ENDOMETRIOSIS MANAGEMENT OPTIONS

Assessment of the reproductive goals of the endometriosis patient is necessary in order to determine the best treatment. Treatment objectives are to remove or destroy endometrial implants, relieve symptoms, maintain or restore normal anatomy, maintain or improve fertility, and avoid or delay recurrence of the disease.

Reflective of its elusive pathophysiology, treatment options for endometriosis are varied and numerous and can be divided into symptomatic treatment including analgesia with non-steroidal anti-inflammatory drugs (NSAIDs) or low dose intermittent narcotics, ovarian suppression, surgical treatment, combinations of the latter two, ovarian stimulation and/or the assisted reproductive technologies. Since some of the treatments prevent pregnancy and others are specifically directed at achieving conception, thorough knowledge of the patient's objectives are essential. ?

SYMPTOMATIC TREATMENT

Expectant management, and/or limited use of analgesics and NSAIDs do not treat disease but alleviate symptoms. These may be especially helpful for women with dysmenorrhea associated with endometriosis.

OVARIAN SUPPRESSION

Ovarian suppression can consist of oral contraceptives (OCs), progestins, danazol, GnRH agonists or GnRH antagonists. Oral contraceptives can be given cyclically, but many patients do better with continuous active ingredient tablets for three months, followed by withdrawal, and then repetition. The most commonly used progestin is medroxyprogesterone acetate (Provera). Progestins alone may be useful in a few women who cannot tolerate oral contraceptives.

Danazol (Danocrine), 200-400 mg twice a day, is an isoxazol derivative of 17 alpha-ethinyltestosterone. Side effects include increased hair growth, mood changes, depression, and an adverse effect upon serum lipid profiles.

?Gestrinone (ethylnorgestrienone) is a 19-nortestosterone derivative that acts as an androgen receptor agonist and a progesterone receptor agonist/antagonist, the net result being amenorrhea. The potential side effects are androgenic and anti-estrogenic, similar to those of danazol, tend to be mild and transient, and less frequent than danazol.

?GnRH agonists are synthetic decapeptides. Nafarelin acetate (Synarel) 200 m g nasal spray used twice a day while leuprolide acetate (Lupron Depot) is usually given as a single monthly 3.75 mg intramuscular injection or sometimes a single 3-month injection. Side effects include hot flashes in about 90% of patients, decreased libido, vaginal dryness, mastalgia, joint stiffness, skin changes, headaches, fatigue, emotional lability, and insomnia. Cardiovascular and liver enzyme parameters show favorable changes relative to danazol. The major concern with GnRH agonists is the loss of bone density, about 3-8%, which occurs over 6 months of drug therapy, with a 2-3% loss persisting about one year following treatment. Hot flashes can be effectively managed with norethindrone (Micronor) 2.5 mg per day. Higher doses of norethindrone may provide some protection against bone loss, but have an unfavorable side effect profile for liver and cardiovascular systems, and patients are often very symptomatic. Low doses of estrogen (Premarin 0.6 mg per day) have also been used as "add-back" therapy to reduce bone loss and show some promise. More recently add-back therapy for 6 to 12 months with norethindrone 2.5 mg to 5 mg and alendronate 10 mg per day has been suggested, along with calcium 1,000 mg per day.

A new therapeutic class of drugs, the gonadotropin releasing hormone (GnRH) antagonists have significant physiologic differences with the widely used GnRH agonists. While the agonists cause an initial flare or stimulatory response with subsequent down-regulation and inhibition, the antagonists cause prompt competitive inhibition of native GnRH actions. The antagonists may therefore be given later in the follicular phase when suppression of luteinizing hormone (LH) is required, allowing endogenous LH and follicle stimulating hormone (FSH) to be present early in the cycle. Gonadotropin releasing hormone antagonists (GnRH antagonists) such as Antagon and Cetrotide are just being introduced into clinical care. Their potential advantages and disadvantages for endometriosis treatment have yet to be determined, but their immediate down-regulation effect and resulting hypoestrogenemia may be beneficial in some endometriosis pain patients.

SURGERY

Most patients undergoing endometriosis surgery wish to have disease alone removed and retain functionality of their pelvic organs. For some, however, hysterectomy and/or oophorectomy is a reasonable approach if other treatments have failed and/or other indications for extirpation exist. At the time of surgery all lesions should be treated regardless of whether or not organ extirpation is performed. Elimination of endometrial implants may be achieved via laser ablation, sharp resection, or electrosurgery

Prior to the advent of laparoscopy, laparotomy was the treatment of choice for advanced endometriosis. The main advantage over laparoscopy is the ability of the surgeon to directly palpate different structures. Laparotomy may also be preferred in cases requiring removal of large endometriomas or in cases deemed too complex for laparoscopic treatment such as bowel resection.

Diagnostic laparoscopy provides a relatively safe and simple method of diagnosing endometriosis. When appropriate, operative laparoscopy enables treatment to be initiated and possibly completed at the same time. Medical and surgical treatment modalities sometimes produce similar results, but surgical treatment completed at the time of diagnosis has a distinct advantage over medical therapy because of decreased time, cost, and side effects. The patient can also be spared a second operation (laparotomy) if operative laparoscopy can be performed at the time of diagnosis. Operative laparoscopy offers several advantages to laparotomy, primarily because of better visualization, less tissue trauma, and much shorter recovery time. The guiding surgical principle is complete removal of all endometriosis lesions, fibrosis, and adhesions, including those requiring deep dissection.

Adhesions can disrupt normal anatomic relationships and restrict the mobility and distensibility of organs, potentially resulting in pain. A correlation, however, between the extent or location of adhesions and the severity of pain has yet to be demonstrated. Despite the uncertainty in the relationship between adhesions and pain, lysis or removal of adhesions is reasonable in the setting of endometriosis-associated pain, especially when the location of adhesions and pain correlate.

COMBINED OVARIAN SUPPRESSION AND SURGERY

Laparoscopic treatment of endometriosis may sometimes be combined with ovarian suppression. The purpose of combined treatment is to improve treatment success or facilitate surgical procedures, for example by preventing functional ovarian cysts so that they are not present or confused with endometriosis. Metastatic or extensive superficial disease is suppressed and becomes atrophic. Other uses of GnRH agonists prior to surgery include reduction of symptoms, increased time for adequate preoperative evaluation, easier scheduling of surgery, and even delay or avoidance of surgery for a woman approaching menopause. Postoperative ovarian suppression may be indicated if complete resection of disease has not been accomplished, for treatment of microscopic or metastatic disease, or for treatment of pain. Preoperative or postoperative treatment is usually given for 2 months to 6 months, but 3 months is adequate for most patients. A very successful treatment approach is to use oral contraceptives continuously for 3 months, withdraw for one week, and repeat the 3 months of treatment. This cycle can be continued even to menopause or to the time of attempting pregnancy. It is the most cost-effective approach for many patients.

CONTROLLED OVARIAN HYPERSTIMULATION

Controlled ovarian hyperstimulation (COH) is the intentional induction of multiple ovulation to increase the number of eggs which are ovulated in an otherwise normally ovulating woman. COH is often carried out with intrauterine insemination (IUI) with prepared sperm. COH-IUI may be helpful for women with stage I-II endometriosis. Generally, three to six cycles of COH-IUI are clinically appropriate. A maximum number would be six cycles of CC-IUI and six cycles of hMG-IUI in selected patients.

ASSISTED REPRODUCTIVE TECHNOLOGIES

Results for 1997 from the United States IVF Registry gave a 27.9% delivery rate per retrieval for IVF, a 30.0% delivery rate for GIFT, and a 28.0% rate for ZIFT. There is only a slight reduction in the success rates with IVF with increasing numbers of cycles, each cycle after the first having approximately 90% the success rate of the first. An increasing duration of fertility also decreases success rates. Previous pregnancy and live birth increases success rates slightly.

COMPREHENSIVE MANAGEMENT APPROACH

It is critical that physicians recognize the degree to which endometriosis can physically and emotionally disrupt patients’ lives, and provide comprehensive understanding and an empathetic management approach. Attention to healthy lifestyle with respect to diet, exercise, sleep, and stress reduction through mind-body techniques can be very helpful. Focus on a better quality of life as defined by what the patient wants to do, such as whether she gets to school or work every day, is a more useful measure of outcome.

TREATMENT OUTCOMES

PAIN OUTCOMES WITH OVARIAN SUPPRESSION

No treatment and/or mild analgesics or NSAIDs may be entirely appropriate for many young patients with minimal symptoms or for women who have just completed a course of ovarian suppression. Women who remain symptomatic with minimal or mild pain may frequently be successfully treated with cyclic oral contraceptives, and this treatment should be attempted in most women.

Placebo-controlled studies have demonstrated that medroxyprogesterone acetate, 100 mg/day, danazol, 600 mg/day, nafarelin acetate 200 μg twice daily and leuprolide acetate 3.75 mg/month for six months produce significant and substantial improvement in pain scores for 70 to 90% of patients. Six months following discontinuation of treatment about two-thirds of patients experience dysmenorrhea, about half have pelvic pain and one-third have dyspareunia. Endometriosis recurs annually in 5% to 20% of patients, reaching a cumulative rate as high as 50% at 5 years following completion of conservative therapy, comprised of about 35% for minimal disease and 75% for severe disease. Therefore, ovarian suppression therapies are superior to placebo in the treatment of endometriosis-associated pain, and all the medications are approximately equivalent.

PAIN OUTCOMES WITH SURGICAL TREATMENT

There are limited data from good studies to evaluate the outcome of pain relief following surgery for endometriosis. Laparoscopic and laparotomy treatment appears effective with approximately 60 to 90% of patients showing significant clinical improvement following complete resection of disease. Approximately 60% to 90% should have reasonable symptom relief at one year and 50% to 80% at 5 years and 50% at 10 years if the disease is completely resected. Pain relief is often initially better in patients with more severe disease, but patients with more severe disease are at higher risk of recurrence than those with mild disease. Recurrence rates overall are approximately 10% to 20% per year.

A relationship between the extent or location of adhesions and the severity and duration of pain has not been demonstrated. Despite this uncertainty regarding the relationship between adhesions and pain, lysis of adhesions appears reasonable in the presence of endometriosis-associated pain, especially when the location of adhesions and pain correlate.

Endometriosis-associated pain may be effectively reduced by definitive surgery with hysterectomy and/or salpingo-oophorectomy. Pain relief following hysterectomy will be observed in up to 90% of patients and elimination of dyspareunia in 66%. Symptoms recur in 15% and additional surgery is needed in 5% to 10% of patients. If the ovaries are removed, the recurrence rate is about 8% and the reoperation rate about 3% to 5%. Properly performed initial surgery appears superior to medical treatment for pain, especially in patients with more severe disease, but not necessarily in patients with chronic pelvic pain and minimal or mild disease, especially once that disease has been initially resected.

PAIN OUTCOMES WITH COMBINED OVARIAN SUPPRESSION AND SURGERY

Three randomized, placebo-controlled trials have evaluated the use of post-operative medical therapy as a means of further providing pain relief. The results fail to present a consistent view of the value of combination therapy; further studies are needed to clarify the picture.

OUTCOMES FROM OVARIAN ENDOMETRIOMA TREATMENT

Due to the ineffectiveness of medical treatment in eradicating endometriomas, traditional therapy has required laparotomy. The improvement in laparoscopic technique and technology has allowed the advanced treatment of endometriomas. Pain relief following surgery has been observed in approximately 60% to 100% of patients.

Pregnancy rates following endometriomectomy at laparoscopy or laparotomy are approximately 50% at 2 to 3 years by life-table analysis, and are not dependent on the number or size of endometriomas, but can be affected by the extent of adhesive disease. Resected endometriomas have been shown to have a recurrence rate of approximately 10%, with an approximately 20% incidence of de novo adhesion formation and an approximately 80% incidence of partial dense adhesion recurrence.

INFERTILITY OUTCOMES WITH OVARIAN SUPPRESSION

Four randomized trials have compared ovarian suppression with placebo or no treatment and eight have compared ovarian suppression medications with danazol. All have been summarized in a meta-analysis by Hughes, et al. The results of our meta-analysis also provided strong evidence that there was no significant difference in crude pregnancy rates between medical treatment and no treatment (Figure 1). The combined estimated risk ratio was 0.98 with a 95% confidence interval of 0.81 to 1.18. No increase in fertility can be demonstrated with these medications when compared with expectant management; nor has any medication proven superior to danazol in this regard. Use of ovarian suppression also delays fertility in that the patient is unable to conceive while being medicated for several months. There is also additional cost and associated side effects, including bone loss. Thus, there appears to be little or no role for primary medical therapy in the treatment of endometriosis-associated infertility. A summary of the meta-analysis estimates for the various comparisons is presented in Figure 1.

INFERTILITY OUTCOMES WITH SURGERY

In light of the difficulties in evaluating the data in the literature, the lack of rigorous clinical studies showing an improvement in fertility, and the variable length of follow-up in infertility studies, the conventional wisdom has been that surgical treatment for minimal or mild endometriosis does not confer an advantage over expectant management. A meta-analysis of non-randomized trials suggested that surgical treatment of early-stage endometriosis-associated infertility might be of value; however, there was sufficient heterogeneity among the studies to diminish confidence in such a conclusion. The average pregnancy rate from several studies evaluating the surgical approach was approximately 58% compared with an average pregnancy rate following expectant management of approximately 45%. (Table 1) However, the average monthly fecundity rate (in which it could be calculated) for expectant management was 6.8%. This was not significantly different than the monthly fecundity rate following surgery. Thus, the effectiveness of surgery for minimal or mild endometriosis has been difficult to demonstrate.

Recently, data have been reported that support the surgical approach to infertile patients with minimal or mild endometriosis. In a prospective, multicenter, double-blinded, controlled, randomized study by Marcoux and colleagues in a Canadian collaborative trial named ENDOCAN, surgical treatment by laparoscopy resulted in a significantly higher pregnancy rate (37.5% vs. 22.5%, p=0.002). This study provides convincing evidence that surgery is beneficial in the treatment of minimal or mild endometriosis-associated infertility. Shortly thereafter, however, a second multi-center study demonstrated a live birth rate of 19.6% in the treatment group and 22.2% in the controls within one year of surgery. In summary, the issue of efficacy of surgery in the enhancement of early-stage endometriosis-associated infertility remains unclear. There may well be an advantage to treatment, but its effect is likely small. Even if ENDOCAN is correct, the number needed to treat (NNT) to produce one additional pregnancy is 7.7 surgeries.

It is widely accepted that endometriosis of sufficient severity to cause distortion of the pelvis (Stages III and IV) impairs fertility by interfering with oocyte pickup and transport. The available evidence supports the surgical approach compared with the nonsurgical approach for invasive, adhesive, and/or endometriotic disease.

Patients with endometriosis as the only infertility factor have similar crude pregnancy rates for all stages whether treated with laparoscopy or laparotomy. Life-table analysis of patients without other infertility factors, however, revealed that laparoscopy was similar to laparotomy for minimal/mild disease and superior to laparotomy for moderate/severe disease. Survival analysis with multiple fixed covariates concur with these findings in that laparoscopy was significantly better than laparotomy in the endometriosis-only group (87% higher pregnancy rate, p = 0.031).

INFERTILITY OUTCOMES COMPARING SURGERY WITH OTHER TREATMENTS

Results of endometriosis treatment with surgery, and laparoscopy in particular, appear superior to all other types of treatment. This conclusion is based on numerous large studies, including life-table analysis, survival analysis with fixed covariates, meta-analysis, prospective randomized trials, and summary of all the literature. Each study has its own deficiencies, but all have shown results favoring surgery. Pregnancy rates following medical treatment usually are 5% to 10% lower at 2 years, and the pregnancies take longer to occur, especially with medical treatment that consumes 6 or more months of time.

INFERTILITY OUTCOMES WITH OVARIAN STIMULATION

Controlled ovarian hyperstimulation can be performed with either clomiphene citrate (CC) and/or gonadotropins, often in conjunction with intrauterine insemination (IUI). These treatments are intended to increase the overall fecundity and do not cause regression of endometrial implants. (Table 2) Randomized trials have addressed the value of ovulation induction, and two have combined it with intrauterine insemination. These data suggest a control population fecundity of 2% to 4.5% per cycle and treated population of 9.5% to 15%. From these results it is apparent that fertility can be hastened in women with endometriosis by using COH and IUI. There is a wide range of success reported with cycle fecundity with CC-IUI increasing the baseline fecundity from 25% to 200%, and with gonadotropins increasing the baseline fecundity from 50% to 400%. The addition of intrauterine insemination appears to be increase pregnancy rates only slightly with clomiphene but possibly double the success with gonadotropins. Baseline cycle fecundity may range from 0 to 2% per cycle with severe endometriosis to 6% to 8% per cycle for minimal endometriosis in women less than 30 years of age. In patients without significant anatomic distortion, it could be expected that CC-IUI might create a fecundity rate of 6% to 8% per cycle or higher, and gonadotropins 12% to 20% per cycle. Randomized controlled studies of COH/IUI treatment in moderate or severe endometriosis are lacking. The expectation, however, would be for no improvement in pregnancy rates because of the high probability of significant anatomic distortion that could interfere with the mechanism of oocyte transport to the fallopian tube.

INFERTILITY OUTCOMES WITH ART

Results for 1997 from the United States IVF Registry gave a 27.9% delivery rate per retrieval for IVF. Pregnancy rates depend on patient age, ranging from about 35% per cycle at age 30 to 15% per cycle at age 40. There are no convincing data that one type of ART is superior to another. The impact of the diagnosis of endometriosis on outcomes with IVF treatment is not yet clear. With respect to endometriomas, there are no randomized trials and cohort data are conflicting. Small endometriomas may not matter and large endometriomas may. Pelvic abscess has been reported following egg retrieval in patients with endometriomas, thus providing a potential indication for pre-IVF surgical treatment in some patients.

While it is probably self-evident that IVF is of value in advanced disease due to the very low background pregnancy rate and the tangible rate of success with the procedure, the value of this approach in early-stage disease is as yet unproven. In other words, while pregnancies certainly occur quite rapidly with IVF in women with endometriosis or any other diagnosis, it is unclear whether one cycle of IVF is comparable to one month, six months, two years or longer of attempting conception naturally.

Overall, while IVF is clearly worthwhile, its degree of value, cost effectiveness, and optimal method of employment has not yet been satisfactorily answered.

 

ALGORITHM FOR MANAGEMENT OF ENDOMETRIOSIS

Endometriosis is obviously an extremely complex medical condition and treatment is similarly complicated. Treatment needs to be based on each patient’s individual circumstances and objectives. (Table 3) However, the following algorithm is suggested as a possible model that can be modified for individual patients. (Figure 2)

FIGURE 1

SUMMARY OF META-ANALYSIS ESTIMATES OF RELATIVE RISK OF PREGNANCY (POINT ESTIMATE AND 95% CONFIDENCE INTERVAL)

DIFFERENT ENDOMETRIOSIS TREATMENT COMPARISONS

 

From: Adamson GD, Pasta DJ. Surgical treatment of endometriosis-associated infertility: meta-analysis compared with survival analysis. Am J Obstet Gynecol 1994 Dec;171(6):1488-1505.

 

 

FIGURE 2

POSTLAPAROSCOPY MANAGEMENT OF ENDOMETRIOSIS

TABLE 1Ý

ESTIMATED CUMULATIVE LIFE TABLE PREGNANCY RATES
BY TREATMENT GROUP FOR DIFFERENT STAGES OF ENDOMETRIOSIS

From: Adamson GD, Hurd SJ, Pasta DJ, Rodriguez BD. Laparoscopic endometriosis treatment: Is it better? Fertil Steril 1993 Jan;59(1):35-44

TABLE 2

PREGNANCY RATES FOLLOWING TREATMENT
FOR UNEXPLAINED INFERTILITY

TABLE 3

PREGNANCY RATES FOLLOWING TREATMENT
OF ENDOMETRIOSIS-ASSOCIATED INFERTILITY

ÝBIBLIOGRAPHY

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2. Olive DL, Schwartz LB. Endometriosis. N Engl J Med 1993; 328:1759-1769.

5. Adamson GD. Laparoscopic treatment of endometriosis. In: Adamson GD, Martin DC, Eds. Endoscopic Management of Gynecologic Disease. Philadelphia, PA: Lippincott-Raven Publishers; 1996:147-187.
6. Guzick DS, Sullivan MW, Adamson GD, Cedars MI, Falk RJ, Peterson EP, Steinkampf MP. Efficacy of treatment for unexplained infertility. Fertil Steril, 1998; 70(2):207-213.

11. ACOG Technical Bulletin #223. Pain Management Principles. ACOG. Washington DC. May 1996.
12. Kim AH, Adamson GD. Endometriosis. In Advances in Medicine edited by RF Edlich. Vandemere Press, 2000.
13. Olive DL, Blackwell RE, Copperman AB. Endometriosis and pelvic pain. In: Blackwell RE, Olive DL, Eds. Chronic Pelvic Pain. New York, NY: Springer; 1998:61-83.
14. Guzick DS, Silliman NP, Adamson GD, Buttram VC,Canis M, Malinak LR, Schenken RS. Prediction of pregnancy in infertile women based on the American Society for Reproductive Medicine’s revised classification of endometriosis. Fertil Steril 1997; 67:822-829.
15. Surrey ES, and the Add-Back Consensus Working Group. Add-back therapy and gonadotropin-releasing hormone agonists in the treatment of patients with endometriosis: can a consensus be reached? Fertil Steril, 1999;71:420-424.
16. Pierce SJ, Gazvani MR, Farquharson RG. Long-term use of gonadotropin releasing hormone analogs and hormone replacement therapy in the management of endometriosis: a randomized trial with a 6-year follow-up. Fertil Steril 2000;74:964-968.
17. Adamson GD, Pasta DJ. Surgical treatment of endometriosis-associated infertility: meta-analysis compared with survival analysis. Am J Obstet Gynecol, 1994; 171(6):1488-1505.
18. Marcoux S, Maheux R, Berube S. Laparoscopic surgery in infertile women with minimal or mild endometriosis. N Engl J Med, 1997;337(4):217-222.
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