Looking for a better way to manage endometriosis- related pain

By Craig A. Winkel, MD, MBA

Why do some women have debilitating symptoms while others don't even realize they have the disease? In light of unanswered questions on the effectiveness of medical versus surgical treatment, an expert proposes a conservative strategy that begins with medical therapy and proceeds to laparoscopy.

A growing public health problem, endometriosis is a leading cause of hysterectomy and the number three reason women are hospitalized during their childbearing years.¹ And the numbers have climbed steadily over the past 10 to 15 years. Nearly one of every two women may now be affected. It's unclear whether this rise is a result of our better ability to recognize the disease, the growing number of laparoscopic procedures, or the emergence of predisposing factors. But one thing is clear: Patients and physicians are becoming more aware of the disease. On the plus side, we better understand the mechanisms by which this disease arises, and we know more about the immunological processes involved in its progression and about its associated conditions, too.

But progress in the clinical management of women with this condition is another story. We can't say whether medical or surgical management offers the better outcome for pain management. Nor can we confidently document the benefits of surgical therapy in a woman with reduced fecundity. Finally, we still don't know why some women with endometriosis have debilitating symptoms while others go about their daily lives oblivious to the fact that they even have the disease.

The prevalence of endometriosis and the large proportion of women with this disease who complain of related symptoms create a significant public health issue. An estimated 45% of women have endometriosis based on laparoscopic visualization of lesions with the appearance of endometriosis.^2,3 The high hospitalization rate during childbearing years cited earlier is for endometriosis-related complaints of pain, infertility, and dyspareunia, and development of pelvic and ovarian masses.¹ Total annual costs for inpatient care of women with endometriosis-related problems were estimated at $579 million in 1992.⁴ Fifteen percent of women between 18 and 50 years complain of pelvic pain while only 25% of those women seek gynecological care.⁵ Not surprisingly, given the more than 62 million American women between those ages, the direct costs of care for all women with chronic pelvic pain (most of which may be endometriosis-related) is estimated at $2.8 billion. On top of that, indirect costs come to an additional $600 million.⁶

Women with endometriosis commonly complain of chronic pelvic pain, but other causes of pelvic pain are often seen among this group. Irritable bowel syndrome (IBS) is one example, although any causal link between that condition and endometriosis is unproved. Interstitial cystitis (IC) and fibromyalgia also occur in women with pelvic pain. When managing women with endometriosis and pelvic pain, it's critical to eliminate other conditions like those mentioned above.

Pain therapy falls into two general categories: medical and surgical. Unfortunately, no head-to-head, prospective, randomized controlled trials (RCTs) compare these two options. Moreover, the published data are often conflicting and even confusing. Consequently, treatment frequently fails to alleviate symptoms, frustrating physician and patient alike.

Clearly a strategy for evaluating and managing endometriosis can only be as good as our current understanding. My goal here is to review our knowledge of this condition, citing pertinent evidence, and discuss medical and surgical treatments. I'll then offer my own strategy for managing pain associated with endometriosis, which diverges somewhat from usual approaches.

Treatments for endometriosis

Endometriosis can be observed at the time of laparoscopy in 78% to 86% of women who have chronic pelvic pain.⁷ It can also be observed laparoscopically in 45% of asymptomatic, fertile women undergoing tubal ligation and, surprisingly, it may be present in 25% of women with no visible lesions.^1,8 To add further confusion, the positive predictive value of laparoscopic visualization of endometriosis lesions is only 43% to 45%.^9,10

Given these statistics, diagnostic inaccuracies can confound much of the available data on various treatment modalities, if histological proof of endometriosis is not required for patients' inclusion in clinical trials. Regardless of whether the treatment studied is medical or surgical, the data are only as good as the accuracy of the diagnosis.

Medical approaches

Medical treatments are based on the presumption that endometriosis requires cyclic estrogen action to remain active as a disease. Thus, therapies usually aim to create a pseudopregnant state (typically through the use of oral contraceptives or progestins) or a pseudomenopausal state—through the use of danazol or GnRH analogs.⁶

OCs. Most gynecologists are quite experienced in prescribing OCs, making the Pill probably the most common medical therapy for women with endometriosis-related pain. Frequently used in combination with NSAIDs, OCs are effective in managing dysmenorrhea.¹¹ While there are no prospective trials to compare cyclic and continuous OCs, continuous therapy (skipping the placebo pills) makes the most sense, theoretically, with a goal of inducing amenorrhea. OCs in conjunction with nonsteroidal anti-inflammatory drugs (NSAIDs) are an appropriate first-line therapy for a woman with endometriosis and pelvic pain. If her symptoms do not respond within 3 months, consider a second-line medical therapy. No scientific rationale exists for trying a different OC formulation if the one tried fails to reduce symptoms.

Progestins. Both orally administered and parenteral progestins are also effective therapies. Medroxyprogesterone acetate (MPA), when administered orally in daily doses up to 50 mg, significantly reduces pain.¹² Depot medroxyprogesterone acetate (DMPA) is effective as well.¹¹ High doses of progestins result in downregulation of the pituitary gonadotrophs and decrease ovarian steroidogenesis. DMPA and large oral doses of MPA commonly induce amenorrhea through direct suppression of the endometrium and may thus directly suppress endometriosis lesions.

Danazol. An inhibited androgen, danazol is effective for managing endometriosis-related symptoms as well.¹³ Acting through pituitary downregulation, the drug suppresses gonadotropin and decreases ovarian function. It also affects the immune system and theoretically inhibits the immunological response to endometriosis lesions.

GnRH analogs. These include both agonists and antagonists. The action of long-acting agonists on the pituitary gland is similar to that observed during continuous GnRH stimulation, namely, diminished biosynthesis and secretion of FSH and LH.¹⁴ As a result, the ovaries don't receive pituitary stimulation and remain quiescent, producing little estrogen, androgen, or progesterone. GnRH antagonists directly inhibit GnRH action on the pituitary and have an effect much like GnRH agonists. Although the GnRH antagonists act immediately, GnRH agonists take 10 to 14 days to induce pituitary downregulation.

Side effects. Prospective RCTs suggest that the second-line medical therapies (MPA, danazol, GnRH analogs) are about equally effective in reducing pain symptoms.⁶ Therefore, the significance of side effects seems to be the key factor to consider when selecting one of these drugs. Like most medications, each does have side effects. For example, DMPA is associated with irregular uterine bleeding, weight gain, fluid retention, and unpredictable return of pituitary-ovarian function. If a patient experiences these side effects, the only effective means for managing them is to discontinue the drug.

The side effects associated with danazol are related to its inherent androgenicity. Some women experience anabolic effects, hirsutism, acne, weight gain, and pigmentation changes. Again, if a patient experiences these side effects, your only course of action is to discontinue the drug.

GnRH analogs cause ovarian quiescence and symptoms of estrogen deficiency such as vasomotor instability, vaginal dryness, arthralgia, myalgia, and decreased libido. These can be effectively ameliorated by adding an oral progestin to the regimen or a combination of low-dose estrogen and progestin similar to that prescribed for menopausal symptoms. Add-back therapy is successful in reducing side effects with GnRH analogs and reducing bone demineralization while maintaining therapeutic effectiveness.¹⁵ There are no comparative trials to determine which add-back therapy is the best. Do not use OCs formulated with estrogen and progestin as add-back therapy, however, since the estrogen dose in OCs is high enough to stimulate endometriosis lesions.

Surgical approaches

To date no RCTs have compared the effectiveness of medical and surgical therapies for managing endometriosis-related pain. Most surgical studies are retrospective, reported by the very best surgeons with great breadth of experience, and often confounded by the addition of adjunctive procedures in addition to destruction or excision of endometriosis lesions.

Surgical therapy for women with endometriosis is based on the concepts that lesions can be observed at the time of surgery and can be destroyed or excised using some predefined technique. While the two surgical approaches to pelvic endometriosis—laparotomy and laparoscopy—appear to reduce symptoms to a similar extent, most gynecologists and patients prefer the minimally invasive approach.^16-18

With the preference for laparoscopy, a shift in thinking regarding diagnosing and treating lesions has occurred. Reports of the "protean appearances" of endometriosis and subsequent educational materials have ensured that most gynecologists today are aware of the many possible appearances of lesions.¹⁹ Nearly every study on surgical treatment of endometriosis relies on visualization at the time of the surgical procedure as a diagnostic criterion. In some, histological confirmation also was required.

We know, however, that endometriosis implants are often found in asymptomatic women presenting for tubal ligation.¹ The presence of implants, then, is not equivalent to a diagnosis of endometriosis as a cause of pain. Moreover, we must question the accuracy of visualization, since excised visible lesions that are then histologically examined are often not confirmed histologically.^9,10 Indeed, while on the one hand, the black lesions in the posterior cul-de-sac are commonly confirmed histologically, the more subtle red, clear, and white lesions frequently are not.^9,10

Identifying the best technique for surgically managing endometriosis lesions is difficult. Are lesions best managed by excision, by laser or electrosurgical ablation, dessication, or vaporization? Unfortunately, data are limited from which to answer these important questions. They are largely retrospective, uncontrolled studies subject to biases in choice of technique, patient selection, and method of follow-up. In addition, proponents of a given technique often report only on their "pet" approach.

Currently, the results of only one prospective RCT comparing surgery to sham therapy for endometriosis-related pain are available.²⁰ The authors found that laser ablation in conjunction with laser uterosacral nerve ablation (LUNA) was significantly more effective than sham surgery.²⁰ Three months following surgery, 56% of the treated women reported pain relief but so did 48% of the sham-operated women, a difference that was not significant. Six months following surgery, 62.5% of the treated women reported continued pain relief while significantly fewer (22%) of the sham-treated women continued to report pain relief. These results are confounded by the addition of LUNA to endometriosis ablation—making it impossible to determine whether lesion ablation, LUNA, or a combination of both led to the results observed. Importantly, LUNA alone and presacral neurectomy alone have not proved effective for managing endometriosis-related pain, although they are somewhat successful in managing dysmenorrhea.²¹

A number of other studies address the merits of surgical treatment of endometriosis, but as already noted, they are uncontrolled time series or retrospective reports. Redwine suggested that laparoscopic excision of endometriosis resulted in a cumulative recurrence rate 5 years postsurgery of only 19%. These results, however, were based on repeat laparoscopic visualization of endometriosis rather than assessment of pain symptoms.²² Other investigators found that 70% of women were pain-free 1 year following CO₂ vaporization of lesions.²³ Another study compared the results of excision of lesions to ablation of lesions alone or followed by treatment with a GnRH agonist.²⁴ At the end of a 2-year follow-up, 23% of women who'd had lesions excised had pain recur compared to 69% of women who'd undergone ablation alone. Interestingly, pain recurred 24 months following the end of treatment in only 31% of women who had had ablation followed by treatment with a GnRH agonist. Thus, ablation plus treatment with a GnRH agonist seems to yield results tantamount to those observed after excision of lesions.

The efficacy of the above approach was the subject of a randomized, placebo-controlled trial. Hornstein and colleagues reported on the percentage of women treated with a GnRH agonist following laser ablation of endometriosis whose pain recurred sufficiently to require pain medications. They found it to be significantly less (31%) than that of women treated by ablation of lesions alone (57%) 24 months following surgery.²⁵

When considering treating women with endometriosis surgically, it is important to recognize the complications associated with laparoscopy in general and operative laparoscopy procedures specifically. Most gynecologists feel relatively comfortable performing laparoscopy and ablation of lesions. Excision of endometriosis lesions, on the other hand—and especially deep lesions in the posterior cul-de-sac and along the pelvic sidewalls—requires greater technical skill and is more likely to cause serious complications. Even in the hands of excellent surgeons with vast experience, the extensive dissection required to excise deep endometriosis is associated with high rates of bowel injury (6%) and ureteral injury (0.5%).²⁶

Laparoscopy per se causes more complications than is commonly discussed. For example, among more than 2,000 gynecologists surveyed in 1999, 5% reported major vascular injuries, 3.8% reported ureteral injuries, and 17.5% cited bowel injuries during laparoscopy.²⁷

A treatment strategy for managing pain

Given the available data, a strategy for the evaluation and management of a woman with chronic pelvic pain associated with endometriosis should begin with a thorough work-up and physical examination (Figure 1). Pay special attention to eliminating conditions such as fibromyalgia, IBS, and IC that may be confused with endometriosis. If the patient's physical examination is not normal, order appropriate imaging and other laboratory studies. Then, if all is normal and she is not trying to conceive, consider using continuous OCs as your first line of therapy, in conjunction with an NSAID. Among women undergoing such a structured evaluation—barring the discovery of another condition—endometriosis will be confirmed in 78% to 96%.⁷

If initial therapy fails to relieve pain symptoms, test a second-line drug. While MPA, danazol, and GnRH agonists appear to work equally well, side effects are managed best if you opt for a trial of GnRH agonist. Combat its side effects with a concurrent add-back regimen that will not compromise therapeutic effectiveness. Note that GnRH antagonists are now available and might be substituted for agonists.

If treatment with a GnRH analogue relieves pain, you can then be reassured that the woman's disease is behaving as would be expected of endometriosis. But if GnRH analogue therapy fails to bring relief, reconsider the results of the previous evaluation to confirm that you haven't missed some other cause of pain. Some would recommend laparoscopy at this time to rule out the possibility of pelvic adhesive disease.

For the patient with pain who wants to achieve pregnancy as soon as possible, surgery would seem more appropriate. At the same time, you must consider the relationship between endometriosis and fertility. Many investigators believe that the cascade of events associated with the pathophysiology of endometriosis is related to the infertility that some researchers suspect is associated with endometriosis.²⁸ Most recent data are conflicting regarding how destruction of endometriosis lesions affects subsequent fertil-ity in women who lack any anatomical abnormality to explain the infertility. On the one hand, a Canadian RCT suggested that destruction of lesions among such women improves fecundity, while on the other, a similarly designed Italian study found no improvement in fertility after lesions were destroyed.^29,30 Therefore, laparoscopy seems unwarranted for infertile women on the chance of finding endometriosis. If endometriosis is found at the time you perform laparoscopy on an infertile woman for some other indication, however, destroying the lesions will not likely reduce her chances for conception and might even increase them.

This strategy is somewhat of a departure from the status quo, even though most gynecologists practice according to their own interpretation of clinical information. The American College of Obstetricians and Gynecologists has affirmed that treatment of endometriosis on the basis of clinical diagnosis is appropriate provided a thorough evaluation has failed to demonstrate some other cause for pain.³¹ In addition, a recent consensus panel, composed of practicing gynecologists from across the US and based upon review of the appropriate literature, recently recommended a similar strategy for treating women with chronic pelvic pain believed to be associated with endometriosis.³²

What we do—and do not—know

There's still a great deal we need to learn about endometriosis. Why some women with endometriosis lesions are symptom free and others are debilitated by pain remains a major question. Whether endometriosis causes infertility in women without anatomic abnormalities is unknown. In fact, we could develop a long list of questions regarding this disease, the answers to which remain unknown. Perhaps as we learn more about this disease, treatment strategies will change. At the present, however, and until the results of comparative trials emerge, a conservative approach that begins with medical therapy and proceeds to laparoscopy seems prudent given that the outcomes with surgery seem to be no more impressive than those following treatment with second- line medications. Clearly, the risks of complications are considerably less with medical therapy than with extensive surgery.

Key points

REFERENCES

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Dr. Winkel is a paid consultant to and serves on the Speakers Bureaus of TAP Pharmaceuticals, Ortho McNeil, and Wyeth-Ayerst.

Dr. Winkel is Professor and Chairman, Department of Obstetrics and Gynecology, Georgetown University School of Medicine, Washington, D.C.

Craig Winkel. Cover Story: Looking for a better way to manage endometriosis-related pain.

Contemporary Ob/Gyn

Apr. 1, 2003;48:44-56.