Unexplained Infertility and Recurrent Implantation Failure: The Immune System Connection.

Infertility and recurrent implantation failure (RIF) are not simply matters of chance, even though you might have heard otherwise from your medical team. Your immune system could be playing a significant role in these issues.

The American Society for Reproductive Medicine classifies infertility as a disease of the reproductive system. However, scientific research has linked infertility to broader imbalances, such as inflammatory conditions and neuroendocrine disruptions, beyond just the reproductive organs. In addition, studies have shown that diet and lifestyle factors can cause hormonal imbalances, contributing to infertility. But despite scientific evidence linking infertility to immune system disorders, conventional medicine often focuses only on the reproductive system’s diseases.

As more scientific publications shed light on unexplained infertility, RIF and immunes system disorders, it becomes crucial to reconsider conventional medicine’s approach to resolving unexplained infertility and RIF. That is, answers for the root causes of infertility can be found by examining imbalances throughout the entire body, starting with common conditions associated with chronic inflammation and immune dysfunction.

What is Chronic Inflammation and Immune Dysfunction?

Inflammation is the body’s natural response to injury or infection. It involves the immune system releasing proteins such as proinflammatory cytokines (interleukins, interferons, and tumor necrosis factors), chemokines, and leukocytes to protect the affected area and initiate the healing process. This response can cause redness, heat, swelling, and pain at the site of an acute injury, which is vital in preventing subsequent infections caused by other bacteria and viruses.

While acute inflammation is essential for healing and maintaining health, chronic or low-grade inflammation that persists over time is problematic and a root cause of various health issues. When chronic inflammation is present, the immune system becomes overactive, causing a continuous release of inflammatory proteins that result in systemic inflammation. This ongoing inflammation can lead to conditions such as anxiety, depression, fatigue, digestive issues, hormone imbalances, diabetes, heart disease, autoimmune conditions and even cancer.

Chronic inflammation often beings quietly in the body, long before these conditions become noticeable or diagnosable. By the time symptoms appear and a diagnosis is made, significant damage to bodily tissues has already occurred. The progression from health to disease is not an “on” or “off” switch; it is a gradual transition along the inflammation spectrum. The same principles apply to known causes of infertility, such as endometriosis and PCOS. Chronic inflammation drives immune system dysfunction, impacting the reproductive, endocrine, nervous, and digestive systems, all of which play a role of infertility.

Hidden chronic inflammation can affect conception and pregnancy even before it manifests as a disease. Persistent low-grade inflammation creates unfavorable conditions during a woman’s menstrual cycle, leading to hormonal imbalances like estrogen dominance, hypothyroidism, and insulin resistance. Symptoms such as premenstrual syndrome and heavy, irregular, or painful periods may be early indicators of chronic inflammation. As inflammation intensifies and immune dysfunction progresses, it often leads to diagnoses of infertility, chronic, or autoimmune diseases.

In extensive circumstances of immune dysfunction, it can also present as autoimmune diseases where the immune system mistakenly attacks the body’s own tissues. Autoimmune diseases can be organ-specific, affecting only particular organs, such as Hashimoto’s Thyroiditis affecting the thyroid gland, or systemic, impacting multiple tissues throughout the body, such as systemic lupus erythematosus (SLE).

The Link Between Immune Dysfunction and Infertility

When it comes to unexplained infertility and RIF, abnormal inflammatory immune activity is often the underlying culprit. Immunological evaluation is typically excluded from standard diagnostic infertility testing, which is why immune dysfunction and is frequently overlooked by conventional medicine. Women experiencing multiple failed IVF attempts or recurrent implantation failure may be dealing with hidden chronic inflammation, possibly indicative of the early stages of an autoimmune disease. Even modest chronic inflammatory environments can create inhospitable conditions for pregnancy.

The primary treatment strategy for those seeking pregnancy involves enhancing the quality of the embryo and improving the uterine lining’s (endometrium) ability to receive the embryo. In IVF procedures, embryologists assess embryo morphology to select the best one for transfer, aiming for implantation success. Fertility clinics may also us pre-implantation genetic screening (PGS) and pre=implantation genetic diagnosis (PGD) to evaluate embryo quality. While the risks associated with poor-quality embryos can be mitigated with focused testing, understanding the endometrium’s receptivity to the embryo is more complex. After recurrent implantation failure, many women feel left behind in this aspect of the treatment.

Endometrial receptivity is a complex process involving multiple molecular pathways, including hormones, growth factors, and immune tolerance. The innate and adaptive immune systems must work together harmoniously to allow the embryo (then blastocyst) to implant. Innate immune cells, such as macrophages, dendritic cells, and uterine natural killer (uNK) cells, support immune regulation and enhance endometrium receptivity, while the adaptive immune system contains inflammation and prevents the release of additional proinflammatory immune markers.

In a normal pregnancy, natural killer (NK) cells circulating in the bloodstream (peripheral NK cells) decrease in quantity and activity. However, in women experiencing recurrent implantation failure and pregnancy loss, peripheral NK cells are significantly increased in concentration and immune activity. An increase in peripheral NK cells can release harmful cytokines, such as interferon-gamma and TNF-alpha, which disrupt implantation and cell division. High levels of TNF-alpha can also cause inflammation and blood clotting, potentially harming the uterine lining and increasing pregnancy risks. Additionally, autoimmune antibodies (anti-nuclear antibodies, anti-cardiolipin antibodies, and anti-phospholipid antibodies) are implicated in recurrent implantation failure or early pregnancy loss, further complicating the situation.

Symptoms – How to Recognize Immune Dysfunction in Infertility?

How would you even know if this is an issue? Hidden chronic inflammation can affect conception and pregnancy even before it manifests into a disease. When low-grade inflammation is persistent, it generates unfavorable inflammatory conditions during a women’s menstrual cycle. The signs of chronic inflammation begin as hormonal imbalances including estrogen dominance, hypothyroidism and insulin resistance. It’s only when a woman presents the onset of symptoms which include premenstrual syndrome and heavy, irregular or painful periods that an issue may be finally flagged.

Disease, and infertility for that matter, do not simply develop overnight, rather it’s a transition that is either gradual or more rapid depending on the level of inflammation fueling it. At the lower end of the inflammation spectrum, symptoms may be unnoticeable. However, as inflammation intensifies, immune dysfunction progresses and severe symptoms are likely, often leading to a diagnosis of infertility, chronic or autoimmune disease.

Conditions Associated with Chronic Inflammation

• Autoimmune disorders of all types
• Bone and joint disorders (back pain, muscle pain, arthritis)
• Cancers of all types
• Cardiovascular diseases (heart disease, atherosclerosis)
• Digestive disorders (acid reflux, GERD, irritable bowel syndrome, ulcers, gallstones, fatty liver, diverticulitis, food sensitivities, food allergies)
• Emotional and cognitive disorders (anxiety, brain fog, depression)
• Hormonal disorders (fibrocystic breasts, endometriosis, fibroids)
• Infertility
• Metabolic disorders (obesity, diabetes)
• Neurological disorders (ADD/ADHD, Alzheimer’s, autism, dementia)
• Psychiatric disorders (bipolar disorder, schizophrenia)
• Respiratory disorders (sinusitis, seasonal allergies, asthma)
• Skin conditions (acne, eczema, rosacea)

Many health conditions and disease, such as anxiety, depression, fatigue, digestive issues, hormone imbalances, diabetes, heart disease, autoimmune conditions and cancer begin with systemic, chronic low-grade inflammation. Inflammation often initiates quietly in the body long before these conditions become noticeable or diagnosable. By the time symptoms appear and a diagnosis of disease is made, significant damage to bodily tissues has already occurred. 

What To Do If You Suspect Immune Dysfunction?

What do we do if this is the issue? Unraveling the causes of chronic inflammation is the biggest challenge in treating inflammatory diseases and unexplained infertility. This is because chronic inflammation can result from various combinations of inflammatory triggers, affecting people differently and causing them to express different symptoms. As such, there is no “one-size-fits-all” solution to address chronic inflammation, as the underlying causes are unique to each individual.

This complexity justifies the need for holistic, more personalized healthcare, integrative treatment strategies, and greater collaboration between the patient and providers. The journey to healing from unexplained infertility begins with the patient recognizing symptom patterns, family history and how diet, infections, exposures, and lifestyle habits might be driving their condition. Discipline and consistency in uncovering your root causes are essential. By uncovering and addressing the unique inflammatory triggers affecting your body, you can begin to mitigate chronic inflammation and its impact on your fertility. Although personalized medicine may not be available to everyone, you can still take proactive steps to improve your health and fertility with the support of functional medicine practitioners.

Understanding and addressing chronic inflammation is crucial for improving overall health and fertility. The first step in healing from unexplained infertility involves understanding your body’s signals and seeking a comprehensive approach to treatment that considers all contributing factors. By identifying and managing inflammatory triggers such as chronic infections, stress, toxins, food sensitivities, and nutritional imbalances, it is possible to mitigate the impact of chronic inflammation to treat the underlying causes of unexplained infertility and other chronic conditions.

For more information of infertility and immune dysfunction, how to uncover and address root causes and how to restore your fertility – including my story and how I overcame unexplained infertility – check out my book available on Amazon.

Key Takeaway

Unexplained infertility and RIF are complex conditions that involve immune system dysfunction and chronic inflammation. While conventional medicine primarily focuses on the reproductive system, scientific evidence suggests that broader systemic imbalances, such as inflammatory conditions and neuroendocrine disruptions, significantly contribute to these fertility issues. Recognizing the interconnectedness of the body’s systems, functional medicine emphasizes the need to consider the entire body’s health to effectively address unexplained or complex infertility.

Hidden chronic inflammation is a common form of immune dysfunction that creates unfavorable conditions for pregnancy long before it manifests as a diagnosable disease. Persistent low-grade inflammation impacts hormonal balances and immune function, leading to symptoms like premenstrual syndrome, heavy periods, and eventually autoimmune disease. By identifying and managing inflammatory triggers, such as chronic infections, stress, toxins, food sensitivities, and lifestyle factors, it is possible to mitigate chronic inflammation’s impact. Adopting a holistic and personalized approach to healthcare can help uncover and address the underlying causes of unexplained infertility and other chronic conditions, ultimately improving overall health and fertility outcomes.

Study References

Vannuccini S, Clifton VL, Fraser IS, Taylor HS, Critchley H, Giudice LC, Petraglia F. Infertility and reproductive disorders: impact of hormonal and inflammatory mechanisms on pregnancy outcome. Hum Reprod Update. 2016 Jan-Feb;22(1):104-15. doi: 10.1093/humupd/dmv044. Epub 2015 Sep 22. PMID: 26395640; PMCID: PMC7289323.

Franasiak JM, Alecsandru D, Forman EJ, Gemmell LC, Goldberg JM, Llarena N, Margolis C, Laven J, Schoenmakers S, Seli E. A review of the pathophysiology of recurrent implantation failure. Fertil Steril. 2021 Dec;116(6):1436-1448. doi: 10.1016/j.fertnstert.2021.09.014. Epub 2021 Oct 19. Erratum in: Fertil Steril. 2022 Mar;117(3):653. doi: 10.1016/j.fertnstert.2022.01.002. PMID: 34674825.

Yamada H, Morikawa M, Kato EH, Shimada S, Kobashi G, Minakami H. Pre-conceptional natural killer cell activity and percentage as predictors of biochemical pregnancy and spontaneous abortion with normal chromosome karyotype. Am J Reprod Immunol. 2003 Oct;50(4):351-4. doi: 10.1034/j.1600-0897.2003.00095.x. PMID: 14672340.

Wang Q, Sun Y, Fan R, Wang M, Ren C, Jiang A, Yang T. Role of inflammatory factors in the etiology and treatment of recurrent implantation failure. Reprod Biol. 2022 Dec;22(4):100698. doi: 10.1016/j.repbio.2022.100698. Epub 2022 Sep 23. PMID: 36162310.