Clinical Review

Endometriosis: Expert answers to 7 crucial questions on diagnosis

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1. Why such a long delay in diagnosis?
Investigators exploring the length of time between a patient’s presentation with symptoms and diagnosis have found it to be particularly long for endometriosis, ranging from 6 to 11 years.

Because endometriosis is usually not high on the list of differential diagnoses for chronic pelvic pain in the primary care setting, a patient may not be referred to a gynecologist unless those symptoms include severe dysmenorrhea, dyspareunia, or similar findings. Once the referral is made, the gynecologist “will usually try contraceptive steroids, nonsteroidal anti-inflammatory drugs, or second-line progestins before a diagnosis is made,” says Dr. Giudice.5

The delay in diagnosis “is astounding,” she adds, “and has its roots in empiric medical therapies and a combination of patients fearing a diagnosis of cancer and reluctance of gynecologists to perform laparoscopy on adolescents.”6

Another possible cause of diagnostic delay: Some adolescent girls may not realize when their pain is severe. Because they may have always experienced a high degree of pain since menarche, they may assume it to be a normal aspect of womanhood and delay seeking help, says Pamela Stratton, MD, chief of the gynecology consult service at the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

2. Have any biomarkers proved to be useful diagnostic tools?
Any biomarker proven to reliably identify endometriosis would be a boon to medicine, as it would provide a noninvasive or minimally invasive alternative to diagnostic laparoscopy, the current gold standard. Regrettably, the search for such a biomarker has produced “disappointing results,” says Dr. Giudice.

“Recent systematic reviews of all proposed endometriosis-related biomarkers over the last 25 years in serum, plasma, urine, and endometrium could not identify an unequivocally clinically useful biomarker or panel of biomarkers,” she notes.7,8 “This is due mainly to low numbers of subjects, small populations for validations, cycle/hormonal- and disease stage-­dependence, poorly defined controls, and low sensitivity and specificity.”

One hopeful development: “Whole genome transcriptomics of archived endometrial tissue and machine learning found several classifiers to diagnose and stage endometriosis with high accuracy that were validated on an independent sample set,” says Dr. Giudice.9 “However, these data now warrant a prospective, multisite study for further validation.”

Environmental factors, estrogen, and endometriosis

“There is increasing evidence that in utero and also adult exposures to endocrine-disrupting chemicals (EDCs) play a role in the pathogenesis and progression of disease,” says Linda Giudice, MD, PhD, the Robert B. Jaffe, MD, Endowed Professor in the reproductive sciences and chair of obstetrics, gynecology, and reproductive sciences at the University of California, San Francisco.

“For example, the Nurses’ Health Study II, a prospective cohort study of more than 80,000 women, revealed that daughters exposed to diethylstilbestrol (DES) had an 80% increased risk (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.2–2.8) of developing endometriosis,” she says.1

“Also, dioxin (TCDD) exposure in rats in utero on gestational day 8 increased the size of endometriosis lesions when combined with an adult exposure,” Dr. Giudice says.2 Although we do not know the precise mechanisms underlying in utero events that result in disease onset as a teen or adult, abnormal programming of the female reproductive tract by EDCs and similar agents is believed to play a role, she says.3

Because estrogen is essential for endometriosis lesions and associated symptoms to progress, “EDCs that have either estrogenic activity or interfere with estrogen metabolism or action, or both, have been proposed as contributors to progression of disease. Abundant animal data using nonhuman primate and rodent models and exposures to organochlorines and other EDCs support this hypothesis,” Dr. Giudice says.4

“The weight of human evidence of associations of EDCs and the risk of endometriosis in adult women depends on the class of endocrine disrupter,” Dr. Giudice continues. “Strongest correlations are with polychlorobiphenyls (PCBs), where 10 of 12 studies found significant odds of disease and circulating or omental fat concentrations of these compounds. PCBs inhibit peripheral natural killer cell activity and interleukin 1b and 12 production, relevant to the immune component of endometriosis progression.”

“Significant risk has also been associated with organochlorines (in three of three studies) and perfluorochemicals. In contrast, data linking endometriosis with exposures to dioxins, phthalates, and bisphenol A are equivocal, with some studies finding significant odds ratios and others failing to find significant correlations. Interestingly, dioxins have a significant association with deep infiltrating endometriotic lesions.”5

References
1. Missmer SA, Hankinson SE, Spiegelman D, Barbieri RL, Michels KB, Hunter DJ. In utero exposures and the incidence of endometriosis. Fertil Steril. 2004;82(6):1501–1508.
2. Cummings AM, Hedge JM, Birnbaum LS. Effects on prenatal exposure to TCDD on the promotion of endometriotic lesion growth by TCDD in adult female rats and mice. Toxicol Sci. 1999;52(1):45–49.
3. Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–279.
4. Crain DA, Janssen SJ, Edwards TM, et al. Female reproductive disorders: the roles of endocrine disrupting compounds and developmental timing. Fertil Steril. 2008;90(4):911–940.
5. Heilier JF, Donnez J, Nackers F, et al. Environmental and host-associated risk factors in endometriosis and deep endometriotic nodules: a matched case-control study. Environ Res. 2007;103(1):121–129.

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