While copious reproductive immunology data exists in mouse and rat, research on human reproductive immunology is indefensibly more sparse.
- Role of gender in human immune responses is under-studied (1, 2).
- Role of Menstrual Cycle related hormonal fluctuations in human immune responses is under-studied (3).
Lack of copious human data notwithstanding, there is at least some that lets us infer some generalities, namely, that Menstrual Cycle hormonal fluctuations influence
- Circulating immune cell numbers and function (4, 5).
- Local immune cell numbers and function (4).
- Autoimmune disease symptoms (6)
- Microbiota composition (and hence baseline immune responses, certainly locally, perhaps also systemically) (7)
Menstrual Cycle hormonal fluctuations influence circulating immune cell numbers and function
First, a brief outline of the human female Menstrual Cycle:
- Follicular/Proliferative Phase: ~2 weeks of progressively higher levels of estrogen until pituitary secretes luteinizing hormone, which induces ovulation and progesterone.
- Luteal/Secretory Phase: ~2 weeks of high progesterone levels.
- Menstruation: If no fertilization and implantation during Luteal/Secretory Phase, then uterine endometrium sloughed off.
What happens to circulating immune cells during human female Menstrual Cycle?
To summarize the data from this figure (3)
- Studies on how circulating immune cells fluctuate with the Menstrual Cycle are sparse.
- Circulating B cell numbers appear to not change over the Menstrual Cycle.
- Circulating NK cell data are contradictory.
- Circulating Regulatory T cells (Tregs*) and capacity of circulating monocytes to secrete IL-1, a cytokine representative of acute inflammatory processes, have similar pattern:
- Increased during the Follicular/Proliferative Phase, i.e. as estrogen levels rise locally prior to ovulation.
- Decreased during the Luteal/Secretory Phase.
- However, circulating monocyte capacity to secrete TNF-a, another major acute inflammatory molecule, increases during the Luteal/Secretory, not Follicular/Proliferative Phase.
What happens to local immune cells during human female Menstrual Cycle?
A summary of studies (8, 9, 10, 11) over the past 2 decades suggests a coordinated increase in numbers of NK (Natural Killer) cells, Macrophages and Neutrophils during Menstruation. Implication? Since these are the ‘clean-up cells‘ of the immune system, that normally quietly clear off the dying and dead cells, and tissue debris, normal Menstruation consists of a properly regulated Endometrial immune response.
- As estrogen levels rise locally prior to ovulation, a T cell subset called Treg* (Regulatory T cell) increases locally in the endometrium (12).
- Other leukocytes also increase in the endometrium at the time of menstruation. They include immature and mature dendritic cells (13) and mast cells (14).
- CD10+ endometrial stromal cells increase in the uterus-draining lymph nodes during menstruation (15). This fits with the old notion that part of the superficial endometrial layer is resorbed, not shed, during menstruation (16).
*Caveat to Treg studies: Subsequent to the 2007 and 2010 studies referred above, much has been uncovered regarding appropriate anti-FoxP3 (Treg marker) antibody clones, fixation and staining protocols for optimally identifying human Tregs (17, 18). Thus, these previous data may/may not be accurate in identification and/or quantification of Tregs.
What happens to local immune cell secretions during human female Menstrual Cycle?
Concentrations and patterns of local immune cell molecules, typically those involved in acute inflammatory responses, also vary with the Menstrual Cycle (8, 19).
To summarize, high local Follicular/Proliferative Phase estrogen levels correlate with reduced endometrial and vaginal levels of acute inflammatory molecules such as TNF-a, IL-1b, IL-6 and IL-8.
What happens to local anti-microbial peptide secretions during human female Menstrual Cycle?
Like the gastrointestinal tract, the female reproductive tract is endowed with abundant capacity to secrete anti-microbial peptides (20), i.e. female reproductive tract cells have immune function capability, a feature common to tissue sites that harbor microbes.
- Interesting to see that many anti-microbial peptides are increased locally in cervico-vaginal fluids during the Follicular/Proliferative Phase of the Menstrual Cycle, at the same time that local immune response appears skewed towards regulatory rather than inflammatory function.
- Pattern seems to be increased local estrogen <—> local regulatory, not inflammatory, immune cell function <—> higher local anti-microbial peptides.
- In other words,
- Local inflammatory immune responses may antagonize those local milieu changes that are necessary to maximize fertilization and implantation.
- Estrogen keeps the former in check. However, this creates a temporary ‘vulnerability’ in local immunity.
- Such ‘vulnerability‘ is plugged by simultaneous increase in anti-microbial peptides.
Menstrual Cycle hormonal fluctuations influence autoimmune disease symptoms
It’s well known that women are disproportionately diagnosed with autoimmune diseases. Why? While the mechanisms are complex and disease-specific, sex hormones are obvious candidates. So it’s not surprising autoimmune disease symptoms vary with stages of the Menstrual Cycle (3).
- Symptoms of many, not all, autoimmune diseases appear to worsen during the Luteal/Secretory Phase of the Menstrual Cycle. Implication? High local estrogen and progesterone levels may favor autoimmune disease manifestation.
Caveats to existing studies:
- Few studies in the literature on how Menstrual Cycle influences autoimmune disease symptoms, in particular few recent studies.
- Many of the existing studies have small sample sizes, making their results difficult to generalize.
- Contraceptive effects not well-controlled in existing studies.
Menstrual Cycle hormonal fluctuations influence microbiota composition
- Microbiota influence estrogen (21).
- Antibiotics reduce estrogen levels (21).
- Urinary estrogen levels correlate with fecal microbiota composition (22).
- Human estriol and estradiol could inhibit Quorum Sensing (QS) and virulence in Agrobacterium tumefaciens and Pseudomonas aeruginosa (23). QS is the process bacteria use to sense each other to communicate and coordinate growth, motility and virulence. In other words, female reproductive tract hormonal milieu itself may be directly selectively anti-microbial. Caveat to this study is extremely high levels of hormones needed to produce such effects.
Mechanistic studies suggest Menstrual Cycle hormonal fluctuations influence local female reproductive tract microbiota composition (19, 24).
- Interesting that in vitro uterine epithelial secretions don’t inhibit Lactobacillus crispatus, a common vaginal commensal.
- Evidence of local microbiota-human female reproductive tract co-adaptation?
Mechanistic studies also implicate specific hormones such as estradiol in sculpting local female reproductive tract microbiota (19, 25).
A proposed Menstrual Cycle ‘Window of Vulnerability‘ for STI (Sexually Transmitted Infections)
- High estrogen and progesterone during the Luteal/Secretory Phase of the Menstrual Cycle is also construed to be a ‘Window of Vulnerability’ for sexually transmitted diseases such as HIV-1 (26).
- Preparing the female reproductive tract for fertilization and implantation of the fertilized egg, these high local estrogen and progesterone levels inhibit or minimize local immune responses that are teleologically considered antagonistic to these processes. Idea is those same local immune responses are also normally effective against STI microbes. Hence the notion that certain STIs (Sexually Transmitted Infections) exploit this ‘Window of Vulnerability‘ to establish infections in the female reproductive tract.
- Klein, Sabra L. “Immune cells have sex and so should journal articles.” Endocrinology 153.6 (2012): 2544-2550. Page on endocrine.org.
- Markle, J. G., and Eleanor N. Fish. “SeXX matters in immunity.” Trends in immunology 35.3 (2014): 97-104.
- Oertelt-Prigione, Sabine. “Immunology and the menstrual cycle.” Autoimmunity reviews 11.6 (2012): A486-A492.
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- Klein, Sabra L., Ian Marriott, and Eleanor N. Fish. “Sex-based differences in immune function and responses to vaccination.” Transactions of The Royal Society of Tropical Medicine and Hygiene 109.1 (2015): 9-15. Sex-based differences in immune function and responses to vaccination
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- Yurkovetskiy, Leonid, et al. “Gender bias in autoimmunity is influenced by microbiota.” Immunity 39.2 (2013): 400-412. Page on els-cdn.com
- Lee, Sung Ki, et al. “Immune Cells in the Female Reproductive Tract.” Immune network 15.1 (2015): 16-26. Page on koreamed.org
- Givan, Alice L., et al. “Flow cytometric analysis of leukocytes in the human female reproductive tract: comparison of fallopian tube, uterus, cervix, and vagina.” American journal of reproductive immunology 38.5 (1997): 350-359.
- Salamonsen, Lois A., and David E. Woolley. “Menstruation: induction by matrix metalloproteinases and inflammatory cells.” Journal of reproductive immunology 44.1 (1999): 1-27.
- Flynn, L., et al. “Menstrual Cycle Dependent Fluctuations in NK and T‐Lymphocyte Subsets from Non‐Pregnant Human Endometrium.” American Journal of Reproductive Immunology 43.4 (2000): 209-217.
- Berbic, Marina, et al. “The role of Foxp3+ regulatory T-cells in endometriosis: a potential controlling mechanism for a complex, chronic immunological condition.” Human reproduction (2010): deq020. a potential controlling mechanism for a complex, chronic immunological condition
- Schulke, L., et al. “Endometrial dendritic cell populations during the normal menstrual cycle.” Human reproduction 23.7 (2008): 1574-1580. Endometrial dendritic cell populations during the normal menstrual cycle
- Salamonsen, Lois A., and Louise J. Lathbury. “Endometrial leukocytes and menstruation.” Human Reproduction Update 6.1 (2000): 16-27. Page on oxfordjournals.org
- Berbic, Marina, et al. “A novel pilot study of endometrial stromal cells and immune cell populations in sentinel uterine-draining lymph nodes during the menstrual cycle and in endometriosis.” Reproductive sciences (2013): 1933719113485298.
- Blackwell, Peter M., and Ian S. Fraser. “Superficial lymphatics in the functional zone of normal human endometrium.” Microvascular research 21.2 (1981): 142-152.
- Law, Jacqueline P., et al. “The importance of Foxp3 antibody and fixation/permeabilization buffer combinations in identifying CD4+ CD25+ Foxp3+ regulatory T cells.” Cytometry Part A 75.12 (2009): 1040-1050. The importance of Foxp3 antibody and fixation/permeabilization buffer combinations in identifying CD4+CD25+Foxp3+ regulatory T cells
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- Wira, Charles R., et al. “Regulation of mucosal immunity in the female reproductive tract: the role of sex hormones in immune protection against sexually transmitted pathogens.” American Journal of Reproductive Immunology 72.2 (2014): 236-258.
- Wira, Charles R., et al. “Innate immunity in the human female reproductive tract: endocrine regulation of endogenous antimicrobial protection against HIV and other sexually transmitted infections.” American journal of reproductive immunology 65.3 (2011): 196-211. Page on wiley.com
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- Wira, C. R., et al. “Epithelial cell secretions from the human female reproductive tract inhibit sexually transmitted pathogens and Candida albicans but not Lactobacillus.” Mucosal immunology 4.3 (2011): 335-342. Page on nature.com
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