sustained, high levels of inflammation lead to an overworked, over-tired immune system that cannot properly protect you. That is why you often won’t catch a cold or flu during times of high stress but after. I remember spending a few PJ days with a Kleenex box close by during the holidays post an intense series of exams (I also didn’t have my Naturopathic Doctor wisdom at that time!).
Sex hormones affect the immune system by increasing the number of circulating immune cells. Sex hormones are steroids that are lipophilic in nature which facilitates their diffusion through cell membrane. This makes them affect the genetic material in the cells directly. Due to their lipophilic nature, sex steroids can alter membrane properties by integrating into their membrane. This integration changes the function of immune cells. The sex hormones estrogen, progesterone, and testosterone are one of the major factors that regulate the immune system due to the presence of hormone receptors on immune cells.5-7 The interaction of sex hormones and immune cells through the receptors on these cells effect the release of cytokines which determine the path of different types of immunocytes (a type of white blood cell that is able to induce an immune response by creating antibodies) and as a result the outcome of inflammatory or autoimmune diseases.
How is immunity different in men and women?
The sex hormones all influence immunity and inflammation. The regulation of immune response in both the innate and adaptive categories is different in males and females due to the presence of different hormones.8 In male’s it is testosterone that plays a major role as sex hormones and in females the predominant role is that of estrogen and progesterone. Steroid hormones, such as estrogens, prolactin, progesterone, and glucocorticoids (GCs) regulate the development and activity of both innate and adaptive immunity differently in men and women. 9-14 Androgens, including testosterone and dihydrotestosterone (DHT) are mainly anti-inflammatory and immunosuppressive12, whereas estrogens have both pro- and anti-inflammatory roles and overall are immunoenhancing. The levels of DHEA an androgen produced by the adrenal gland which breaks down into estrogen and testosterone are reduced in those with rheumatoid arthritis (RA)15 and inflammatory bowel disease (IBD)16 suggesting that DHEA may be linked to many aspects of immune regulation of sex hormones.
Why are women more prone to autoimmune disease (AD) compared to men?
It is apparent that females have better immune capabilities with higher immunoglobulin levels and stronger humoral and cell-mediated immune responses than males.17 This helps women have a reduced incidence of certain tumors and generally resist a variety of bacterial and viral infections better than men. However this increased immunity also increases the risk of autoimmune conditions in women vs men. The effects of female sex hormones on cells of the adaptive immune system such as Th cell differentiation and B cells may underlie the higher predisposition of women to AD.8,17
What happens to immunity and hormones in men?
For men levels of testosterone remain consistent until andropause (male menopause). The hormonal influence on immunity thus also is consistent. Men generally have a weaker immune response as compared to women partially due to the fact that androgens, including dihydrotestosterone (DHT) and testosterone, generally suppress immune cell activity, by reducing inflammation.
What happens to immunity and hormones in women?
Women have fluctuations in immunity due to their cyclic variations in sex hormones.18 In particular estradiol (one type of estrogen) regulates immune molecules like cytokine. This is the reason for an increased immune response in females than in males.19
Estrogen receptors are present in immune cells including lymphocytes, macrophages, monocytes and dendritic cells.20,21 Progesterone is expressed in different immune cells including NK, macrophages, DCs, and T cells.22 and have broad anti-inflammatory effects of the immune system.
Figure 1 – Female Cyclic Hormone Chart23
Because women have fluctuation hormone levels during their menses cycle, immunity and inflammation also fluctuates. The first half of a women’s cycle is known as the follicular phase from menses to ovulation where estrogen rises and progesterone is at its lowest. Ovulation then occurs mid-cycle. The second half of the menses cycle is known as the luteal phase from ovulation to menses. During this phase progesterone rises to its peak approximately seven days before menstruation while estrogen remains lower.
For woman immunity is at its highest in the follicular phase or first part of the menstrual cycle.24,25 During this time women tend to have higher levels of antibodies in their body and have an increased inflammatory response that is partially triggered by the rising estrogen levels.24,26,27 Estrogen interacts with immune cells by attaching to receptors on the outside of the cells, and by interacting with cell processes occurring in the nucleus and cytoplasm.24,27 This interaction increases inflammation during menses and reduces the risk of infection.24,25 It is believed that the body functions in this way to promote pregnancy.24 During this time, your bodies want to fight off all foreign invaders so that you can stay healthy enough to become pregnant.
Although immunity is higher during the first part of the menses cycle the chronic health conditions such as asthma or arthritis may become worse due to the rise of inflammation and the levels of a hormone-acting lipid called prostaglandin increases.24,25
It’s all about balance though as elevated estrogen does not necessarily mean better health, as the higher inflammatory response caused by estrogen can lead to a worsening of chronic disease24,25,26 and an increased risk of certain cancers, such as breast cancer.28
At ovulation or approximately mid-cycle immunity reduces to allow sperm to enter increasing the opportunity for pregnancy. Estrogen levels drop-off26, and your immune system is downregulated by progesterone to help prevent immune cells from attacking a fertilized egg and thus preventing implantation.24 Testosterone, depending on where in the cycle a woman is, will support or suppress regulation of different immune cells to support fertility.26
In the second half of the menstrual cycle or the luteal phase, estrogen tends to be lower while progesterone is higher and cellular changes that influence testosterone take place. The shifts of progesterone and testosterone may positively or negatively affect a women’s health who is unwell depending on the disease. The lower estrogen in the luteal phase reduces immunity increasing the risk of infections as the body is less likely to produce an inflammatory response.24,25 Although inflammation is commonly viewed as a bad thing, relative to immunity having a suppressed inflammatory response increases a person’s risk of infection.24,25 Conversely, the reduced inflammation may have a positive effect on certain chronic diseases conditions that are made worse by the inflammation such as asthma or arthritis.24,25
Early research suggests that the decrease inflammatory response during the luteal phase may also be linked to a woman’s reduced ability to build muscle during the second half of the cycle.
The impact of testosterone on the immune system is less clear. The effects of testosterone may vary not only in response to estrogen and progesterone, but also possibly in response to sexual activity.25,28 More research is needed on how a women’s menstrual cycle, the hormones associated and testosterone impact the immune system.
What happens with the birth control pill (BCP)?
The BCP contains a synthetic progesterone known as progestin and some types also contain estrogen.29 The BCP works by increasing the levels of sex hormones, keeping them high to prevent ovulation and or thickens cervical mucus. Present research suggests that the BCP has both positive and negative effects for long-term health. In the short-term, some studies suggest that the BCP, particularly progestin-only forms may be similar to the luteal phase of menses with a reduced inflammatory state which increases the risk of infection.24,29-31 The BCP long-term may deplete key nutrients including B5, B6, and B12 which have a negative impact on hormone production, serotonin levels, melatonin levels, and overall energy. For a clearer understanding, more research is needed.
How does aging impact hormones and immunity?
Aging in both sexes is associated with changes in immune cells.32
What happens to immunity and hormones in men in the aging process?
In men plasma testosterone concentrations remain stable almost up to 60 years of age and decline with aging. Androgens, including dihydrotestosterone (DHT) and testosterone, generally suppress immune cell activity, by reducing inflammation.
What happens to immunity and hormones in women in the aging process?
Sex steroid levels change rapidly for women when they are menopausal. Women are more at risk or inflammatory diseases with aging due to the heightened immune response and accumulation of antibodies.
Both hormones and immunity are vital to overall wellness. Men and women have different responses to immunity. Men tend to have a lower immune response that remains consistent until approximately age 60 which reduces their risk for autoimmune conditions but increases their risk of certain cancers. Women have fluctuations in immunity which is influenced by the hormone cycle. In the first half of the menses cycle immunity his higher as well as the risk of autoimmune inflammatory conditions such as asthma or arthritis. In the second half of the cycle immunity, inflammation, and associated autoimmune symptoms are reduced. There are many options for natural immune and hormone support which we recommend tailoring by working with your Naturopathic Doctor. Customized strategies on top of basic immune support is important as digestive, stress and sleep imbalance healing strategies are vital to your comprehensive immune plan.
1. Alvergne A, Tabor VH. Is Female Health Cyclical? Evolutionary Perspectives on Menstruation. arXiv preprint arXiv:1704.08590. 2017 Apr 26.
2. PubMed Health. How does the immune system work?. 2016. Retrieved from https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0072548/
3. PubMed Health. The innate and adaptive immune systems. 2016. Retrieved from https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0072580/
4. Dumbell R, Matveeva O, Oster H. Circadian clocks, stress, and immunity. Front Endocrinol (2016) 7:37. I. Berczi and E. Nagy, Immune Modulating Agents, Marcel Dekker, New York, NY, USA, 1998.
5. T. Yamaguchi, H. Watanuki, and M. Sakai, “Effects of estradiol, progesterone and testosterone on the function of carp, Cyprinus carpio, phagocytes in vitro,” Comparative Biochemistry and Physiology, vol. 129, no. 1, pp. 49–55, 2001.
6. C. R. Wira and C. P. Sandoe, “Hormonal regulation of immunoglobulins: influence of estradiol on immunoglobulins A and G in the rat uterus,” Endocrinology, vol. 106, no. 3, pp. 1020–1026, 1980.
7. Ortona E, Pierdominici M, Maselli A, Veroni C, Aloisi F, Shoenfeld Y. Sex-based differences in autoimmune diseases. Ann Ist Super Sanita (2016) 52(2):205–12.
8. Olsen NJ, Kovacs WJ. Gonadal steroids and immunity. Endocr Rev (1996) 17(4):369–84. doi:10.1210/edrv-17-4-369
9. Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol (2016) 16(10):626–38.
10. Hewitt SC, Winuthayanon W, Korach KS. What’s new in estrogen receptor action in the female reproductive tract. J Mol Endocrinol (2016) 56(2):R55–71.
11. Gilliver SC. Sex steroids as inflammatory regulators. J Steroid Biochem Mol Biol (2010) 120(2–3):105–15.
12. Straub RH. The complex role of estrogens in inflammation. Endocr Rev (2007) 28(5):521–74.
13. Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev (2011) 32(1):81–151.
14. Straub RH, Harle P, Atzeni F, Weidler C, Cutolo M, Sarzi-Puttini P. Sex hormone concentrations in patients with rheumatoid arthritis are not normalized during 12 weeks of anti-tumor necrosis factor therapy. J Rheumatol (2005) 32(7):1253–8.
15. Straub RH, Vogl D, Gross V, Lang B, Scholmerich J, Andus T. Association of humoral markers of inflammation and dehydroepiandrosterone sulfate or cortisol serum levels in patients with chronic inflammatory bowel disease. Am J Gastroenterol (1998) 93(11):2197–202.
16. Batchelor JR, et al, Hormonal control of antibody formation, in Regulation of the Antibody Response, 1968 276-293
17. A. Barakonyi, B. Polgar, and J. Szekeres-Bartho, “The role of γ/δ T-cell receptor-positive cells in pregnancy: part II,” The American Journal of Reproductive Immunology, vol. 42, no. 2, pp. 83–87, 1999.
18. S. A. Ahmed, W. J. Penhale, and N. Talal, “Sex hormones, immune responses, and autoimmune diseases. Mechanisms of sex hormone action,” The American Journal of Pathology, vol. 121, no. 3, pp. 531–551, 1985.
19. Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol (2016) 16(10):626–38.
20. Straub RH. The complex role of estrogens in inflammation. Endocr Rev (2007) 28(5):521–74.
21. Teilmann SC, Clement CA, Thorup J, Byskov AG, Christensen ST. Expression and localization of the progesterone receptor in mouse and human reproductive organs. J Endocrinol (2006) 191(3):525–35.
22. Photo, Retrieved 4,2,20 https://parenting.firstcry.com/articles/luteal-phase-what-it-is-and-its-relation-to-pregnancy/
23. C. Grossman, “Possible underlying mechanisms of sexual dimorphism in the immune response, fact and hypothesis,” Journal of Steroid Biochemistry, vol. 34, no. 1–6, pp. 241–251, 1989.
24. C. R. Wira and C. P. Sandoe, “Hormonal regulation of immunoglobulins: influence of estradiol on immunoglobulins A and G in the rat uterus,” Endocrinology, vol. 106, no. 3, pp. 1020–1026, 1980.
25. A. Barakonyi, B. Polgar, and J. Szekeres-Bartho, “The role of γ/δ T-cell receptor-positive cells in pregnancy: part II,” The American Journal of Reproductive Immunology, vol. 42, no. 2, pp. 83–87, 1999.
26. S. A. Ahmed, W. J. Penhale, and N. Talal, “Sex hormones, immune responses, and autoimmune diseases. Mechanisms of sex hormone action,” The American Journal of Pathology, vol. 121, no. 3, pp. 531–551, 1985.
27. L. Gross, “Influence of sex on the evolution of a transplant mouse sarcoma,” Proceedings of Society of Experimental Biology and Medicine, vol. 47, pp. 273–276, 1941.
28. Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR. 2016; 65(3):1-108
29. Michel KG, Huijbregts RP, Gleason JL, Richter HE, Hel Z. Effect of hormonal contraception on the function of plasmacytoid dendritic cells and distribution of immune cell populations in the female reproductive tract. Journal of acquired immune deficiency syndromes (1999). 2015 Apr 15;68(5):511.
30. Murphy K, Irvin SC, Herold BC. Research gaps in defining the biological link between HIV risk and hormonal contraception. American journal of reproductive immunology. 2014 Aug 1;72(2):228-35.
31. Rea IM, Gibson DS, McGilligan V, McNerlan SE, Alexander HD, Ross OA. Age and age-related diseases: role of inflammation triggers and cytokines. Front Immunol. (2018) 9:586.
Leave a Reply