Endometriosis phenotyping is a developing field of research that is opening new perspectives on this chronic and often bewildering condition. Phenotypes are distinctive characteristics shaped by genetic and environmental factors. In medical research, phenotypes establish specific attributes and deviations in diseases, and can have a profound impact on effective treatments.

Endometriosis causes abnormal tissue that resembles the tissue of the uterine lining (endometrium) to grow outside of the uterus. It can affect numerous organs throughout the pelvis and abdomen. The disease affects as many as 10 percent of women of reproductive age, and is typically treated with costly and risky surgeries and medications, sometimes with limited effect. With a better understanding of variations of the disease through phenotypes, researchers hope endometriosis treatment can be more precisely targeted to the individual.

To learn more about phenotypes in endometriosis, MyEndometriosisTeam spoke with Dr. Georgine Lamvu, a gynecologic surgeon and specialist in pelvic pain. Dr. Lamvu is a professor in obstetrics and gynecology at the University of Central Florida in Orlando, Florida, and serves as a board member of the International Pelvic Pain Society. She is also the director of the Fellowship in Advanced Minimally Invasive Surgery and Advanced Gynecology at the Orlando VA Medical Center.

“Researching phenotypes is really research about mechanisms of disease,” said Dr. Lamvu.

Controversies With Endometriosis Staging

Disease staging is used to objectively measure the progress and severity of a condition. The revised American Society of Reproductive Medicine (rASRM) staging system is commonly used for endometriosis. Four stages rank disease severity based on the extent, severity, and location of endometriosis implants, adhesions, and cysts that form from abnormal endometrial-like tissue:

• Stage 1 — Minimal or superficial disease with few implants
• Stage 2 — Mild disease with superficial implants on one or both ovaries and deeper implants on the pelvic lining (peritoneum)
• Stage 3 — Moderate disease with deeper implants and cysts on one or both ovaries, and filmy adhesions (scarring) on one or both fallopian tubes
• Stage 4 — Severe disease with many deep implants, dense adhesions, and large cysts

With diseases such as cancer, staging usually guides treatment. But endometriosis can take on many different forms that do not consistently respond to treatments. The diversity of the disease has been confounding. In recent years, a growing consensus has developed to encourage more individualized care for people living with endometriosis because of problems with standardized treatment.

While staging measures the size of lesions, area covered, and infiltration of the disease, some professionals believe that the rASRM staging system does not always correlate well with symptoms and treatment for pain and infertility, the two main issues with the disease. “We figured out over the years that that staging is actually not anywhere near adequate for what's going on with endometriosis,” said Dr. Lamvu.

Staging Versus Phenotypes

Phenotyping may provide a more exact way of understanding different manifestations of endometriosis, because the disease does not conform to the current staging system, Dr. Lamvu said. “We have a phenotype of endometriosis that is stage 1 or stage 2, so early disease. It has a lot of pain,” she said. On the other hand, “You could have advanced staging with no pain whatsoever,” she added.

Fertility problems pose other questions for endometriosis staging. High rates of infertility are associated with endometriosis. Approximately 30 percent to 50 percent of women with endometriosis are infertile, and in the general population, approximately 25 percent to 50 percent of infertile women have been found to have endometriosis.

The common thinking is that later-stage endometriosis is likely to cause infertility, but that is not always the case, Dr. Lamvu said. “You could have women who have microscopic endometriosis and are infertile,” she said. “And then you have women who have stage 4 endometriosis and have four children.”

In addition, variation exists in how people respond to treatment, making staging problematic. “There are some phenotypes, for example, that have very early disease and don't respond to any kind of treatment,” Dr. Lamvu said. “They don't respond to medical therapies very well, and they don't respond to surgeries. Then there are some women who have stage 4 endometriosis, and you just put them on a little pill and they're fine. Every one of those things is a different phenotype,” she said.

Endometriosis has been categorized into three types, based on biological characteristics. These three types of endometriosis resemble staging, but are considered distinctive variations of the disease. However they do not currently determine symptoms or indicate specific treatments.

• Peritoneal superficial endometriosis (SUP) — Lesions are on the surface of the peritoneum or ovaries
• Endometrioma (OMA) — Fluid-filled lesions may be found deep within the ovaries
• Deeply infiltrating endometriosis (DIE) — Deep lesions impact anatomic structures surrounding the uterus, which may include the bladder or bowels

Rethinking Endometriosis Through Phenotypes

Research involving endometriosis phenotypes is evolving. Currently, there is no definitive system for phenotypes in the disease, but research indicates that one key to understanding endometriosis better is to monitor its effects more closely. “As soon as we can figure out all the different permutations of what the endometriosis phenotype is, then we will be able to individualize treatment to a particular phenotype,” Dr. Lamvu said.

In one study designed to identify endometriosis phenotypes, more than 4,000 participants were asked to record symptoms of endometriosis over two years using a smartphone app. The study generated a wide variety of symptoms. A systematic review identified four potential phenotypes of the disease, based on a prevalence of symptoms, treatments, and quality of life:

• Phenotype A — Associated with severe pain, including gastrointestinal and genitourinary symptoms, low quality of life, painful sex, and a higher rate of surgical procedures
• Phenotype B — Associated with moderate pain, a light menstrual cycle, and a good quality of life
• Phenotype C — Associated with moderate pain, regular menstruation, no medical treatments, and good quality of life
• Phenotype D — Associated with moderate pain and significant pelvic pain, a light menstrual cycle, and a variety of medical treatments

More Research Is Needed on Phenotypes

Research on endometriosis phenotypes is beginning to give doctors new ways of understanding both the diagnosis of endometriosis and treatment options. “I'm willing to bet that when it's all said and done, there will be at least four or five different phenotypes,” Dr. Lamvu said. “And when we figure that out, we will make huge strides.”

Phenotypes could transform endometriosis treatment, Dr. Lamvu noted. The current protocols for treating endometriosis suggest first either using hormone treatments to stop the production of estrogen or prescribing pain medication. Minimally invasive laparoscopic surgery to remove abnormal tissue can be very effective, but is not typically the first course of treatment.

“There may be particular phenotypes that respond very well to surgery,” Dr. Lamvu said. “And those women should have surgery first. Why not? If research can figure out what phenotype responds particularly well to surgery, then why delay surgery in those women?”

At the same time, Dr. Lamvu explained that evidence already exists indicating that for some phenotypes, surgery will not stop pain symptoms because of underlying chronic pelvic pain that may occur more frequently in that phenotype. “In those women, surgery may not be appropriate, and in fact, may make them worse,” she said.

“These are women that are having a really difficult time and they've moved from doctor to doctor, from guideline to guideline, and expert to expert,” said Dr. Lamvu. “Those are the challenging phenotypes that we don't understand very well.”

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