WOMEN'S HEALTH
April 4, 2012

Endometriosis, It's Complicated

Kenan Omurtag, M.D., and Amber R. Cooper, M.D., M.S.C.I.
When tissue from the lining of the uterus starts to grow outside it, fertility can be affected.
Dr. Omurtag is Fellow and Dr. Cooper is Assistant Professor, in Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO.

Endometriosis is one of the most difficult diseases faced by OBGYNs and primary care physicians – not to mention the women it affects. About 3-10% of women will develop endometriosis during their reproductive years. The number rises to 12-32% of women who have pelvic pain and 9-50% of women who cannot conceive.

Endometriosis is a chronic disease that can destroy a woman’s ability to have children, as well as cause considerable pain and irregular menstrual periods. It occurs when the tissue from the lining of the uterus (endometrium) migrates, implants, and starts to grow outside the uterus. It is generally benign. Tissue can migrate to and grow on the ovaries, bowel, bladder, and on the wall of the pelvis. Other symptoms include pelvic or abdominal pain, severe cramping for up to two weeks before and during menstruation, back pain, abnormal bleeding during periods, pain during intercourse and/or bowel movements, and infertility.

Because endometriosis is notoriously difficult to diagnose, doctors often use a progression of treatments to see what works and rule things out based on that.

Most experts believe that “retrograde flow” is a leading cause of endometriosis. Retrograde flow occurs when the tissues that are being shed by the body during menstruation flows “upwards” into the body cavity through the fallopian tubes, rather than out through the vagina. However, since retrograde flow is thought to occur normally in the vast majority of women (about 75-90% of women who menstruate), there must be more to the story. Many of the factors that lead to endometriosis are still being worked out, but our understanding has increased greatly in the last 20 years.

The Triggers: Immune System and Genetics

The immune system is believed to play a role in endometriosis risk. Some women may have immune system changes that could predispose them to endometriosis. For example, if the body’s immune system cannot effectively scavenge the “rogue” cells that migrate into the body cavity, endometriosis could develop. This idea is supported by the fact that links have been found between endometriosis and autoimmune diseases like Sjogren’s syndrome, rheumatoid arthritis, lupus and multiple sclerosis; and people with endometriosis appear to have molecular changes in their immune systems. Still, not all evidence supports this theory, and researchers are still working to discover other factors that are involved in the development of endometriosis.

Endometriosis often runs in families: women who have first-degree relatives with endometriosis are at higher risk of developing it. There are several genes that may be linked to elevated endometriosis risk, but much of the way in which endometriosis is handed down through generations is still unclear. Endometriosis remains a poorly understood condition in many ways, but in all likelihood, various aspects of genetics, anatomy, altered immunity, and the environment all play roles in the development of the disease.

Seeking Relief from Symptoms, A Case Study

Patients with endometriosis often desire two things from treatment: pain relief and pregnancy. Unfortunately, it is often the case that, the treatments may be in conflict with each other. Managing pain and/or infertility in women with endometriosis is very complex. Because endometriosis varies in both its severity and in one’s response to treatment, it is easy for patients and their doctors to become frustrated. Therefore, it is critical for one’s doctor to keep the patient’s short- and long-term goals in mind (for example, a woman’s desire to become pregnant) when managing the disease.

Surgical examination (via laparoscopy) is generally considered the gold standard means of diagnosis. Biopsies of the suspicious tissue can confirm endometriosis in 50-65% of cases.

Here, we’ll look at the experience of one woman, a composite case we'll call Brittany, with endometriosis who wishes to manage her pain and eventually become pregnant. Following her treatment history can help paint a more vivid picture of the current treatment options for endometriosis.

Brittany is a 23-year-old woman who has never had children and comes into our office because she has irregular menstrual cycles and experiences pain during sex. She has had little relief using over-the-counter (OTC) ibuprofen for her pain. She is also looking for reliable, effective contraception.

The Initial Workup

Doctors typically ask many questions about a patient’s medical history. A patient may be suffering from pelvic pain after menarche (her first period), urinary or bowel dysfunction or discomfort, and pain with intercourse. A pelvic exam can be uncomfortable for the patient, but is generally “unremarkable” to the doctor, in that nothing out of the ordinary is revealed. An ultrasound may be performed, but does not always find anything irregular, except in the instance of more advanced cases (more on this later).

Making the Diagnosis
Because endometriosis is notoriously difficult to diagnose, doctors often use a progression of treatments to see what works and rule things out based on that. Some women may response to non-steroidal anti-inflammatory drugs (NSAIDS) like ibuprofen combined with oral contraceptives. Sometimes seeing if symptoms diminish after a few months of gonadotropin-releasing hormone (GnRH) therapy may be helpful in diagnosing endometriosis. Since other conditions, like irritable bowel syndrome, may also respond to this treatment, additional methods for diagnosis are often needed.

There are also other ways to treat endometriosis using alternative methods. The most common recommendations for women are heat wraps and exercise, or at least increasing one’s physical activity.

Surgical examination (via laparoscopy) is generally considered the gold standard means of diagnosis. Biopsies of the suspicious tissue can confirm endometriosis in 50-65% of cases. After confirming that endometriosis is the cause of a woman’s symptoms and/or infertility, doctors generally rate the severity of the disease, which can influence treatment options.

Some rating methods are more successful than others, but recently the Endometriosis Fertility Index (EFI) was developed to predict pregnancy rate and remains the only effective endometriosis classification system to predict a clinical outcome.

Treating Endometriosis

Oral contraceptives and/or NSAIDS are often used to treat endometriosis, and about 80% of patients with known or suspected endometriosis try these lines of treatments. The two major lines of attack on endometriosis are to reduce inflammation and control hormone levels.

Attacking inflammation
Because inflammation is a major factor in endometriosis, reducing it in women with the condition is often a central goal. Based on the studies that have been done, there is no one type of NSAID that is more effective than others. Drugs like ibuprofen (Advil) and naproxen (Aleve) are often used first, since they are common and cost-effective. But it is necessary to speak with your doctor first before beginning any type of treatment, even OTC medications.

We often recommend combined oral contraceptive pills (OCPs) as initial therapy for women who are not seeking pregnancy, because there is a very high response rate: 75-90%.

There are also other ways to treat endometriosis using alternative methods. The most common recommendations for women are heat wraps and exercise, or at least increasing one’s physical activity. This is especially important in pain-free times, in order to improve any musculoskeletal factors (low back spasm or strain) that could be involved in pelvic pain. We recommend 30 minutes of exercise at least 5 days a week with moderate low back and hamstring stretches usually performed under the guidance of a physical therapist.

Attacking Hormone Imbalances
Estrogen can encourage the growth of endometriotic implants , so decreasing the estrogen environment is important. Estrogen comes from three places in women with endometriosis: (1) the ovary, (2) the normal conversion of male hormones to estrogen and (3) the tissues that become implanted outside the uterus. Reducing estrogen can be achieved in a number of ways.

We often recommend combined oral contraceptive pills (OCPs) as initial therapy for women who are not seeking pregnancy, because there is a very high response rate: 75-90%. The COCs contain both estrogen and progestins. No one formulation is superior to the other, although a recent study suggests that pill users may have more satisfaction then patch users. Additionally, it doesn’t seem to matter whether one uses cyclic or continuous delivery.. Given their effectiveness, some experts have proposed the use of COCs as a primary way to prevent endometriosis from developing in patients at higher risk for it (i.e., family history), although there’s still some question about whether this is the best idea.

Progestins by themselves (pill, injectable, implantable formulations) can also be used to treat endometriosis. Higher doses of progestin will stop ovulation and menstruation from occurring totally, which may result in pain relief. The levonorgestrel intrauterine device is also sometimes used to help patients with severe endometriosis that affects the vagina and rectum.

To Scope or NOT To Scope? (Part 1)
The big question is whether or not Brittany should have a diagnostic surgery (laparoscopy) at this point in time. Because Brittany is interested in birth control anyway and because nothing showed up on the physical exam or ultrasound, we recommended two to three months of COCs. If pain remains, however, the time might come for diagnostic surgery.

Our Clinical Case Continued: Surgical Options

Brittany tries the oral contraceptives but does not get immediate relief and eventually seeks a second opinion. There, she undergoes laparoscopy, and endometriotic lesions are removed. She was on oral contraceptive pills after surgery, and her pain relief was better, but now her pain has returned and she feels worse 12 months after surgery. ; She returns, stating that she was told she has severe endometriosis. She says that she would like to avoid further surgery. She is not currently trying to become pregnant, nor does she anticipate doing so during the next two to three years.

Surgery and Post-Operative Treatment
Surgical treatment varies depending on the severity of the disease. In women with less severe endometriosis, surgery is probably equal to medical treatment in terms of pain relief. Still, recurrence can occur in 10-20% of women within the first year.

In women with severe endometriosis-related pain, the goal of surgery is to restore the woman’s anatomy to normal. Hormone therapy like GnRH agonists, OCPs, and progestins, is often used to discourage growths from developing again, and to make for longer pain-free intervals. The type of medications one will be prescribed will vary, of course, on whether or not a woman wishes to become pregnant in the future or not.

Another Way of Attacking Hormone Imbalances
Brittany unfortunately falls into the 10-20% of women who have a recurrence of endometriosis. At this point she is a candidate for more aggressive hormone therapy; however, one’s doctor must always consider the patient’s plans for pregnancy. In this case, our patient is not interested in conception.

Danazol was the first FDA-approved drug for the treatment of endometriosis in the United States. It works by creating an environment in which there are high androgen levels, and low estrogen levels, which can be effective at keeping the disease under control. An undesirable effect of this hormone environment is weight gain, oily skin, decreased breast size, excessive hair growth, and other related symptoms. These can affect up to 80% of women in treatment. However, only 10% of women who experiences these side effects opt to discontinue the medication because of them .

Since Brittany does not see pregnancy in her near future, and wants to reduce her pain as much as possible (and avoid surgery), she wishes to try another hormone treatment. We prescribe her a regimen, commonly referred to as “GnRH plus add back,” and consists of a leuprolide subcutaneous injection monthly plus norethindrone acetate daily. Although this combination suppresses ovulation, it is not an approved form of contraception and women should use a back-up contraceptive method. Finally, women on this therapy should always be counseled about adequate calcium, vitamin D, nutrition and exercise recommendations to protect bone health long term.

Sometimes low-dose estrogen can be added to the treatment to reduce unwanted side-effects of the hormone treatment above. This regimen has not been approved by the FDA, but it is effective and has good evidence from clinical trials. Still, it’s generally reserved for specific situations, in which other treatments cannot be tolerated. The type of treatment a woman will be prescribed will vary on her specific case, her symptoms, history, and wish to have children or not.

Our Clinical Case Becomes More Complicated: Infertility

Brittany continued her hormone treatment for one year and experienced moderate relief from her pain. She also got married recently and life has changed. She is now ready to conceive. She wants to know whether the endometriosis will make it more difficult and what if any interventions might improve her chances of conception.

Endometriosis and Infertility
We’ve mainly focused on pelvic pain as the central complaint in endometriosis. But infertility can be as important an issue for women in their reproductive years. Estimates suggest that up to 40% of infertile women have the disease. Unfortunately, there’s not much evidence to suggest that “suppressing” endometriosis with medical management (for example, pain medication or hormones) will improve a woman’s fertility in the future.

In fact, patients with endometriosis and infertility might find medical management a drawback, since it suppresses ovulation. And along with the treatment comes the necessary sacrifice of time, which is a major enemy when trying to conceive, particularly in older women whose fertility declines with age.

Unfortunately, there’s not much evidence to suggest that “suppressing” endometriosis with medical management (for example, pain medication or hormones) will improve a woman’s fertility in the future.

In cases like Brittany’s, we would recommend stopping her medications and beginning timed intercourse (having sex at certain times of the month when ovulation is likely to be occurring). If she is not pregnant within one year (or 6 months given the fact that she has endometriosis, a risk factor for infertility), she deserves a workup with x-rays, assuming she is ovulating monthly. Her partner may be asked to have a semen analysis as well. Surgery may still be postponed until results from these tests return.

To Scope or NOT To Scope (Part 2)
Since Brittany is young and has not tried to conceive yet, we would postpone surgery. If the situation were different and she had already attempted pregnancy for at least 6-12 months or was older, more aggressive management might be warranted.

Some evidence suggests that women with unexplained infertility and mild endometriosis are twice as likely to conceive over a three-year period after lesions are removed in surgery than those whose lesions are left alone at the time of surgery – but other evidence has not found this to be the case. Some studies suggest a 30-50% pregnancy rate 1-3 years after surgery in women with moderate to severe endometriosis, but still, pregnancy rates for women with endometriosis are still somewhat unclear. The amount of pain a woman is in should be taken into account when making the decision of whether to undergo surgery.

Medical treatment of endometriosis should not be recommended as a means for improving pregnancy rates in patients with a mild form of the disease.

If the patient remains pain and symptom-free and has not conceived after one year, surgery (laparoscopy) may be offered, but we would generally proceed with hormone therapy (oral fertility medications and intrauterine insemination. For patients with longer histories of infertility and more severe endometriosis, we would consider moving directly to in vitro fertilization (IVF).

There is some debate about how effective IVF is for women with endometriosis compared to other infertility diagnoses – patients with severe endometriosis have a lower chance of pregnancy with IVF than those with infertility due to blocked tubes. As mentioned above, medical treatment of endometriosis should not be recommended as a means for improving pregnancy rates in patients with a mild form of the disease.

Clinical Case Conclusion

Brittany, unfortunately, did not have success in becoming pregnant after one year of unprotected intercourse. Her infertility workup did not show anything out of the ordinary, and she began a treatment of clomiphene citrate with intrauterine insemination (CC/IUI).

During a cycle, she noted increasing abdominal pain that was keeping her up at night. An ultrasound showed a 4.5-cm growth on her right ovary, which looked like it might be an endometrioma: an ovarian cyst that is common in endometriosis. At the time, she had completed two cycles of CC/IUI but had not yet become pregnant. After discussion the patient decided to proceed with IVF, but she was curious how we would approach the endometrioma.

The Endometrioma Question
Brittany’s experience highlights one of the biggest controversies in the management of patients with concurrent endometriosis and infertility. Removing a patient’s endometrioma cyst has generally been shown to improve her likelihood of becoming pregnant. Still, surgery remains controversial because it may damage the ovary and perhaps harm her reserve of eggs along with her response to hormone treatment during IVF. In patients whose endometriomas do not produce symptoms, one could argue that the only reason to pursue surgery would be to confirm the diagnosis.

It’s important to stress that a woman’s feelings about having children should be an important consideration in designing a treatment with one’s doctor. In patients with minimal pain and unexplained infertility, there may be a benefit to removing endometriotic lesions surgically.

Some experts feel that endometriomas should be removed prior to IVF if they are larger than 4 cm, although this remains controversial. And again, the degree of pain the woman experiences drives the intervention. Because the pain is disrupting her daily life, Brittany may benefit from removal of her endometrioma. If her pain was not bothersome and she was preparing for IVF, we would likely skip surgery and proceed with IVF. Ultimately, one should have an extensive risk/benefit discussion with one’s doctor, keeping at the forefront the fact that without surgery the endometrioma will not go away by itself.

New Understanding is Improving Outcomes

Whereas surgical management was once the go-to treatment for patients with pain, there are not many more options for medical management. As we discussed, birth control pills and NSAIDs provide frontline treatment, while the use of GnRH agonists with “add-back” therapy are second line treatments best prescribed by gynecologists who are familiar with these methods.

It’s important to stress that a woman’s feelings about having children should be an important consideration in designing a treatment with one’s doctor. In patients with minimal pain and unexplained infertility, there may be a benefit to removing endometriotic lesions surgically. There is still debate about how to manage endometriosis in patients undergoing IVF, particularly in more severe cases and if endometriomas are present. These cases are best managed individually in consult with a reproductive endocrinologist.

There is still much to learn about why endometriosis occurs in the first place. But newer clues, like altered functioning of the immune system and certain genetic factors, are helping us understand and manage the disease more effectively. The management of pain and infertility that are associated with endometriosis has evolved dramatically over the last 20 years. Based on what we are learning every day about the disease, we expect the next 20 years to provide even deeper insights into non-invasive diagnosis and more effective treatments for the women who are affected by endometriosis.

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