Endometriosis / Adenomyosis

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Endometriosis and Adenomyosis

Understanding Endometriosis and Adenomyosis: How Your Immune System Affects Your Fertility

 

What Are Endometriosis and Adenomyosis?

Endometriosis and adenomyosis are two closely related conditions that affect millions of women worldwide. While they share many features — including pain, heavy bleeding, and difficulty conceiving — they involve different locations within the body.

Endometriosis occurs when tissue similar to the lining of the uterus (the endometrium) grows outside the uterus — on the ovaries, fallopian tubes, the tissue lining the pelvis, and sometimes even beyond the pelvic area. It is estimated to affect approximately 10% of women of reproductive age, which translates to roughly 190 million women worldwide.

Adenomyosis occurs when that same type of tissue grows into the muscular wall of the uterus itself. It was once thought to mainly affect women over 40, but thanks to improved imaging, it is now increasingly recognized in younger women, including those struggling with infertility.

These two conditions frequently occur together, and when they do, the impact on fertility and pregnancy can be compounded.

More Than a Hormonal Problem: The Immune Connection

For many years, endometriosis and adenomyosis were viewed primarily as hormonal disorders — conditions driven by estrogen. While hormones certainly play a role, a growing body of research has revealed that the immune system is a central player in both conditions. In fact, many experts now consider endometriosis to be a chronic inflammatory, immune-mediated disease.

To understand why, it helps to know what happens during a normal menstrual cycle. Each month, a small amount of menstrual blood flows backward through the fallopian tubes into the pelvic cavity — a process called retrograde menstruation. This happens in most women. Normally, the immune system quickly clears away these stray cells. But in women with endometriosis, the immune system fails to do its job properly, allowing those cells to survive, implant, and grow where they should not.

How the Immune System Goes Wrong

Natural Killer (NK) Cells: When the Guards Stand Down

Natural killer cells are one of the body’s first lines of defense. They are designed to identify and destroy abnormal or misplaced cells. In women with endometriosis, NK cells in the pelvic cavity show significantly reduced killing ability. Rather than eliminating the stray endometrial cells, these weakened NK cells allow them to survive and establish themselves as endometriotic lesions.

This NK cell dysfunction is not just about numbers — it is about function. Research has shown that the NK cells in women with endometriosis have altered receptors on their surface, which impairs their ability to recognize and attack the ectopic tissue. This creates a “permissive” immune environment where endometriotic lesions can thrive.

Macrophages: Helpers Turned Enablers

Macrophages are immune cells that normally engulf and destroy foreign material. In endometriosis, however, macrophages in the peritoneal fluid (the fluid surrounding the pelvic organs) behave abnormally. Instead of clearing away endometrial debris, they shift toward a state that actually promotes the growth of endometriotic lesions. These altered macrophages release high levels of inflammatory chemicals — including TNF-alpha, interleukin-1, interleukin-6, and VEGF (a factor that promotes new blood vessel growth) — which help the ectopic tissue establish its own blood supply and continue to grow.

The Inflammatory Cascade

The peritoneal fluid of women with endometriosis contains elevated levels of prostaglandins, cytokines, and other inflammatory mediators. This creates a chronically inflamed pelvic environment that can damage eggs, impair sperm function, interfere with fertilization, and disrupt the ability of an embryo to implant in the uterus.

T Cell Imbalances and Immune Tolerance

The adaptive immune system — the part that involves T cells and B cells — is also disrupted in endometriosis. Research has found increased concentrations of Th17 cells (a type of pro-inflammatory T cell) in the peritoneal fluid of women with endometriosis, which promotes chronic inflammation. At the same time, regulatory T cells (Tregs), which normally keep the immune system in check, may be altered in ways that allow the ectopic tissue to evade immune detection — much like how cancer cells can hide from the immune system.

Interestingly, the immune profile differs between endometriosis and adenomyosis. While endometriosis tends to involve local immune suppression that allows lesions to survive, adenomyosis is characterized more by pro-inflammatory changes with a deficiency of regulatory T cells, creating a hostile environment within the uterine wall itself.

The Autoimmune Connection

Women with endometriosis have a significantly increased risk of developing autoimmune diseases. Large population studies have found that women with endometriosis are at 30% to 80% higher risk for conditions such as rheumatoid arthritis, systemic lupus erythematosus (lupus), Sjögren’s syndrome, celiac disease, and multiple sclerosis. Genetic studies have confirmed that endometriosis shares common genetic pathways with several of these autoimmune conditions.

Additionally, antibodies against the body’s own endometrial and ovarian tissues have been detected in the blood of women with endometriosis, further supporting the idea that the immune system is not functioning normally.

This autoimmune tendency is important for fertility because it suggests that the immune system is in a heightened state of alert — a state that can interfere with the delicate immune tolerance required for embryo implantation and pregnancy.

How This Affects Your Fertility

Endometriosis and adenomyosis can impair fertility through multiple pathways:

Endometriosis and Fertility:

– The inflamed pelvic environment can damage eggs and sperm and interfere with fertilization.

– Endometriomas (cysts on the ovaries) can reduce ovarian reserve and the number of mature eggs available.

– Adhesions and scar tissue can distort the anatomy of the pelvis, blocking the fallopian tubes or preventing the ovaries from releasing eggs normally.

– The inflammatory chemicals in the peritoneal fluid can be directly toxic to embryos.

– Even in mild endometriosis, the altered immune environment can impair implantation.

Adenomyosis and Fertility:

– The invasion of endometrial tissue into the uterine muscle creates a chronically inflamed uterine wall.

– Inflammatory cytokines such as IL-6, IL-8, and TNF-alpha disrupt the immune barrier at the junction between the endometrium and the muscle, creating an environment hostile to embryo survival.

– The expression of key implantation genes (such as HOXA-10) is reduced, impairing the uterus’s ability to accept an embryo.

– Local estrogen overproduction in the uterine wall interferes with the normal hormonal signals needed for implantation.

– Women with adenomyosis undergoing IVF have been shown to have significantly lower live birth rates compared to women without the condition.

Pregnancy Risks

Both conditions are associated with increased risks during pregnancy. Women with endometriosis — particularly deep infiltrating endometriosis — face higher risks of placenta previa (a low-lying placenta), preterm delivery, and, in rare cases, internal bleeding during pregnancy. Women with adenomyosis are at increased risk for miscarriage, preeclampsia, preterm delivery, low birth weight, and postpartum hemorrhage. The effect on miscarriage appears to be even larger in women with adenomyosis than in those with endometriosis alone.

Diagnosis

Endometriosis can be suspected based on symptoms such as painful periods, chronic pelvic pain, pain during intercourse, and infertility. The American College of Obstetricians and Gynecologists (ACOG) recommends that a clinical diagnosis based on symptoms and physical examination is sufficient to begin treatment. Transvaginal ultrasound is the recommended first-line imaging test, and MRI can provide additional detail, especially for deep endometriosis. While laparoscopy (a minimally invasive surgery) was once considered the gold standard for diagnosis, it is no longer required to start treatment.

Endometriosis is classified into subtypes based on location: superficial peritoneal lesions, ovarian endometriomas, deep endometriosis (which penetrates more than 5 mm below the surface), and extrapelvic endometriosis. The traditional staging system (stages I through IV) does not reliably predict pain severity or fertility outcomes.

Adenomyosis is typically diagnosed through imaging. Transvaginal ultrasound is the recommended first-line test, where characteristic findings include a globular uterus, fan-shaped shadowing, myometrial cysts, and an irregular junctional zone. When ultrasound findings are equivocal — particularly when focal adenomyosis needs to be distinguished from fibroids — MRI offers higher specificity and can provide greater diagnostic certainty. However, the definitive diagnosis of adenomyosis is confirmed through histopathology.

Treatment: A Reproductive Immunology Perspective

Because both endometriosis and adenomyosis involve significant immune dysfunction, treatment strategies increasingly look beyond hormones alone.

Standard Treatments:

– Hormonal therapies (birth control pills, progestins, GnRH agonists or antagonists) can suppress the growth of endometriotic tissue and reduce inflammation.

– Surgical excision of endometriotic lesions can restore anatomy and reduce the inflammatory burden.

– For women with adenomyosis undergoing IVF, pretreatment with GnRH agonists before frozen embryo transfer may improve pregnancy rates.

Immunomodulatory Approaches:

Given the central role of immune dysfunction, targeted immunomodulatory therapies are an area of active research and clinical application:

– TNF-alpha inhibitors (such as adalimumab) have shown promise in women with endometriosis and/or adenomyosis undergoing IVF, with studies demonstrating improved implantation and clinical pregnancy rates when used around the time of embryo transfer.

– Anti-inflammatory agents and antioxidants may help counteract the toxic peritoneal environment and improve egg quality.

– Immunomodulatory therapies such as those used in recurrent implantation failure — including IVIG, corticosteroids, hydroxychloroquine, and tacrolimus — are being explored for women with endometriosis-related immune dysregulation, though more research is needed.

– Platelet-rich plasma (PRP) and other novel approaches are being studied for their ability to improve endometrial receptivity in women with repeated IVF failures.

There Is Hope

Despite the challenges posed by endometriosis and adenomyosis, many women with these conditions go on to have successful pregnancies — especially when the underlying immune factors are identified and addressed. The field of reproductive immunology is rapidly advancing, offering new tools to understand why these conditions cause infertility and new strategies to overcome it.

If you have been diagnosed with endometriosis or adenomyosis and are struggling to conceive, a comprehensive evaluation that includes immune profiling — in addition to standard fertility testing — may reveal treatable factors that have been overlooked. By addressing the immune imbalance at the root of these conditions, it is possible to shift the body from a state of inflammation to one that supports a healthy pregnancy.

 

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