Causes and Risk Factors of Endometriosis

Endometriosis is a condition in which the lining of the uterus, called the endometrium, grows outside the uterus, often extending to the fallopian tubes, ovaries, and pelvic wall. Nearly half of the women affected by endometriosis will have chronic pelvic pain, while around 70 percent will have pain during their periods (dysmenorrhea). Infertility is also common, affecting as many as one in every two women with the condition.

No one currently knows the exact cause of endometriosis. Genetics, environment, and lifestyle are believed to play a major role. There are also certain risk factors that may increase your likelihood of developing endometriosis, although they tend to be non-modifiable (such as your age or family history).

It is unclear what can be done to reduce your personal risk other than to exercise regularly and generally maintain optimal health. Doing so may reduce high estrogen levels that contribute to the severity and frequency of symptoms.

Common Causes

According to a 2016 study in the Lancet, more than 10 million women are believed affected by endometriosis worldwide. It is most common in women in their 30s and 40s but can affect girls as young as 10 years of age.

Theories

Though it isn't clear exactly what causes endometriosis, there are several theories that attempt to explain why endometriosis occurs and why some women are affected and others aren't.

Retrograde Menstruation

Perhaps the oldest hypothesis is the theory of retrograde menstruation. It suggests that some of the cells and tissues from a woman's menstrual flow may flow backward through the fallopian tubes and into the peritoneal cavity (the space within the abdomen that contains the abdominal organs).

If this happens, it is believed that the cells may implant themselves and establish "anchors" onto which endometrial tissues from the uterus can begin their outward invasion. Retrograde menstruation, however, isn't able to fully explain the genesis of endometriosis given that endometriosis can develop in prepubescent girls.

Induction Theory

Another theory proposes that certain hormones or immune factors may inadvertently transform certain cells of the peritoneum (the lining of the peritoneal cavity) into endometrial cells.

Called the induction theory, the hypothesis is supported by animal research in which uterine tissues grafted onto the peritoneum of baboons induced endometriosis. Later evaluation of the tissues found that they were biologically distinct from the endometrial lesions that naturally occur with endometriosis.

The theory may better explain why prepubescent girls get endometriosis, as well as why certain cases of endometriosis affect distant organs such as the brain, lungs, or skin. It is still unclear which factor or combination of factors (such as hormones, autoimmune disease, toxins, among others) may act as the "trigger" for endometrial induction.

Embryonic Cell Theory

Another theory, called the embryonic cell transformation theory, suggests that the estrogen may inadvertently transform undifferentiated embryonic cells (cells in an embryo that have not yet specialized) into endometrial cells during puberty.

According to the theory, residual embryonic cells in the developing female reproductive tract (called müllerian ducts) may persist after birth and be induced into endometriosis under the influence of estrogen. This may explain why some younger girls get endometriosis given that puberty will usually begin in girls between the ages of eight and 14.

Where the theory falls short is in cases where endometriosis develops outside of the female reproductive tract. Some scientists believe that this occurs when dislodged endometrial cells are transported by the lymphatic system to distant parts of the body, much in the same way as lymphoma and metastatic cancers.

Genetics

Most scientists agree that genetics play a large part in the development of endometriosis. Statistics alone provide evidence to support this.

Even having a second- or third-degree relative with endometriosis can increase your risk.

Beyond the inheritance of genes, genetics may also contribute indirectly by influencing hormone production. Endometriosis commonly occurs in the presence of persistently elevated estrogen levels. Aromatase excess syndrome (AEX) is an extreme example in which high estrogen output is linked to a specific genetic mutation.

It is believed that endometriosis is caused not by one but multiple genetic mutations. They may be somatic mutations (which occur after conception and cannot be inherited), germline mutations (which are passed to offspring), or combination of the two.

Scientists have identified a number of genetic mutations closely linked to endometriosis, including:

• 7p15.2, which influences uterine development
• GREB1/FN1, which helps regulate estrogen production
• MUC16, responsible for forming protective mucus layers in the uterus
• CDKN2BAS, which regulates tumor suppressor genes believed to be linked to endometriosis
• VEZT, which aids in the creation of tumor suppressor genes
• WNT4, which is vital to the development of the female reproductive tract

Despite these early findings, there are no genetic or genomic tests yet that can reliably identify or predict the risk of endometriosis.

Other Risk Factors

Beyond a familial risk, there are a number of other characteristics typically seen in women with endometriosis. All of these risks (or any of them) aren't necessary for the development of endometriosis. However, it is not surprising when a person with endometriosis does have one or a few of these risk factors present.

Age

Endometriosis affects women of reproductive age, usually between 15 and 49. While it can sometimes develop before a girl's first period, endometriosis usually occurs several years after the onset of menstruation (menarche).

Most cases are identified between the ages of 25 and 35, the time in life when many women are trying to get pregnant. In many such women, infertility may be the first overt sign of endometriosis (or the one that compels them to seek medical attention).

Estimates suggest that between 20 percent and 50 percent of women being treated for infertility have endometriosis, according to a 2010 review of studies in the Journal of Assisted Reproduction and Genetics.

Weight

A low body mass index (BMI) has long been considered a key risk factor for the development of endometriosis. (This is contrary to many health disorders in which a high BMI contributes to disease risk.)

According to a 2017 review involving 11 clinical trials, the risk of endometriosis was 31 percent less in women with a BMI over 40 (defined as obese) than women of normal weight (BMI of 18.5 to 24.9). Even compared to overweight women, women with obesity had a lower overall risk of endometriosis.

Menstrual Characteristics

There are certain menstrual cycle characteristics that are commonly experienced in women with endometriosis:

• Starting your period before the age of 12
• Having short menstrual cycles, generally less than 27 days
• Experiencing heavy periods lasting longer than seven days
• Going through menopause at an older age

The same applies to the severity of menstrual symptoms, which commonly occurs with high estrogen levels.

Uterine Abnormalities

Uterine abnormalities may increase the risk of endometriosis by facilitating retrograde menstruation. These include conditions that alter the position of the uterus or obstruct the menstrual flow. Examples include:

• Uterine fibroids
• Uterine polyps
• Retrograde uterus (also known as a tilted uterus) in which the uterus curves in a backward position at the cervix rather than forward
• Congenital uterus malformations, including cryptomenorrhea (in which menstruation occurs but cannot be seen due to a congenital obstruction)
• Asynchronous vaginal contractions, in which the vagina contracts abnormally and/or excessively during menstruation

Pregnancy Characteristics

Women who have never been pregnant are at greater risk of endometriosis. It is unclear whether this is solely a risk factor for endometriosis or if it is the consequence of infertility that affects nearly one of every two women with the disease.

On the flip side, pregnancy and breastfeeding are associated with a reduced risk of endometriosis. They do so by prolonging the absence of menstrual periods (postpartum amenorrhea), thereby reducing the level of estrogen and other hormones associated with endometriosis symptoms.

Contrary to popular belief, pregnancy does not "cure" endometriosis. It may provide temporary relief, (particularly if combined with breastfeeding), but it doesn't eradicate the underlying endometrial overgrowth.

In some cases, endometriosis may go away completely with the onset of menopause (unless you are taking estrogen).

Abdominal Surgery

Abdominal surgeries like a cesarean section (C-section) or hysterectomy can sometimes displace endometrial tissue. Any remaining tissues not destroyed by the immune system may implant themselves outside of the uterus, leading to endometriosis.

A 2013 analysis from Sweden concluded that women who had a C-section with their first child were 80 percent more likely to be later diagnosed with endometriosis than those who delivered vaginally.

No risk was seen after two or more C-sections.

Environment

Lifestyle plays less of a role in the development of endometriosis than one might imagine. This makes mitigating the risk all the more challenging given that there are few modifiable factors you can change.

You may be able to reduce your chances by lowering the levels of estrogen in your body. This is especially true if you have known risk factors for endometriosis, including family history, polymenorrhea, or cryptomenorrhea.

The Office of Women's Health in Washington, D.C. recommends the following steps to help lower and normalize your estrogen levels:

• Exercise regularly, ideally more than four hours per week.
• Reduce your alcohol intake to no more than one drink per day.
• Cut back on caffeine, ideally to no more than one caffeinated drink per day.
• Ask your healthcare provider about low-dose estrogen birth control, including pills, patches, or intravaginal rings.