By Paul Nicolaus
May 14, 2020 | An international group of researchers has revealed that tall, slim girls may be at an increased risk of endometriosis—a painful, chronic, and inflammatory disease that impacts an estimated 5 to 10% of the female population worldwide. The findings suggest that the significant diagnostic delays associated with the disease could potentially be reduced.
Endometriosis occurs when tissue similar to the lining of the womb grows outside of the uterus, and several of its most common symptoms involve discomfort, such as pain in the lower abdomen before and during periods, painful urination or bowel movements during periods, and pain during or after sex. Other symptoms include fatigue, heavy bleeding, infertility, and gastrointestinal issues.
Experts say the disease can negatively impact physical and emotional well-being, productivity at work and home, and quality of life issues such as appetite or sleep.
While body size in adulthood is likely associated with the risk of endometriosis, little is known about associations with body size earlier in life, so a group of researchers from Denmark and the United States set out to learn more.
Using data from the Copenhagen School Health Records Register—a large Danish population-based cohort—the researchers analyzed over 170,000 girls born between 1930 and 1996 to see whether birth weight, childhood body mass index (BMI), and height at ages 7 to 13 are linked to risk of endometriosis and adenomyosis, a related condition in which endometrial tissue grows into the uterine wall.
The findings, published in Annals of Human Biology (doi: 10.1080/03014460.2020.1727011), reveal an association between BMI and height early in life and the risk of endometriosis in reproductive-aged women. In other words, tall, lean girls appear to have an increased risk.
More specifically, a one z-score difference in height between two girls of either average height or taller than average height (equivalent to a roughly 5 centimeter or 2-inch difference) is associated with a 9% increased risk of endometriosis for the taller girl. The study results suggest that indicators of endometriosis risk are already apparent at early ages.
“A critical time window during which the disease develops is often missed, with women often experiencing diagnostic delays of several years,” said Julie Aarestrup from Denmark’s Center for Clinical Research and Prevention in a statement announcing the study. “Our findings suggest that indicators of risk can be picked up at an earlier age, which might help speed up diagnosis so treatment can be started to slow the growth of endometrial tissue.”
While the research contributes important information to the understanding of the etiology of this disease, the findings do not have immediate implications for clinical practice, acknowledged Britton Trabert of the National Cancer Institute’s Division of Cancer Epidemiology and Genetics.
“One study alone is not sufficient basis for practice changes related to earlier diagnosis of endometriosis,” she told Diagnostics World. “However, the findings do open up new avenues for exploration into the mechanisms that influence risk for this common gynecological health outcome.”
Reactions to the Study
This study is unique in the sense that it explores childhood BMI, said Paul Yong, research director at the BC Women’s Centre for Pelvic Pain & Endometriosis and associate professor, Division of Gynaecologic Specialties and Reproductive Endocrinology & Infertility at the University of British Columbia (who was not involved in the research).
In most studies, he explained, the BMI measurements are taken at the time of diagnosis or sometime in adulthood. “I think the childhood measurement is helpful,” he said. And because this measurement was handled prospectively rather than using retrospective recall, “that makes it much more accurate.”
Another advantage of this study’s approach is that the Scandinavian registers enabled the researchers to look at anatomical subtypes of endometriosis. “That’s quite unique for population registry data,” he said. “I know in our population data we can’t look with that level of resolution.” This sub-analysis enabled the researchers to find the same associations in both ovarian and peritoneum endometriosis.
Yet another upside, he said, is the study’s inclusion of adenomyosis. (Unlike endometriosis, the researchers did not find an apparent link between BMI or height in girls and risk of the disease later in life.) “Less is known in terms of its etiology,” Yong said, so “it was novel in the sense that they at least tried to look at it.”
Still, there are several notable limitations. For one, the diagnosis rate “was quite low,” Yong said, “which suggests to me they may not have captured everybody.”
Specifically, there were 2,149 women diagnosed with endometriosis out of over 171,000, which comes out to between 1% and 2% (when the condition is estimated to affect up to 10% of the general female population). This may be because of the nature of these registers, which were based on International Classification of Diseases (ICD) codes from inpatient contact and wouldn’t necessarily include outpatient contact.
Another caveat, he explained, is that adenomyosis diagnosis was made on hysterectomy specimen, whereas it is now diagnosable by ultrasound and MRI. “Because historically it was diagnosed by hysterectomy, there was bias in what was thought to be risk factors,” he said. “For example, it was thought to be a disease in older women, but that’s actually just an artifact of the fact that it was diagnosed with hysterectomy. So I think that’s a bit reflected here in the sense that they had very few women with adenomyosis.”
Again, this is inpatient contact with someone entering the ICD code, Yong said, and he suspects these cases were mostly diagnosed with hysterectomy, which could be why the researchers weren’t able to find an association for adenomyosis.
“Nowadays it’s a completely different picture because you can make a diagnosis on ultrasound, so now you commonly will see it in younger patients. That’s not their fault,” he added. “That’s just the nature of how the disease was diagnosed in the past.”
While it is difficult to think of BMI as a means of making a diagnosis, Yong does wonder about the possibility of including it as part of a diagnostic algorithm. If there were efforts to develop a model to predict endometriosis or diagnose it in adolescence, BMI is one aspect that could be explored to see if it has some predictive value. However, he isn’t sure about its level of accuracy.
“Even though decreased BMI is a risk factor,” he said, “I’m not sure it would have the adequate predictive value—like good enough sensitivity and specificity—to be included in some sort of clinical prediction model.”
Reasons for Diagnostic Delay
Laparoscopy with biopsy of lesions remains the gold standard, according to Paulami Guha, an obstetrician-gynecologist in Jacksonville, Fla., (who was not involved with the newly published study), but this invasive method has its risks.
Other methods have shortcomings as well. A skilled ultrasonographer is required for ultrasound diagnosis other than an obvious ovarian endometrioma, she explained, and ultrasound may not be able to diagnose small patches of endometriosis or bowel endometriosis. MRI is expensive and may not be covered by insurance.
This array of diagnostic hurdles can result in a sizable lag time from the onset of symptoms to the time of diagnosis. Studies have reported an average diagnostic delay of 7 to 12 years, Guha pointed out. The diagnostic barriers don’t necessarily end with the shortcomings of existing diagnostic tools and methods, however.
The Society for Women’s Health Research (SWHR) convened an interdisciplinary group of researchers, clinicians, and patients for a roundtable meeting to evaluate endometriosis diagnostics and treatment. The result of that discussion, which includes Yong as a co-author, was published last year in the American Journal of Obstetrics & Gynecology (doi: 10.1016/j.ajog.2019.02.033).
Among the issues highlighted were stigma and the normalization of women’s pain, which can also play a central role in diagnostic delay. One study, they noted, found that women wait, on average, over two years from the onset of symptoms before seeking help, and women may not recognize their pain as a treatable condition. Societal normalization of women’s pain as well as the taboo nature of certain topics, like menstruation or painful sex, can keep women from seeking care and support.
Beyond that, the lack of understanding about the disease’s etiology and range of symptoms can contribute to diagnostic delay. Chronic pelvic pain, the most commonly reported symptom, is not specific to endometriosis. Some other gynecologic diseases (like pelvic inflammatory disease, uterine fibroids, or adenomyosis) and nongynecologic diseases (like irritable bowel syndrome, painful bladder syndrome, or fibromyalgia) have symptoms that can overlap with endometriosis.
To complicate matters, nearly all women with endometriosis report at least one comorbid disorder, such as migraine, depression, anxiety, irritable bowel syndrome (IBS), painful bladder syndrome, chronic fatigue syndrome, fibromyalgia, uterine fibroids, or ovarian cysts. The process of ruling out other diseases can take time and wind up slowing the diagnosis of endometriosis.
Future of Endometriosis Diagnosis
When Yong considers the future of endometriosis diagnosis, three main ideas come to mind. The first is that there have been many advances when it comes to imaging diagnosis of endometriosis—particularly ultrasound, but also MRI.
At this time, however, that’s mostly available at specialized centers. There’s a need for greater knowledge, translation, and dissemination of these advances in the imaging guidance of endometriosis, he said.
The second notion relates to deemphasizing the need to always make the gold standard surgical diagnosis. Even though the accuracy doesn’t measure up to surgery or imaging, symptoms and physical exam can be relied upon to help make a preliminary diagnosis. The rationale is to get patients started on treatment.
“First of all, validate the symptoms and then second, get them started on medical treatment early rather than having to wait a long time for the surgical diagnosis,” he said.
Finally, he points to the future of biomarker diagnosis. Among the blood-based biomarkers under investigation are inflammatory markers, tumor markers, growth factors, regulators of gene expression, and hormonal markers as well as endometrial and menstrual effluent biomarkers.
There is still a ways to go, though, according to Yong. “There have been a lot of studies saying such and such biomarker in the blood seems to be associated with endometriosis,” he said, “but the problem is externally validating it in other studies and other populations.”
Paul Nicolaus is a freelance writer specializing in science, nature, and health. Learn more at www.nicolauswriting.com.