Janelle Yates

IN THIS ARTICLE
• When is laparoscopy indicated?
• Excision versus ablation
• How to reduce the risk for postoperative recurrence

Endometriosis has always posed a treatment challenge. In the early 19th century, before the widespread advent of surgery, the disease was managed by applying leeches to the cervix. In fact, as Nezhat and colleagues note in their comprehensive survey of the 4,000-year history of endometriosis, “leeches were considered a mainstay in treating any condition associated with menstruation.”¹

In the 21st century, the picture is clearer, though still not crystal clear. The optimal approach to endometriosis depends on many factors, foremost the patient’s chief complaint: pain or infertility (or both).

This article focuses on medical and surgical management of pain. Six experts address such questions as: When is laparoscopy indicated? Is excision or ablation of lesions preferred? What is the role of hysterectomy in eliminating pain? And what can be done about the problem of recurrence?

1. WHAT ARE THE OPTIONS FOR EMPIRIC THERAPY?
One reason for the diagnostic delay with endometriosis, which still averages about six years, is that definitive diagnosis is achieved only through laparoscopic investigation and histologic confirmation. For many women who experience pain thought to be associated with endometriosis, however, clinicians begin empiric treatment with medical agents as a way to avert the need for surgery, if at all possible.

“There is no cure for endometriosis,” says John R. Lue, MD, MPH, “but there are many ways that endometriosis can be treated” and the impact of the disease reduced in a patient’s life. (Editor’s Note: See below for biographical information on each clinician interviewed in this article.)

Medical and hormonal options include
• NSAIDs, often used with combined oral contraceptives (OCs). NSAIDs are not a long-term treatment option because of their effect on cyclo-oxygenase (COX) 1 and 2 enzymes, says Dr. Lue. COX-1 protects the gastrointestinal (GI) system, and prolonged use of NSAIDs can cause adverse GI effects.
• Cyclic combined OCs “are recommended as firstline therapy in the absence of contraindications,” says Dr. Lue, and are often used in combination with NSAIDs. However, the failure rate may be as high as 20% to 25%.² “If pain persists after a trial of three to six months of cyclic OCs, consider switching to continuous low-dose combined OCs for an additional six months,” Dr. Lue adds. When combined OCs were compared with placebo in the treatment of dysmenorrhea, they reduced baseline pain scores by 45% to 52%, compared with 14% to 17% for placebo (P < .001).² They also reduced the volume of endometriomas by 48%, compared with 32% for placebo (P = .04). According to Linda C. Giudice, MD, PhD, “In women with severe dysmenorrhea who have been treated with cyclic combined OCs, a switch to continuous combined OCs reduced pain scores by 58% within six months and by 75% at two years” (P < .001).²
• Depot medroxyprogesterone acetate (DMPA) or the levonorgestrel-releasing intrauterine system (LNG-IUS). These agents suppress the hypothalamic-pituitary-ovarian (HPO) axis to different degrees. DMPA suppresses the HPO completely, preventing ovulation. The LNG-IUS does not fully suppress the HPO but acts directly on endometrial tissue, with antiproliferative effects on eutopic and endometriotic implants, says Dr. Lue. The LNG-IUS also is effective at suppressing disease after surgical treatment, says Dr. Giudice.²
• Gonadotropin-releasing hormone (GnRH) agonist therapy, with estrogen and/or progestin add-back therapy to temper the associated loss in bone mineral density, “may be effective—if only temporarily—as it inhibits the HPO axis and blocks ovarian function, thereby greatly reducing systemic estrogen levels and inducing artificial menopause,” says Dr. Lue.
• Norethindrone acetate, a synthetic progestational agent, is occasionally used as empiric therapy for endometriosis because of its ability to inhibit ovulation. It has antiandrogenic and antiestrogenic effects.
• Aromatase inhibitors. Dr. Lue points to considerable evidence that endometriotic implants are an autocrine source of estrogen.³ “This locally produced estrogen results from overexpression of the enzyme P450 aromatase by endometriotic tissue,” he says. Consequently, in postmenopausal women, “aromatase inhibitors may be used orally in a daily pill form to curtail endometriotic implant production of estrogen and subsequent implant growth.”⁴ In women of reproductive age, aromatase inhibitors are combined with an HPO-suppressive therapy, such as norethindrone acetate. These strategies represent off-label use of aromatase inhibitors.
• Danazol, a synthetic androgen, has been used in the past to treat dysmenorrhea and dyspareunia. Because of its severe androgenic effects, however, it is not widely used today.

“For those using medical approaches, endometriosis-related pain may be reduced by using hormonal treatments to modify reproductive tract events, thereby decreasing local peritoneal inflammation and cytokine production,” says Pamela Stratton, MD. Because endometriosis is a “central sensitivity syndrome,” multidisciplinary approaches, such as physical therapy, may be beneficial to treat myofascial dysfunction and sensitization. “Chronic pain conditions that overlap with endometriosis-associated pain—such as migraines, irritable bowel syndrome, or painful bladder syndrome—should be identified and treated. Mood changes of depression and anxiety common to women with endometriosis-associated pain also warrant treatment,” she says.

Continue on to find out when laparoscopy is indicated >>

2. WHEN IS LAPAROSCOPY INDICATED? 
When medical and hormonal treatments fail to control a patient’s pain, laparoscopy is indicated to confirm the diagnosis of endometriosis. During that procedure, it is also advisable to treat any endometriosis that is present, provided the surgeon is highly experienced in such treatment.

Proper treatment is preferable—even if it requires expert consultation. “No treatment and referral to a more experienced surgeon are better than incomplete treatment by an inexperienced surgeon,” says Ceana Nezhat, MD. “Not all GYN surgeons have the expertise to treat advanced endometriosis.”

Dr. Stratton agrees about the importance of thorough treatment of endometriosis at the time of diagnostic laparoscopy: “At the laparoscopy, the patient benefits if all potential sources of pain are investigated and addressed.” At surgery, the surgeon should look for and treat any lesions suspicious for endometriosis, as well as any other finding that might contribute to pain, she says. “For example, routinely inspecting the appendix for endometriosis or other lesions, and removing affected appendices is reasonable; also, lysis and, where possible, excision of adhesions is an important strategy.”

If a medical approach fails for a patient, “then surgery is indicated to confirm the diagnosis and treat the disease,” agrees Tommaso Falcone, MD.

“Surgery is very effective in treating the pain associated with endometriosis,” Dr. Falcone adds. “Randomized clinical trials have shown that up to 90% of patients who obtain pain relief from surgery will have an effect lasting one year.⁶ If patients do not get relief, then the association of the pain with endometriosis should be questioned and other causes sought.”

The most common anatomic sites of implants
“The most common accepted theory for pathogenesis of endometriosis suggests that implants develop when debris from retrograde menstruation attaches to the pelvic peritoneum,” says Dr. Stratton.⁷ “Thus, the vast majority of lesions occur in the dependent portions of the pelvis, which include the ovarian fossae (posterior broad ligament under the ovaries), cul de sac, and the uterosacral ligaments.⁸ The bladder peritoneum, ovarian surface, uterine peritoneal surface, fallopian tube, and pelvic sidewall are also frequent sites. The colon and appendix are less common sites, and small bowel lesions are rare.”

“However, pain location does not correlate with lesion location,” Dr. Stratton notes. “For this reason, the goal at surgery is to treat all lesions, even ones that are not in sites of pain.”

Continue to find out how disease should be staged >>

3. HOW SHOULD DISEASE BE STAGED? 
Most surgeons with expertise in treating endometriosis attempt to stage the disease at the time of initial laparoscopy, even though a patient’s pain does not always correlate with the stage of disease.

“The staging system for endometriosis is a means to systematically catalogue where lesions are located,” says Dr. Stratton. The most commonly used classification system was developed by the American Society for Reproductive Medicine (ASRM). It takes into account such characteristics as how deep an implant lies, the extent to which it obliterates the posterior cul de sac, and the presence and extent of adhesions. Although the classification system is broken down into four stages ranging from minimal to severe disease, it is fairly complex. For example, it assigns a score for each lesion as well as the size and location of that lesion, notes Dr. Stratton. The presence of an endometrioma automatically renders the disease as stage III or IV, and an obliterated cul de sac means the endometriosis is graded as stage IV.

“This system enables us to communicate with each other about patients and may guide future surgeries for assessment of lesion recurrence or the planning of treatment for lesions the surgeon was unable to treat at an initial surgery,” says Dr. Stratton.

“Women with uterosacral nodularity, fixed pelvic organs, or severe pain with endometriomas may have deep infiltrating lesions. These lesions, in particular, are not captured well with the current staging system,” says Dr. Stratton. Because they appear to be innervated, “the greatest benefit to the patient is achieved by completely excising these lesions.” Preoperative imaging may help confirm the existence, location, and extent of these deep lesions and help the surgeon plan her approach “based on clinical and imaging findings.”

“Severity of pain or duration of surgical effect does not correlate with stage or extent of disease,” Dr. Stratton says.⁹ “In fact, patients with the least amount of disease noted at surgery experience pain sooner, suggesting that the central nervous system may have been remodeled prior to surgery or that the pain is in part due to some other cause.¹⁰ This observation underscores the principle that, while endometriosis may initiate pain, the pain experience is determined by engagement of the central nervous system.”

For more information on the ASRM revised classification of endometriosis, visit www.fertstert.org/article/S0015-0282(97)81391-X/pdf.

Continue to learn whether excision or ablation is preferable >>

4. WHICH IS PREFERABLE: EXCISION OR ABLATION?
In a prospective, randomized, double-blind study, Healey and colleagues compared pain levels following laparoscopic treatment of endometriosis with either excision or ablation. Preoperatively, women in the study completed a questionnaire rating various types of pain using visual analogue scales. They then were randomly assigned to treatment of endometriosis via excision or ablation. Postoperatively, they again completed a questionnaire about pain levels at three, six, nine, and 12 months. Investigators found no significant difference in pain scores at 12 months.¹¹

Five-year follow-up of the same population yielded slightly different findings, however. Although there was a reduction in all pain scores at five years in both the excision and ablation groups, a significantly greater reduction in dyspareunia was observed in the excision group at five years.¹²

In an accompanying editorial, Dr. Falcone and a coauthor called excision versus ablation of ovarian, bowel, and peritoneal endometriosis one of the “great debates” in the surgical management of endometriosis.¹³ “When there is deep involvement of adjacent organs, there is general consensus that excision is best for optimal surgical outcome,” they write. “However, for disease involving the peritoneum alone, there are proponents for either option.”¹³

“This is a very controversial issue,” says Dr. Falcone, “and the debate can sometimes be somewhat inflammatory…. It is hard to understand how a comparative trial could even be accomplished between excision and ablation. In my experience, deep disease typically occurs on the pelvic sidewall over the ureter or in the cul de sac on the bowel or infiltrating the bladder peritoneum. Therefore, ablation would increase the risk of damaging any of these structures. With superficial disease away from critical structures, it should be fine to ablate. Everywhere else and with deep disease, you need to excise or leave disease behind.”

“Endometriomas are a special situation,” Dr. Falcone adds. “Excision of the cyst has been shown in randomized controlled trials (RCTs) to be associated with less risk for recurrence.¹⁴ Therefore, it should be the treatment of choice. However, in patients interested in future fertility, we must take into consideration the potential damage to ovarian reserve associated with excision.”

Endometriosis of the ovaries has unique manifestations. “My approach to ovarian cysts depends on their classification,” says Dr. Nezhat.¹⁵ In general, primary endometriomas (type 1) are small, superficial cysts that contain dark “chocolate” fluid. They tend to be firmly adherent to the ovarian tissue and difficult to remove surgically.

Secondary endometriomas (type 2) are follicular or luteal cysts that have been involved or invaded by cortical endometriotic implants or by primary endometrioma. Secondary endometriomas are further classified by the relationship between cortical endometriosis and the cyst wall. Type 2A endometriomas are usually large, with a capsule that is easily separated from ovarian tissue. Type 2B endometriomas have some features of functional cysts but show deep involvement with surface endometriosis. Type 2C endometriomas are similar, showing extensive surface endometrial implants but with deep penetration of the endometriosis into the cyst wall.¹⁵

“For type 1 endometriomas, I biopsy the cyst to ensure the lesion is benign, then vaporize the endometrioma,” Dr. Nezhat says. “In cases of type 2A and 2B endometriomas, the cyst capsule is easily enucleated and removed. Type 2C endometriomas are biopsied as well, and then I proceed with vaporizing the fibrotic area with a low-power energy source, such as neutral argon plasma, avoiding excessive coagulation and thermal injury.” Recent literature supports the idea of evaluation and biopsy of fibrotic endometriomas to confirm benign conditions, followed by ablation without compromising ovarian function.¹⁶

“Excision and ablation both have indications,” Dr. Nezhat asserts. “It depends on the location and depth of penetration of implants, as well as the ­patient’s ultimate goal. For example, if the patient desires future fertility and has endometriosis on the ovary, removal by excision could damage ovarian function. The same holds true for endometriosis on the fallopian tubes. It’s better in such cases to ­ablate.”

“Ablation is different from coagulation, which is not recommended,” Dr. Nezhat explains. “Ablation vaporizes the diseased area layer by layer, like peeling an onion, until the disease is eradicated. It is similar to dermatologic skin resurfacing. Vaporization is preferable for endometriosis on the tubes and ovaries in patients who desire pregnancy. The choice between excision and ablation depends on the location, depth of penetration, and the patient’s desire for fertility.”

Either way—­and regardless of the primary indication for surgery (pain versus infertility)—a minimally invasive gynecologic surgeon is expected to have the ability to perform both techniques, Dr. Nezhat says.

Continue to find out if hysterectomy is definitive treatment >>

5. IS HYSTERECTOMY DEFINITIVE TREATMENT?
“Not necessarily,” says Dr. Nezhat. “Hysterectomy by itself doesn’t take care of endometriosis unless the patient has adenomyosis. If a patient has endometriosis, the first step is complete treatment of the disease to restore the anatomy. Then the next step might be hysterectomy to give a better long-term result, especially in cases of adenomyosis. Removal of the ovaries at the time of hysterectomy has to be individualized.”

“The implication that hysterectomy ‘cures’ endometriosis is false yet is stated in some textbooks,” says Dr. Nezhat. “Even at the time of hysterectomy, the first step should be complete treatment of endometriosis and restoration of anatomy, followed by the hysterectomy. Leaving endometriosis behind, believing it will go away by itself or not cause future issues, is a gross misperception.”

Removal of the ovaries at hysterectomy?
“There are few comparative studies on the long-term follow-up of patients who have undergone hysterectomy with or without removal of both ovaries,” says Dr. Falcone. “The conventional dogma has been that, in women undergoing definitive surgery for endometriosis, both ovaries should be removed, even if they are normal. I personally believe that this was because hysterectomy was often performed without excision of the endometriosis. So the uterus was removed and disease was left behind. In these cases, recurrent symptoms were due to persistent disease.”

“We reported our experience at the Cleveland Clinic with a seven-year follow-up,” Dr. Falcone continues. “Hysterectomy was performed with excision of all visible disease. Ovaries were conserved if normal and removed if not. We looked at the reoperation-free frequency over time. In women undergoing hysterectomy with excision of visible disease but ovarian preservation, the reoperation-free percentages at two, five, and seven years were 95%, 86%, and 77%, respectively, versus 96%, 91%, and 91% in those without ovarian preservation. So, overall, there was an advantage over time for removal of the ovaries. However, in the subset of women between ages 30 and 39, there was no difference in the long-term recurrence rate if the ovaries were left in. For this reason, in women younger than 40, we recommend keeping normal ovaries if all disease is removed.”¹⁷

Continue on to find out if the risk for postoperative recurrence can be reduced >>

6. CAN THE RISK FOR POSTOPERATIVE RECURRENCE BE REDUCED?
“The main problem with surgery is the recurrence rate,” Dr. Falcone says. “Studies have shown that the recurrence rate of pain at seven years may be as high as 50%.”¹⁷ Furthermore, “the recurrence of pain may not be associated with visualized endometriosis at laparoscopy.”

“Incomplete removal of lesions may be associated with an increase in pain after surgery,” says Dr. Stratton.¹⁸ “Incomplete removal of lesions may occur because of varying technical skill or specific lesion characteristics. The lesions may be difficult to remove because of their location. Lesions may not be recognized because their appearance can vary from subtle (red or clear or white) to classic (blue-black). The depth of the lesion may not be appreciated until surgery is under way, and a surgeon may not be adequately prepared to treat deep lesions when they are identified.”

Adenomyosis is another reason pain may persist or recur after surgery.¹⁹ “Adenomyosis appears as either diffuse or focal thickening of the junctional zone between the endometrium and myometrium of the uterus on T2-weighted MRI,” says Dr. Stratton. “After excision of endometriosis, chronic pelvic pain is significantly more likely to persist in women who have a junctional zone thickness of more than 11 mm on MRI.”

The frequent recurrence of pain after surgery makes the disease a long-term challenge.

“Pelvic pain caused by endometriosis is a chronic problem that requires a multiyear management plan, involving both surgery and hormonal therapy,” says Robert L. Barbieri, MD. “To reduce the number of surgical procedures in the lifetime of a woman with endometriosis and pain, I suggest hormonal medical therapy following conservative surgery for endometriosis.”

“Definitive surgery, such as hysterectomy or hysterectomy plus bilateral salpingo-oophorectomy (BSO), typically results in prolonged symptom relief,” Dr. Barbieri says. “Following hysterectomy, hormonal therapy may not be needed. Following BSO, low-dose hormonal therapy is often needed to reduce the severity of menopausal symptoms.”

After surgical treatment of endometriosis associated with pain, Dr. Barbieri presents the patient with the following menu of hormonal options:
• No hormonal therapy
• Estrogen-progestin contraceptives, either cyclic or continuous
• The LNG-IUS
• Norethindrone acetate (5 mg/d)
• DMPA (150 mg every three months)
• Leuprolide acetate depot (3.75 mg IM monthly)
• Nafarelin nasal spray (200 µg bid)
• Danazol (200 mg bid).

“I explain the common adverse effects with each approach and have the patient select what she determines to be her best option,” says Dr. Barbieri. “In my experience, conservative surgery followed by hormonal therapy is effective in more than 75% of women.”

“The evidence to support postoperative hormonal therapy is modest,” Dr. Barbieri notes. “The best evidence is available for use of the LNG-IUS, estrogen-progestin contraceptives, and GnRH agonists.”^20-22

In addition, he notes, “major professional socie­ties have highlighted the option of postoperative hormonal therapy to reduce the risk for recurrent pain and repetitive surgical procedures in the future.”^23,24

When pain recurs after surgery for endometriosis, it pays to consider what type of pain it is, says Dr. Barbieri.

“There are two major types of pain—nociceptive and neuropathic,” he says. “Nociceptive pain is caused by an injury, acute or chronic. Neuropathic pain is caused by ‘activation’ of neural circuits, sometimes in the absence of an ongoing injury. Many women with endometriosis and chronic pain have both nociceptive and neuropathic pain. Consequently, it is important to consider the use of a multidisciplinary pain practice in the management of chronic pain syndromes. Multidisciplinary pain practices have special expertise in the management of neuropathic pain. Standard conservative surgical intervention is unlikely to improve pain caused by neuropathic mechanisms. Likewise, opioid analgesics are not recommended for the treatment of neuropathic pain.”

REFERENCES
1. Nezhat C, Nezhat F, Nezhat C. Endometriosis: ancient disease, ancient treatments. Fertil Steril. 2012;98(6S):S1-S62.
2. Giudice LC. Clinical practice. Endometriosis. N Engl J Med. 2010;362(25):2389-2398.
3. Pavone ME, Bulun SE. Aromatase inhibitors for the treatment of endometriosis: a review. Fertil Steril. 2012;98(6):1370-1379.
4. Nothnick WB. The emerging use of aromatase inhibitors for endometriosis treatment. Reprod Biol Endocrinol. 2011;9:87.
5. Chwalisz K, Garg R, Brenner RM, et al. Selective progesterone receptor modulators (SPRMs): a novel therapeutic concept in endometriosis. Ann N Y Acad Sci. 2002;955:373-393, 396-406.
6. Duffy JM, Arambage K, Correa FJ, et al. Laparoscopic surgery for endometriosis. Cochrane Database Syst Rev. 2014;(4):CD011031.
7. Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268-279.
8. Stegmann BJ, Sinaii N, Liu S, et al. Using location, color, size, and depth to characterize and identify endometriosis lesions in a cohort of 133 women. Fertil Steril. 2008;89(6):1632-1636.
9. Hsu AL, Sinaii N, Segars J, et al. Relating pelvic pain location to surgical findings of endometriosis. Obstet Gynecol. 2011;118(2 pt 1):223-230.
10. Stratton P, Berkley KJ. Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications. Hum Reprod Update. 2011;17(3):327-346.
11. Healey M, Ang WC, Cheng C. Surgical treatment of endometriosis: a prospective randomized double-blinded trial comparing excision and ablation. Fertil Steril. 2010;94(7):2536-2540.
12. Healey M, Chang C, Kaur H. To excise or ablate endometriosis? A prospective randomized double blinded trial after 5-year follow-up. JMIG. 2014;21(6):999-1004.
13. Falcone T, Wilson JR. Surgical management of endometriosis: excision or ablation. JMIG. 2014;21(6):969.
14. Hart RJ, Hickey M, Maouris P, Buckett W. Excisional surgery versus ablative surgery for ovarian endometriomata. Cochrane Database Syst Rev. 2008;(2):CD004992.
15. Nezhat C, Nezhat F, Nezhat CH, Seidman D. Classification of endometriosis: improving the classification of endometriotic ovarian cysts. Hum Reprod. 1994;9(12):2212-2216.
16. Roman H, Auber M, Mokdad C, et al. Ovarian endometrioma ablation using plasma energy versus cystectomy: a step toward better preservation of the ovarian parenchyma in women wishing to conceive. Fertil Steril. 2011;96(6):1396-1400.
17. Shakiba K, Bena JF, McGill KM, et al. Surgical treatment of endometriosis: a 7-year follow-up on the requirement for further surgery. Obstet Gynecol. 2008;111(6):1285-1292.
18. McAllister SL, McGinty KA, Resuehr D, Berkley KJ. Endometriosis-induced vaginal hyperalgesia in the rat: role of the ectopic growths and their innervation. Pain. 2009;147(1-3):255-264.
19. Parker JD, Leondires M, Sinaii N, et al. Persistence of dysmenorrhea and nonmenstrual pain after optimal endometriosis surgery may indicate adenomyosis. Fertil Steril. 2006;86(3):711-715.
20. Abou-Setta AM, Al-Inany HG, Farquar CM. Levonorgestrel-releasing intrauterine device for symptomatic endometriosis following surgery. Cochrane Database Syst Rev. 2006;(1):CD005072.
21. Seracchioli R, Mabrouk M, Manuzzi L, et al. Postoperative use of oral contraceptive pills for prevention of anatomic relapse or symptom recurrence following surgery. Hum Reprod. 2009;24(11):2729-2735.
22. Hornstein MD, Hemmings R, Yuzpe AA, Heinrichs WL. Use of nafarelin versus placebo after reductive laparoscopic surgery for endometriosis. Fertil Steril. 1997;68(5):860-864.
23. Practice Committee of the American Society for Reproductive Medicine. Treatment of pain associated with endometriosis: a committee opinion. Fertil Steril. 2014;101(4):927-935.
24. Dunselman GA, Vermeulen N, Becker C, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014;29(3):400-412.

IN THIS ARTICLE
• When is laparoscopy indicated?
• Excision versus ablation
• How to reduce the risk for postoperative recurrence

Endometriosis has always posed a treatment challenge. In the early 19th century, before the widespread advent of surgery, the disease was managed by applying leeches to the cervix. In fact, as Nezhat and colleagues note in their comprehensive survey of the 4,000-year history of endometriosis, “leeches were considered a mainstay in treating any condition associated with menstruation.”¹

In the 21st century, the picture is clearer, though still not crystal clear. The optimal approach to endometriosis depends on many factors, foremost the patient’s chief complaint: pain or infertility (or both).

This article focuses on medical and surgical management of pain. Six experts address such questions as: When is laparoscopy indicated? Is excision or ablation of lesions preferred? What is the role of hysterectomy in eliminating pain? And what can be done about the problem of recurrence?

1. WHAT ARE THE OPTIONS FOR EMPIRIC THERAPY?
One reason for the diagnostic delay with endometriosis, which still averages about six years, is that definitive diagnosis is achieved only through laparoscopic investigation and histologic confirmation. For many women who experience pain thought to be associated with endometriosis, however, clinicians begin empiric treatment with medical agents as a way to avert the need for surgery, if at all possible.

“There is no cure for endometriosis,” says John R. Lue, MD, MPH, “but there are many ways that endometriosis can be treated” and the impact of the disease reduced in a patient’s life. (Editor’s Note: See below for biographical information on each clinician interviewed in this article.)

Medical and hormonal options include
• NSAIDs, often used with combined oral contraceptives (OCs). NSAIDs are not a long-term treatment option because of their effect on cyclo-oxygenase (COX) 1 and 2 enzymes, says Dr. Lue. COX-1 protects the gastrointestinal (GI) system, and prolonged use of NSAIDs can cause adverse GI effects.
• Cyclic combined OCs “are recommended as firstline therapy in the absence of contraindications,” says Dr. Lue, and are often used in combination with NSAIDs. However, the failure rate may be as high as 20% to 25%.² “If pain persists after a trial of three to six months of cyclic OCs, consider switching to continuous low-dose combined OCs for an additional six months,” Dr. Lue adds. When combined OCs were compared with placebo in the treatment of dysmenorrhea, they reduced baseline pain scores by 45% to 52%, compared with 14% to 17% for placebo (P < .001).² They also reduced the volume of endometriomas by 48%, compared with 32% for placebo (P = .04). According to Linda C. Giudice, MD, PhD, “In women with severe dysmenorrhea who have been treated with cyclic combined OCs, a switch to continuous combined OCs reduced pain scores by 58% within six months and by 75% at two years” (P < .001).²
• Depot medroxyprogesterone acetate (DMPA) or the levonorgestrel-releasing intrauterine system (LNG-IUS). These agents suppress the hypothalamic-pituitary-ovarian (HPO) axis to different degrees. DMPA suppresses the HPO completely, preventing ovulation. The LNG-IUS does not fully suppress the HPO but acts directly on endometrial tissue, with antiproliferative effects on eutopic and endometriotic implants, says Dr. Lue. The LNG-IUS also is effective at suppressing disease after surgical treatment, says Dr. Giudice.²
• Gonadotropin-releasing hormone (GnRH) agonist therapy, with estrogen and/or progestin add-back therapy to temper the associated loss in bone mineral density, “may be effective—if only temporarily—as it inhibits the HPO axis and blocks ovarian function, thereby greatly reducing systemic estrogen levels and inducing artificial menopause,” says Dr. Lue.
• Norethindrone acetate, a synthetic progestational agent, is occasionally used as empiric therapy for endometriosis because of its ability to inhibit ovulation. It has antiandrogenic and antiestrogenic effects.
• Aromatase inhibitors. Dr. Lue points to considerable evidence that endometriotic implants are an autocrine source of estrogen.³ “This locally produced estrogen results from overexpression of the enzyme P450 aromatase by endometriotic tissue,” he says. Consequently, in postmenopausal women, “aromatase inhibitors may be used orally in a daily pill form to curtail endometriotic implant production of estrogen and subsequent implant growth.”⁴ In women of reproductive age, aromatase inhibitors are combined with an HPO-suppressive therapy, such as norethindrone acetate. These strategies represent off-label use of aromatase inhibitors.
• Danazol, a synthetic androgen, has been used in the past to treat dysmenorrhea and dyspareunia. Because of its severe androgenic effects, however, it is not widely used today.

“For those using medical approaches, endometriosis-related pain may be reduced by using hormonal treatments to modify reproductive tract events, thereby decreasing local peritoneal inflammation and cytokine production,” says Pamela Stratton, MD. Because endometriosis is a “central sensitivity syndrome,” multidisciplinary approaches, such as physical therapy, may be beneficial to treat myofascial dysfunction and sensitization. “Chronic pain conditions that overlap with endometriosis-associated pain—such as migraines, irritable bowel syndrome, or painful bladder syndrome—should be identified and treated. Mood changes of depression and anxiety common to women with endometriosis-associated pain also warrant treatment,” she says.

Continue on to find out when laparoscopy is indicated >>

2. WHEN IS LAPAROSCOPY INDICATED? 
When medical and hormonal treatments fail to control a patient’s pain, laparoscopy is indicated to confirm the diagnosis of endometriosis. During that procedure, it is also advisable to treat any endometriosis that is present, provided the surgeon is highly experienced in such treatment.

Proper treatment is preferable—even if it requires expert consultation. “No treatment and referral to a more experienced surgeon are better than incomplete treatment by an inexperienced surgeon,” says Ceana Nezhat, MD. “Not all GYN surgeons have the expertise to treat advanced endometriosis.”

Dr. Stratton agrees about the importance of thorough treatment of endometriosis at the time of diagnostic laparoscopy: “At the laparoscopy, the patient benefits if all potential sources of pain are investigated and addressed.” At surgery, the surgeon should look for and treat any lesions suspicious for endometriosis, as well as any other finding that might contribute to pain, she says. “For example, routinely inspecting the appendix for endometriosis or other lesions, and removing affected appendices is reasonable; also, lysis and, where possible, excision of adhesions is an important strategy.”

If a medical approach fails for a patient, “then surgery is indicated to confirm the diagnosis and treat the disease,” agrees Tommaso Falcone, MD.

“Surgery is very effective in treating the pain associated with endometriosis,” Dr. Falcone adds. “Randomized clinical trials have shown that up to 90% of patients who obtain pain relief from surgery will have an effect lasting one year.⁶ If patients do not get relief, then the association of the pain with endometriosis should be questioned and other causes sought.”

The most common anatomic sites of implants
“The most common accepted theory for pathogenesis of endometriosis suggests that implants develop when debris from retrograde menstruation attaches to the pelvic peritoneum,” says Dr. Stratton.⁷ “Thus, the vast majority of lesions occur in the dependent portions of the pelvis, which include the ovarian fossae (posterior broad ligament under the ovaries), cul de sac, and the uterosacral ligaments.⁸ The bladder peritoneum, ovarian surface, uterine peritoneal surface, fallopian tube, and pelvic sidewall are also frequent sites. The colon and appendix are less common sites, and small bowel lesions are rare.”

“However, pain location does not correlate with lesion location,” Dr. Stratton notes. “For this reason, the goal at surgery is to treat all lesions, even ones that are not in sites of pain.”

Continue to find out how disease should be staged >>

3. HOW SHOULD DISEASE BE STAGED? 
Most surgeons with expertise in treating endometriosis attempt to stage the disease at the time of initial laparoscopy, even though a patient’s pain does not always correlate with the stage of disease.

“The staging system for endometriosis is a means to systematically catalogue where lesions are located,” says Dr. Stratton. The most commonly used classification system was developed by the American Society for Reproductive Medicine (ASRM). It takes into account such characteristics as how deep an implant lies, the extent to which it obliterates the posterior cul de sac, and the presence and extent of adhesions. Although the classification system is broken down into four stages ranging from minimal to severe disease, it is fairly complex. For example, it assigns a score for each lesion as well as the size and location of that lesion, notes Dr. Stratton. The presence of an endometrioma automatically renders the disease as stage III or IV, and an obliterated cul de sac means the endometriosis is graded as stage IV.

“This system enables us to communicate with each other about patients and may guide future surgeries for assessment of lesion recurrence or the planning of treatment for lesions the surgeon was unable to treat at an initial surgery,” says Dr. Stratton.

“Women with uterosacral nodularity, fixed pelvic organs, or severe pain with endometriomas may have deep infiltrating lesions. These lesions, in particular, are not captured well with the current staging system,” says Dr. Stratton. Because they appear to be innervated, “the greatest benefit to the patient is achieved by completely excising these lesions.” Preoperative imaging may help confirm the existence, location, and extent of these deep lesions and help the surgeon plan her approach “based on clinical and imaging findings.”

“Severity of pain or duration of surgical effect does not correlate with stage or extent of disease,” Dr. Stratton says.⁹ “In fact, patients with the least amount of disease noted at surgery experience pain sooner, suggesting that the central nervous system may have been remodeled prior to surgery or that the pain is in part due to some other cause.¹⁰ This observation underscores the principle that, while endometriosis may initiate pain, the pain experience is determined by engagement of the central nervous system.”

For more information on the ASRM revised classification of endometriosis, visit www.fertstert.org/article/S0015-0282(97)81391-X/pdf.

Continue to learn whether excision or ablation is preferable >>

4. WHICH IS PREFERABLE: EXCISION OR ABLATION?
In a prospective, randomized, double-blind study, Healey and colleagues compared pain levels following laparoscopic treatment of endometriosis with either excision or ablation. Preoperatively, women in the study completed a questionnaire rating various types of pain using visual analogue scales. They then were randomly assigned to treatment of endometriosis via excision or ablation. Postoperatively, they again completed a questionnaire about pain levels at three, six, nine, and 12 months. Investigators found no significant difference in pain scores at 12 months.¹¹

Five-year follow-up of the same population yielded slightly different findings, however. Although there was a reduction in all pain scores at five years in both the excision and ablation groups, a significantly greater reduction in dyspareunia was observed in the excision group at five years.¹²

In an accompanying editorial, Dr. Falcone and a coauthor called excision versus ablation of ovarian, bowel, and peritoneal endometriosis one of the “great debates” in the surgical management of endometriosis.¹³ “When there is deep involvement of adjacent organs, there is general consensus that excision is best for optimal surgical outcome,” they write. “However, for disease involving the peritoneum alone, there are proponents for either option.”¹³

“This is a very controversial issue,” says Dr. Falcone, “and the debate can sometimes be somewhat inflammatory…. It is hard to understand how a comparative trial could even be accomplished between excision and ablation. In my experience, deep disease typically occurs on the pelvic sidewall over the ureter or in the cul de sac on the bowel or infiltrating the bladder peritoneum. Therefore, ablation would increase the risk of damaging any of these structures. With superficial disease away from critical structures, it should be fine to ablate. Everywhere else and with deep disease, you need to excise or leave disease behind.”

“Endometriomas are a special situation,” Dr. Falcone adds. “Excision of the cyst has been shown in randomized controlled trials (RCTs) to be associated with less risk for recurrence.¹⁴ Therefore, it should be the treatment of choice. However, in patients interested in future fertility, we must take into consideration the potential damage to ovarian reserve associated with excision.”

Endometriosis of the ovaries has unique manifestations. “My approach to ovarian cysts depends on their classification,” says Dr. Nezhat.¹⁵ In general, primary endometriomas (type 1) are small, superficial cysts that contain dark “chocolate” fluid. They tend to be firmly adherent to the ovarian tissue and difficult to remove surgically.

Secondary endometriomas (type 2) are follicular or luteal cysts that have been involved or invaded by cortical endometriotic implants or by primary endometrioma. Secondary endometriomas are further classified by the relationship between cortical endometriosis and the cyst wall. Type 2A endometriomas are usually large, with a capsule that is easily separated from ovarian tissue. Type 2B endometriomas have some features of functional cysts but show deep involvement with surface endometriosis. Type 2C endometriomas are similar, showing extensive surface endometrial implants but with deep penetration of the endometriosis into the cyst wall.¹⁵

“For type 1 endometriomas, I biopsy the cyst to ensure the lesion is benign, then vaporize the endometrioma,” Dr. Nezhat says. “In cases of type 2A and 2B endometriomas, the cyst capsule is easily enucleated and removed. Type 2C endometriomas are biopsied as well, and then I proceed with vaporizing the fibrotic area with a low-power energy source, such as neutral argon plasma, avoiding excessive coagulation and thermal injury.” Recent literature supports the idea of evaluation and biopsy of fibrotic endometriomas to confirm benign conditions, followed by ablation without compromising ovarian function.¹⁶

“Excision and ablation both have indications,” Dr. Nezhat asserts. “It depends on the location and depth of penetration of implants, as well as the ­patient’s ultimate goal. For example, if the patient desires future fertility and has endometriosis on the ovary, removal by excision could damage ovarian function. The same holds true for endometriosis on the fallopian tubes. It’s better in such cases to ­ablate.”

“Ablation is different from coagulation, which is not recommended,” Dr. Nezhat explains. “Ablation vaporizes the diseased area layer by layer, like peeling an onion, until the disease is eradicated. It is similar to dermatologic skin resurfacing. Vaporization is preferable for endometriosis on the tubes and ovaries in patients who desire pregnancy. The choice between excision and ablation depends on the location, depth of penetration, and the patient’s desire for fertility.”

Either way—­and regardless of the primary indication for surgery (pain versus infertility)—a minimally invasive gynecologic surgeon is expected to have the ability to perform both techniques, Dr. Nezhat says.

Continue to find out if hysterectomy is definitive treatment >>

5. IS HYSTERECTOMY DEFINITIVE TREATMENT?
“Not necessarily,” says Dr. Nezhat. “Hysterectomy by itself doesn’t take care of endometriosis unless the patient has adenomyosis. If a patient has endometriosis, the first step is complete treatment of the disease to restore the anatomy. Then the next step might be hysterectomy to give a better long-term result, especially in cases of adenomyosis. Removal of the ovaries at the time of hysterectomy has to be individualized.”

“The implication that hysterectomy ‘cures’ endometriosis is false yet is stated in some textbooks,” says Dr. Nezhat. “Even at the time of hysterectomy, the first step should be complete treatment of endometriosis and restoration of anatomy, followed by the hysterectomy. Leaving endometriosis behind, believing it will go away by itself or not cause future issues, is a gross misperception.”

Removal of the ovaries at hysterectomy?
“There are few comparative studies on the long-term follow-up of patients who have undergone hysterectomy with or without removal of both ovaries,” says Dr. Falcone. “The conventional dogma has been that, in women undergoing definitive surgery for endometriosis, both ovaries should be removed, even if they are normal. I personally believe that this was because hysterectomy was often performed without excision of the endometriosis. So the uterus was removed and disease was left behind. In these cases, recurrent symptoms were due to persistent disease.”

“We reported our experience at the Cleveland Clinic with a seven-year follow-up,” Dr. Falcone continues. “Hysterectomy was performed with excision of all visible disease. Ovaries were conserved if normal and removed if not. We looked at the reoperation-free frequency over time. In women undergoing hysterectomy with excision of visible disease but ovarian preservation, the reoperation-free percentages at two, five, and seven years were 95%, 86%, and 77%, respectively, versus 96%, 91%, and 91% in those without ovarian preservation. So, overall, there was an advantage over time for removal of the ovaries. However, in the subset of women between ages 30 and 39, there was no difference in the long-term recurrence rate if the ovaries were left in. For this reason, in women younger than 40, we recommend keeping normal ovaries if all disease is removed.”¹⁷

Continue on to find out if the risk for postoperative recurrence can be reduced >>

6. CAN THE RISK FOR POSTOPERATIVE RECURRENCE BE REDUCED?
“The main problem with surgery is the recurrence rate,” Dr. Falcone says. “Studies have shown that the recurrence rate of pain at seven years may be as high as 50%.”¹⁷ Furthermore, “the recurrence of pain may not be associated with visualized endometriosis at laparoscopy.”

“Incomplete removal of lesions may be associated with an increase in pain after surgery,” says Dr. Stratton.¹⁸ “Incomplete removal of lesions may occur because of varying technical skill or specific lesion characteristics. The lesions may be difficult to remove because of their location. Lesions may not be recognized because their appearance can vary from subtle (red or clear or white) to classic (blue-black). The depth of the lesion may not be appreciated until surgery is under way, and a surgeon may not be adequately prepared to treat deep lesions when they are identified.”

Adenomyosis is another reason pain may persist or recur after surgery.¹⁹ “Adenomyosis appears as either diffuse or focal thickening of the junctional zone between the endometrium and myometrium of the uterus on T2-weighted MRI,” says Dr. Stratton. “After excision of endometriosis, chronic pelvic pain is significantly more likely to persist in women who have a junctional zone thickness of more than 11 mm on MRI.”

The frequent recurrence of pain after surgery makes the disease a long-term challenge.

“Pelvic pain caused by endometriosis is a chronic problem that requires a multiyear management plan, involving both surgery and hormonal therapy,” says Robert L. Barbieri, MD. “To reduce the number of surgical procedures in the lifetime of a woman with endometriosis and pain, I suggest hormonal medical therapy following conservative surgery for endometriosis.”

“Definitive surgery, such as hysterectomy or hysterectomy plus bilateral salpingo-oophorectomy (BSO), typically results in prolonged symptom relief,” Dr. Barbieri says. “Following hysterectomy, hormonal therapy may not be needed. Following BSO, low-dose hormonal therapy is often needed to reduce the severity of menopausal symptoms.”

After surgical treatment of endometriosis associated with pain, Dr. Barbieri presents the patient with the following menu of hormonal options:
• No hormonal therapy
• Estrogen-progestin contraceptives, either cyclic or continuous
• The LNG-IUS
• Norethindrone acetate (5 mg/d)
• DMPA (150 mg every three months)
• Leuprolide acetate depot (3.75 mg IM monthly)
• Nafarelin nasal spray (200 µg bid)
• Danazol (200 mg bid).

“I explain the common adverse effects with each approach and have the patient select what she determines to be her best option,” says Dr. Barbieri. “In my experience, conservative surgery followed by hormonal therapy is effective in more than 75% of women.”

“The evidence to support postoperative hormonal therapy is modest,” Dr. Barbieri notes. “The best evidence is available for use of the LNG-IUS, estrogen-progestin contraceptives, and GnRH agonists.”^20-22

In addition, he notes, “major professional socie­ties have highlighted the option of postoperative hormonal therapy to reduce the risk for recurrent pain and repetitive surgical procedures in the future.”^23,24

When pain recurs after surgery for endometriosis, it pays to consider what type of pain it is, says Dr. Barbieri.

“There are two major types of pain—nociceptive and neuropathic,” he says. “Nociceptive pain is caused by an injury, acute or chronic. Neuropathic pain is caused by ‘activation’ of neural circuits, sometimes in the absence of an ongoing injury. Many women with endometriosis and chronic pain have both nociceptive and neuropathic pain. Consequently, it is important to consider the use of a multidisciplinary pain practice in the management of chronic pain syndromes. Multidisciplinary pain practices have special expertise in the management of neuropathic pain. Standard conservative surgical intervention is unlikely to improve pain caused by neuropathic mechanisms. Likewise, opioid analgesics are not recommended for the treatment of neuropathic pain.”

REFERENCES
1. Nezhat C, Nezhat F, Nezhat C. Endometriosis: ancient disease, ancient treatments. Fertil Steril. 2012;98(6S):S1-S62.
2. Giudice LC. Clinical practice. Endometriosis. N Engl J Med. 2010;362(25):2389-2398.
3. Pavone ME, Bulun SE. Aromatase inhibitors for the treatment of endometriosis: a review. Fertil Steril. 2012;98(6):1370-1379.
4. Nothnick WB. The emerging use of aromatase inhibitors for endometriosis treatment. Reprod Biol Endocrinol. 2011;9:87.
5. Chwalisz K, Garg R, Brenner RM, et al. Selective progesterone receptor modulators (SPRMs): a novel therapeutic concept in endometriosis. Ann N Y Acad Sci. 2002;955:373-393, 396-406.
6. Duffy JM, Arambage K, Correa FJ, et al. Laparoscopic surgery for endometriosis. Cochrane Database Syst Rev. 2014;(4):CD011031.
7. Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268-279.
8. Stegmann BJ, Sinaii N, Liu S, et al. Using location, color, size, and depth to characterize and identify endometriosis lesions in a cohort of 133 women. Fertil Steril. 2008;89(6):1632-1636.
9. Hsu AL, Sinaii N, Segars J, et al. Relating pelvic pain location to surgical findings of endometriosis. Obstet Gynecol. 2011;118(2 pt 1):223-230.
10. Stratton P, Berkley KJ. Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications. Hum Reprod Update. 2011;17(3):327-346.
11. Healey M, Ang WC, Cheng C. Surgical treatment of endometriosis: a prospective randomized double-blinded trial comparing excision and ablation. Fertil Steril. 2010;94(7):2536-2540.
12. Healey M, Chang C, Kaur H. To excise or ablate endometriosis? A prospective randomized double blinded trial after 5-year follow-up. JMIG. 2014;21(6):999-1004.
13. Falcone T, Wilson JR. Surgical management of endometriosis: excision or ablation. JMIG. 2014;21(6):969.
14. Hart RJ, Hickey M, Maouris P, Buckett W. Excisional surgery versus ablative surgery for ovarian endometriomata. Cochrane Database Syst Rev. 2008;(2):CD004992.
15. Nezhat C, Nezhat F, Nezhat CH, Seidman D. Classification of endometriosis: improving the classification of endometriotic ovarian cysts. Hum Reprod. 1994;9(12):2212-2216.
16. Roman H, Auber M, Mokdad C, et al. Ovarian endometrioma ablation using plasma energy versus cystectomy: a step toward better preservation of the ovarian parenchyma in women wishing to conceive. Fertil Steril. 2011;96(6):1396-1400.
17. Shakiba K, Bena JF, McGill KM, et al. Surgical treatment of endometriosis: a 7-year follow-up on the requirement for further surgery. Obstet Gynecol. 2008;111(6):1285-1292.
18. McAllister SL, McGinty KA, Resuehr D, Berkley KJ. Endometriosis-induced vaginal hyperalgesia in the rat: role of the ectopic growths and their innervation. Pain. 2009;147(1-3):255-264.
19. Parker JD, Leondires M, Sinaii N, et al. Persistence of dysmenorrhea and nonmenstrual pain after optimal endometriosis surgery may indicate adenomyosis. Fertil Steril. 2006;86(3):711-715.
20. Abou-Setta AM, Al-Inany HG, Farquar CM. Levonorgestrel-releasing intrauterine device for symptomatic endometriosis following surgery. Cochrane Database Syst Rev. 2006;(1):CD005072.
21. Seracchioli R, Mabrouk M, Manuzzi L, et al. Postoperative use of oral contraceptive pills for prevention of anatomic relapse or symptom recurrence following surgery. Hum Reprod. 2009;24(11):2729-2735.
22. Hornstein MD, Hemmings R, Yuzpe AA, Heinrichs WL. Use of nafarelin versus placebo after reductive laparoscopic surgery for endometriosis. Fertil Steril. 1997;68(5):860-864.
23. Practice Committee of the American Society for Reproductive Medicine. Treatment of pain associated with endometriosis: a committee opinion. Fertil Steril. 2014;101(4):927-935.
24. Dunselman GA, Vermeulen N, Becker C, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014;29(3):400-412.

IN THIS ARTICLE
• When is laparoscopy indicated?
• Excision versus ablation
• How to reduce the risk for postoperative recurrence

Endometriosis has always posed a treatment challenge. In the early 19th century, before the widespread advent of surgery, the disease was managed by applying leeches to the cervix. In fact, as Nezhat and colleagues note in their comprehensive survey of the 4,000-year history of endometriosis, “leeches were considered a mainstay in treating any condition associated with menstruation.”¹

In the 21st century, the picture is clearer, though still not crystal clear. The optimal approach to endometriosis depends on many factors, foremost the patient’s chief complaint: pain or infertility (or both).

This article focuses on medical and surgical management of pain. Six experts address such questions as: When is laparoscopy indicated? Is excision or ablation of lesions preferred? What is the role of hysterectomy in eliminating pain? And what can be done about the problem of recurrence?

1. WHAT ARE THE OPTIONS FOR EMPIRIC THERAPY?
One reason for the diagnostic delay with endometriosis, which still averages about six years, is that definitive diagnosis is achieved only through laparoscopic investigation and histologic confirmation. For many women who experience pain thought to be associated with endometriosis, however, clinicians begin empiric treatment with medical agents as a way to avert the need for surgery, if at all possible.

“There is no cure for endometriosis,” says John R. Lue, MD, MPH, “but there are many ways that endometriosis can be treated” and the impact of the disease reduced in a patient’s life. (Editor’s Note: See below for biographical information on each clinician interviewed in this article.)

Medical and hormonal options include
• NSAIDs, often used with combined oral contraceptives (OCs). NSAIDs are not a long-term treatment option because of their effect on cyclo-oxygenase (COX) 1 and 2 enzymes, says Dr. Lue. COX-1 protects the gastrointestinal (GI) system, and prolonged use of NSAIDs can cause adverse GI effects.
• Cyclic combined OCs “are recommended as firstline therapy in the absence of contraindications,” says Dr. Lue, and are often used in combination with NSAIDs. However, the failure rate may be as high as 20% to 25%.² “If pain persists after a trial of three to six months of cyclic OCs, consider switching to continuous low-dose combined OCs for an additional six months,” Dr. Lue adds. When combined OCs were compared with placebo in the treatment of dysmenorrhea, they reduced baseline pain scores by 45% to 52%, compared with 14% to 17% for placebo (P < .001).² They also reduced the volume of endometriomas by 48%, compared with 32% for placebo (P = .04). According to Linda C. Giudice, MD, PhD, “In women with severe dysmenorrhea who have been treated with cyclic combined OCs, a switch to continuous combined OCs reduced pain scores by 58% within six months and by 75% at two years” (P < .001).²
• Depot medroxyprogesterone acetate (DMPA) or the levonorgestrel-releasing intrauterine system (LNG-IUS). These agents suppress the hypothalamic-pituitary-ovarian (HPO) axis to different degrees. DMPA suppresses the HPO completely, preventing ovulation. The LNG-IUS does not fully suppress the HPO but acts directly on endometrial tissue, with antiproliferative effects on eutopic and endometriotic implants, says Dr. Lue. The LNG-IUS also is effective at suppressing disease after surgical treatment, says Dr. Giudice.²
• Gonadotropin-releasing hormone (GnRH) agonist therapy, with estrogen and/or progestin add-back therapy to temper the associated loss in bone mineral density, “may be effective—if only temporarily—as it inhibits the HPO axis and blocks ovarian function, thereby greatly reducing systemic estrogen levels and inducing artificial menopause,” says Dr. Lue.
• Norethindrone acetate, a synthetic progestational agent, is occasionally used as empiric therapy for endometriosis because of its ability to inhibit ovulation. It has antiandrogenic and antiestrogenic effects.
• Aromatase inhibitors. Dr. Lue points to considerable evidence that endometriotic implants are an autocrine source of estrogen.³ “This locally produced estrogen results from overexpression of the enzyme P450 aromatase by endometriotic tissue,” he says. Consequently, in postmenopausal women, “aromatase inhibitors may be used orally in a daily pill form to curtail endometriotic implant production of estrogen and subsequent implant growth.”⁴ In women of reproductive age, aromatase inhibitors are combined with an HPO-suppressive therapy, such as norethindrone acetate. These strategies represent off-label use of aromatase inhibitors.
• Danazol, a synthetic androgen, has been used in the past to treat dysmenorrhea and dyspareunia. Because of its severe androgenic effects, however, it is not widely used today.

“For those using medical approaches, endometriosis-related pain may be reduced by using hormonal treatments to modify reproductive tract events, thereby decreasing local peritoneal inflammation and cytokine production,” says Pamela Stratton, MD. Because endometriosis is a “central sensitivity syndrome,” multidisciplinary approaches, such as physical therapy, may be beneficial to treat myofascial dysfunction and sensitization. “Chronic pain conditions that overlap with endometriosis-associated pain—such as migraines, irritable bowel syndrome, or painful bladder syndrome—should be identified and treated. Mood changes of depression and anxiety common to women with endometriosis-associated pain also warrant treatment,” she says.

Continue on to find out when laparoscopy is indicated >>

2. WHEN IS LAPAROSCOPY INDICATED? 
When medical and hormonal treatments fail to control a patient’s pain, laparoscopy is indicated to confirm the diagnosis of endometriosis. During that procedure, it is also advisable to treat any endometriosis that is present, provided the surgeon is highly experienced in such treatment.

Proper treatment is preferable—even if it requires expert consultation. “No treatment and referral to a more experienced surgeon are better than incomplete treatment by an inexperienced surgeon,” says Ceana Nezhat, MD. “Not all GYN surgeons have the expertise to treat advanced endometriosis.”

Dr. Stratton agrees about the importance of thorough treatment of endometriosis at the time of diagnostic laparoscopy: “At the laparoscopy, the patient benefits if all potential sources of pain are investigated and addressed.” At surgery, the surgeon should look for and treat any lesions suspicious for endometriosis, as well as any other finding that might contribute to pain, she says. “For example, routinely inspecting the appendix for endometriosis or other lesions, and removing affected appendices is reasonable; also, lysis and, where possible, excision of adhesions is an important strategy.”

If a medical approach fails for a patient, “then surgery is indicated to confirm the diagnosis and treat the disease,” agrees Tommaso Falcone, MD.

“Surgery is very effective in treating the pain associated with endometriosis,” Dr. Falcone adds. “Randomized clinical trials have shown that up to 90% of patients who obtain pain relief from surgery will have an effect lasting one year.⁶ If patients do not get relief, then the association of the pain with endometriosis should be questioned and other causes sought.”

The most common anatomic sites of implants
“The most common accepted theory for pathogenesis of endometriosis suggests that implants develop when debris from retrograde menstruation attaches to the pelvic peritoneum,” says Dr. Stratton.⁷ “Thus, the vast majority of lesions occur in the dependent portions of the pelvis, which include the ovarian fossae (posterior broad ligament under the ovaries), cul de sac, and the uterosacral ligaments.⁸ The bladder peritoneum, ovarian surface, uterine peritoneal surface, fallopian tube, and pelvic sidewall are also frequent sites. The colon and appendix are less common sites, and small bowel lesions are rare.”

“However, pain location does not correlate with lesion location,” Dr. Stratton notes. “For this reason, the goal at surgery is to treat all lesions, even ones that are not in sites of pain.”

Continue to find out how disease should be staged >>

3. HOW SHOULD DISEASE BE STAGED? 
Most surgeons with expertise in treating endometriosis attempt to stage the disease at the time of initial laparoscopy, even though a patient’s pain does not always correlate with the stage of disease.

“The staging system for endometriosis is a means to systematically catalogue where lesions are located,” says Dr. Stratton. The most commonly used classification system was developed by the American Society for Reproductive Medicine (ASRM). It takes into account such characteristics as how deep an implant lies, the extent to which it obliterates the posterior cul de sac, and the presence and extent of adhesions. Although the classification system is broken down into four stages ranging from minimal to severe disease, it is fairly complex. For example, it assigns a score for each lesion as well as the size and location of that lesion, notes Dr. Stratton. The presence of an endometrioma automatically renders the disease as stage III or IV, and an obliterated cul de sac means the endometriosis is graded as stage IV.

“This system enables us to communicate with each other about patients and may guide future surgeries for assessment of lesion recurrence or the planning of treatment for lesions the surgeon was unable to treat at an initial surgery,” says Dr. Stratton.

“Women with uterosacral nodularity, fixed pelvic organs, or severe pain with endometriomas may have deep infiltrating lesions. These lesions, in particular, are not captured well with the current staging system,” says Dr. Stratton. Because they appear to be innervated, “the greatest benefit to the patient is achieved by completely excising these lesions.” Preoperative imaging may help confirm the existence, location, and extent of these deep lesions and help the surgeon plan her approach “based on clinical and imaging findings.”

“Severity of pain or duration of surgical effect does not correlate with stage or extent of disease,” Dr. Stratton says.⁹ “In fact, patients with the least amount of disease noted at surgery experience pain sooner, suggesting that the central nervous system may have been remodeled prior to surgery or that the pain is in part due to some other cause.¹⁰ This observation underscores the principle that, while endometriosis may initiate pain, the pain experience is determined by engagement of the central nervous system.”

For more information on the ASRM revised classification of endometriosis, visit www.fertstert.org/article/S0015-0282(97)81391-X/pdf.

Continue to learn whether excision or ablation is preferable >>

4. WHICH IS PREFERABLE: EXCISION OR ABLATION?
In a prospective, randomized, double-blind study, Healey and colleagues compared pain levels following laparoscopic treatment of endometriosis with either excision or ablation. Preoperatively, women in the study completed a questionnaire rating various types of pain using visual analogue scales. They then were randomly assigned to treatment of endometriosis via excision or ablation. Postoperatively, they again completed a questionnaire about pain levels at three, six, nine, and 12 months. Investigators found no significant difference in pain scores at 12 months.¹¹

Five-year follow-up of the same population yielded slightly different findings, however. Although there was a reduction in all pain scores at five years in both the excision and ablation groups, a significantly greater reduction in dyspareunia was observed in the excision group at five years.¹²

In an accompanying editorial, Dr. Falcone and a coauthor called excision versus ablation of ovarian, bowel, and peritoneal endometriosis one of the “great debates” in the surgical management of endometriosis.¹³ “When there is deep involvement of adjacent organs, there is general consensus that excision is best for optimal surgical outcome,” they write. “However, for disease involving the peritoneum alone, there are proponents for either option.”¹³

“This is a very controversial issue,” says Dr. Falcone, “and the debate can sometimes be somewhat inflammatory…. It is hard to understand how a comparative trial could even be accomplished between excision and ablation. In my experience, deep disease typically occurs on the pelvic sidewall over the ureter or in the cul de sac on the bowel or infiltrating the bladder peritoneum. Therefore, ablation would increase the risk of damaging any of these structures. With superficial disease away from critical structures, it should be fine to ablate. Everywhere else and with deep disease, you need to excise or leave disease behind.”

“Endometriomas are a special situation,” Dr. Falcone adds. “Excision of the cyst has been shown in randomized controlled trials (RCTs) to be associated with less risk for recurrence.¹⁴ Therefore, it should be the treatment of choice. However, in patients interested in future fertility, we must take into consideration the potential damage to ovarian reserve associated with excision.”

Endometriosis of the ovaries has unique manifestations. “My approach to ovarian cysts depends on their classification,” says Dr. Nezhat.¹⁵ In general, primary endometriomas (type 1) are small, superficial cysts that contain dark “chocolate” fluid. They tend to be firmly adherent to the ovarian tissue and difficult to remove surgically.

Secondary endometriomas (type 2) are follicular or luteal cysts that have been involved or invaded by cortical endometriotic implants or by primary endometrioma. Secondary endometriomas are further classified by the relationship between cortical endometriosis and the cyst wall. Type 2A endometriomas are usually large, with a capsule that is easily separated from ovarian tissue. Type 2B endometriomas have some features of functional cysts but show deep involvement with surface endometriosis. Type 2C endometriomas are similar, showing extensive surface endometrial implants but with deep penetration of the endometriosis into the cyst wall.¹⁵

“For type 1 endometriomas, I biopsy the cyst to ensure the lesion is benign, then vaporize the endometrioma,” Dr. Nezhat says. “In cases of type 2A and 2B endometriomas, the cyst capsule is easily enucleated and removed. Type 2C endometriomas are biopsied as well, and then I proceed with vaporizing the fibrotic area with a low-power energy source, such as neutral argon plasma, avoiding excessive coagulation and thermal injury.” Recent literature supports the idea of evaluation and biopsy of fibrotic endometriomas to confirm benign conditions, followed by ablation without compromising ovarian function.¹⁶

“Excision and ablation both have indications,” Dr. Nezhat asserts. “It depends on the location and depth of penetration of implants, as well as the ­patient’s ultimate goal. For example, if the patient desires future fertility and has endometriosis on the ovary, removal by excision could damage ovarian function. The same holds true for endometriosis on the fallopian tubes. It’s better in such cases to ­ablate.”

“Ablation is different from coagulation, which is not recommended,” Dr. Nezhat explains. “Ablation vaporizes the diseased area layer by layer, like peeling an onion, until the disease is eradicated. It is similar to dermatologic skin resurfacing. Vaporization is preferable for endometriosis on the tubes and ovaries in patients who desire pregnancy. The choice between excision and ablation depends on the location, depth of penetration, and the patient’s desire for fertility.”

Either way—­and regardless of the primary indication for surgery (pain versus infertility)—a minimally invasive gynecologic surgeon is expected to have the ability to perform both techniques, Dr. Nezhat says.

Continue to find out if hysterectomy is definitive treatment >>

5. IS HYSTERECTOMY DEFINITIVE TREATMENT?
“Not necessarily,” says Dr. Nezhat. “Hysterectomy by itself doesn’t take care of endometriosis unless the patient has adenomyosis. If a patient has endometriosis, the first step is complete treatment of the disease to restore the anatomy. Then the next step might be hysterectomy to give a better long-term result, especially in cases of adenomyosis. Removal of the ovaries at the time of hysterectomy has to be individualized.”

“The implication that hysterectomy ‘cures’ endometriosis is false yet is stated in some textbooks,” says Dr. Nezhat. “Even at the time of hysterectomy, the first step should be complete treatment of endometriosis and restoration of anatomy, followed by the hysterectomy. Leaving endometriosis behind, believing it will go away by itself or not cause future issues, is a gross misperception.”

Removal of the ovaries at hysterectomy?
“There are few comparative studies on the long-term follow-up of patients who have undergone hysterectomy with or without removal of both ovaries,” says Dr. Falcone. “The conventional dogma has been that, in women undergoing definitive surgery for endometriosis, both ovaries should be removed, even if they are normal. I personally believe that this was because hysterectomy was often performed without excision of the endometriosis. So the uterus was removed and disease was left behind. In these cases, recurrent symptoms were due to persistent disease.”

“We reported our experience at the Cleveland Clinic with a seven-year follow-up,” Dr. Falcone continues. “Hysterectomy was performed with excision of all visible disease. Ovaries were conserved if normal and removed if not. We looked at the reoperation-free frequency over time. In women undergoing hysterectomy with excision of visible disease but ovarian preservation, the reoperation-free percentages at two, five, and seven years were 95%, 86%, and 77%, respectively, versus 96%, 91%, and 91% in those without ovarian preservation. So, overall, there was an advantage over time for removal of the ovaries. However, in the subset of women between ages 30 and 39, there was no difference in the long-term recurrence rate if the ovaries were left in. For this reason, in women younger than 40, we recommend keeping normal ovaries if all disease is removed.”¹⁷

Continue on to find out if the risk for postoperative recurrence can be reduced >>

6. CAN THE RISK FOR POSTOPERATIVE RECURRENCE BE REDUCED?
“The main problem with surgery is the recurrence rate,” Dr. Falcone says. “Studies have shown that the recurrence rate of pain at seven years may be as high as 50%.”¹⁷ Furthermore, “the recurrence of pain may not be associated with visualized endometriosis at laparoscopy.”

“Incomplete removal of lesions may be associated with an increase in pain after surgery,” says Dr. Stratton.¹⁸ “Incomplete removal of lesions may occur because of varying technical skill or specific lesion characteristics. The lesions may be difficult to remove because of their location. Lesions may not be recognized because their appearance can vary from subtle (red or clear or white) to classic (blue-black). The depth of the lesion may not be appreciated until surgery is under way, and a surgeon may not be adequately prepared to treat deep lesions when they are identified.”

Adenomyosis is another reason pain may persist or recur after surgery.¹⁹ “Adenomyosis appears as either diffuse or focal thickening of the junctional zone between the endometrium and myometrium of the uterus on T2-weighted MRI,” says Dr. Stratton. “After excision of endometriosis, chronic pelvic pain is significantly more likely to persist in women who have a junctional zone thickness of more than 11 mm on MRI.”

The frequent recurrence of pain after surgery makes the disease a long-term challenge.

“Pelvic pain caused by endometriosis is a chronic problem that requires a multiyear management plan, involving both surgery and hormonal therapy,” says Robert L. Barbieri, MD. “To reduce the number of surgical procedures in the lifetime of a woman with endometriosis and pain, I suggest hormonal medical therapy following conservative surgery for endometriosis.”

“Definitive surgery, such as hysterectomy or hysterectomy plus bilateral salpingo-oophorectomy (BSO), typically results in prolonged symptom relief,” Dr. Barbieri says. “Following hysterectomy, hormonal therapy may not be needed. Following BSO, low-dose hormonal therapy is often needed to reduce the severity of menopausal symptoms.”

After surgical treatment of endometriosis associated with pain, Dr. Barbieri presents the patient with the following menu of hormonal options:
• No hormonal therapy
• Estrogen-progestin contraceptives, either cyclic or continuous
• The LNG-IUS
• Norethindrone acetate (5 mg/d)
• DMPA (150 mg every three months)
• Leuprolide acetate depot (3.75 mg IM monthly)
• Nafarelin nasal spray (200 µg bid)
• Danazol (200 mg bid).

“I explain the common adverse effects with each approach and have the patient select what she determines to be her best option,” says Dr. Barbieri. “In my experience, conservative surgery followed by hormonal therapy is effective in more than 75% of women.”

“The evidence to support postoperative hormonal therapy is modest,” Dr. Barbieri notes. “The best evidence is available for use of the LNG-IUS, estrogen-progestin contraceptives, and GnRH agonists.”^20-22

In addition, he notes, “major professional socie­ties have highlighted the option of postoperative hormonal therapy to reduce the risk for recurrent pain and repetitive surgical procedures in the future.”^23,24

When pain recurs after surgery for endometriosis, it pays to consider what type of pain it is, says Dr. Barbieri.

“There are two major types of pain—nociceptive and neuropathic,” he says. “Nociceptive pain is caused by an injury, acute or chronic. Neuropathic pain is caused by ‘activation’ of neural circuits, sometimes in the absence of an ongoing injury. Many women with endometriosis and chronic pain have both nociceptive and neuropathic pain. Consequently, it is important to consider the use of a multidisciplinary pain practice in the management of chronic pain syndromes. Multidisciplinary pain practices have special expertise in the management of neuropathic pain. Standard conservative surgical intervention is unlikely to improve pain caused by neuropathic mechanisms. Likewise, opioid analgesics are not recommended for the treatment of neuropathic pain.”

REFERENCES
1. Nezhat C, Nezhat F, Nezhat C. Endometriosis: ancient disease, ancient treatments. Fertil Steril. 2012;98(6S):S1-S62.
2. Giudice LC. Clinical practice. Endometriosis. N Engl J Med. 2010;362(25):2389-2398.
3. Pavone ME, Bulun SE. Aromatase inhibitors for the treatment of endometriosis: a review. Fertil Steril. 2012;98(6):1370-1379.
4. Nothnick WB. The emerging use of aromatase inhibitors for endometriosis treatment. Reprod Biol Endocrinol. 2011;9:87.
5. Chwalisz K, Garg R, Brenner RM, et al. Selective progesterone receptor modulators (SPRMs): a novel therapeutic concept in endometriosis. Ann N Y Acad Sci. 2002;955:373-393, 396-406.
6. Duffy JM, Arambage K, Correa FJ, et al. Laparoscopic surgery for endometriosis. Cochrane Database Syst Rev. 2014;(4):CD011031.
7. Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268-279.
8. Stegmann BJ, Sinaii N, Liu S, et al. Using location, color, size, and depth to characterize and identify endometriosis lesions in a cohort of 133 women. Fertil Steril. 2008;89(6):1632-1636.
9. Hsu AL, Sinaii N, Segars J, et al. Relating pelvic pain location to surgical findings of endometriosis. Obstet Gynecol. 2011;118(2 pt 1):223-230.
10. Stratton P, Berkley KJ. Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications. Hum Reprod Update. 2011;17(3):327-346.
11. Healey M, Ang WC, Cheng C. Surgical treatment of endometriosis: a prospective randomized double-blinded trial comparing excision and ablation. Fertil Steril. 2010;94(7):2536-2540.
12. Healey M, Chang C, Kaur H. To excise or ablate endometriosis? A prospective randomized double blinded trial after 5-year follow-up. JMIG. 2014;21(6):999-1004.
13. Falcone T, Wilson JR. Surgical management of endometriosis: excision or ablation. JMIG. 2014;21(6):969.
14. Hart RJ, Hickey M, Maouris P, Buckett W. Excisional surgery versus ablative surgery for ovarian endometriomata. Cochrane Database Syst Rev. 2008;(2):CD004992.
15. Nezhat C, Nezhat F, Nezhat CH, Seidman D. Classification of endometriosis: improving the classification of endometriotic ovarian cysts. Hum Reprod. 1994;9(12):2212-2216.
16. Roman H, Auber M, Mokdad C, et al. Ovarian endometrioma ablation using plasma energy versus cystectomy: a step toward better preservation of the ovarian parenchyma in women wishing to conceive. Fertil Steril. 2011;96(6):1396-1400.
17. Shakiba K, Bena JF, McGill KM, et al. Surgical treatment of endometriosis: a 7-year follow-up on the requirement for further surgery. Obstet Gynecol. 2008;111(6):1285-1292.
18. McAllister SL, McGinty KA, Resuehr D, Berkley KJ. Endometriosis-induced vaginal hyperalgesia in the rat: role of the ectopic growths and their innervation. Pain. 2009;147(1-3):255-264.
19. Parker JD, Leondires M, Sinaii N, et al. Persistence of dysmenorrhea and nonmenstrual pain after optimal endometriosis surgery may indicate adenomyosis. Fertil Steril. 2006;86(3):711-715.
20. Abou-Setta AM, Al-Inany HG, Farquar CM. Levonorgestrel-releasing intrauterine device for symptomatic endometriosis following surgery. Cochrane Database Syst Rev. 2006;(1):CD005072.
21. Seracchioli R, Mabrouk M, Manuzzi L, et al. Postoperative use of oral contraceptive pills for prevention of anatomic relapse or symptom recurrence following surgery. Hum Reprod. 2009;24(11):2729-2735.
22. Hornstein MD, Hemmings R, Yuzpe AA, Heinrichs WL. Use of nafarelin versus placebo after reductive laparoscopic surgery for endometriosis. Fertil Steril. 1997;68(5):860-864.
23. Practice Committee of the American Society for Reproductive Medicine. Treatment of pain associated with endometriosis: a committee opinion. Fertil Steril. 2014;101(4):927-935.
24. Dunselman GA, Vermeulen N, Becker C, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014;29(3):400-412.

IN THIS ARTICLE
• The “why” of endometriosis
• Environmental factors, estrogen, and endometriosis
• Is imaging useful?
• When is diagnostic laparoscopy clearly indicated?

CASE M.L. is a 32-year-old nulliparous woman who is referred to your office by her primary care provider for chronic pelvic pain. She reports severe dysmenorrhea as her main symptom, but she also mentions dyspareunia. She says these symptoms have been present for several years but have increased in intensity gradually. She asks what you consider to be the most likely diagnosis.

What potential diagnoses do you mention to her? And how do you identify the cause of her pain?

Although endometriosis—the presence of endometrial tissue outside the uterus—affects at least 5 million women of reproductive age in the United States alone, it can be a challenging diagnosis for several reasons.

“Endometriosis is a great masquerader,” says Linda Giudice, MD, PhD. “It presents with a variety of pain patterns, intensities, and triggers. It can also involve symptoms that overlap those of other disorders, including disorders of the gastrointestinal and urinary tracts.”

Although endometriosis falls within the differential diagnosis of chronic pelvic pain, “it is usually not high on the list in the primary care setting (adult and adolescent),” adds Dr. Giudice.

John R. Lue, MD, MPH, an author of the most recent practice bulletin on endometriosis from the American College of Obstetricians and Gynecologists,¹ sees the situation similarly.

“The main challenge in the diagnosis of endometriosis is that its presentation mimics other causes of chronic pelvic pain,” he says. “Pelvic pain due to endometriosis is usually chronic (lasting ≥ 6 months). It is associated with dysmenorrhea in 50% to 90% of cases, as well as with dyspareunia, deep pelvic pain, and lower abdominal pain with or without back and loin pain. The pain can occur unpredictably and intermittently throughout the menstrual cycle or it can be continuous. In addition, it can be dull, throbbing, or sharp and may be exacerbated by physical activity.^2,3 Up to 20% of women with endometriosis have concurrent pain conditions.”⁴

There are three types of endometriosis lesions—endometriomas, which affect the ovary; superficial lesions; and deep infiltrating endometriosis. Peritoneal lesions may vary widely in appearance. Some may be clear or red; others brown, blue, or black; and some may have a white, scar-like appearance. To identify this elusive disease, it is critical that the clinician be able to recognize its “many faces.”

Among other diseases of the female pelvis that have a relatively similar presentation, Dr. Lue adds, are pathologies of the
• Uterus (adenomyosis, fibroids)
• Fallopian tube (hydrosalpinx)
• Ovaries (ovarian cysts)
• Bladder (interstitial cystitis)
• Bowel (irritable bowel syndrome)
• Musculoskeletal system (piriformis syndrome).
Before pelvic pain is attributed to endometriosis, he says, the provider should rule out bowel, bladder, musculoskeletal, and psychiatric causes.

This article focuses on seven questions, the answers to which are critical to narrowing in on the diagnosis of endometriosis, including essential factors to consider in the patient history, imaging and other diagnostic tools, and considerations in surgical exploration.

1. WHY SUCH A LONG DELAY IN DIAGNOSIS?
Investigators exploring the length of time from a patient’s presentation with symptoms to diagnosis have found it to be particularly long for endometriosis, ranging from six 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, NSAIDs, 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.

Continue to learn any biomarkers proved to be useful diagnostic tools >>

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 past 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.”

Continue for key aspects of patient history >>

3. WHAT ASPECTS OF THE PATIENT HISTORY ARE KEY?
Dr. Stratton recommends that clinicians begin their evaluation of the patient with pain by asking her to describe that pain: how long she has had it, when it occurs, and which areas are affected.

“Most women with endometriosis-associated pain have chronic pelvic pain,” Dr. Stratton continues.⁵ “Up to 90% of those have dysmenorrhea or cyclic pain with menses.”¹⁰ In addition, women with endometriosis “commonly report having pain with any bleeding or spotting. About 30% of women diagnosed with endometriosis initially present to their gynecologist with dyspareunia.”¹¹

“Episodic pain with menses may become more constant, lasting for many days of the month,” says Dr. Stratton. “Women with dyschezia or dysuria may have endometriosis lesions associated with the bowel or bladder, respectively.¹² When women with these symptoms do not have lesions on the bowel or bladder, these pain symptoms may occur because of higher peritoneal hormone and inflammatory factor levels or because adjacent organs share the neural networks.”

Dr. Giudice views the history similarly: “I believe listening to the patient is essential in evaluating the possibility of her having endometriosis. This involves asking her to describe where her pain is, grading it on a scale of 1 to 10, identifying when in her cycle it occurs, and learning what makes it better or worse.”

“It also is important to assess the quality of the pain,” she adds. “Does it radiate, does it limit her daily activities, does it interfere with her relationships, intercourse, work, school? Is it associated with bowel movements, urination, other pain syndromes?”

“Having a pain questionnaire is a great help so that patients have a chance to reflect on these and other questions that help to frame the pain associated with endometriosis when they come for consultation,” she adds.

By determining if pain is associated with menstruation or spotting, the clinician is better informed about the value of menstrual suppression, says Dr. Stratton. “Determining what makes the pain better or worse can help define triggers which, if treated, can decrease the likelihood of episodes of pain.”

“A detailed history of any medical or surgical treatments and their outcome is helpful in guiding future treatment,” she adds. “While hormonal therapy has been a mainstay of treatment, in some women, some hormonal treatments may worsen pain or have unacceptable adverse effects, such as worsening depression or anxiety. In addition, some pain—especially that associated with deep lesions—may be relieved by surgical treatment;^13,14 pain that worsened after surgery may suggest neural damage.”

“As there is an engagement of the central nervous system, endometriosis is considered a central sensitivity syndrome in which women may also have other sites of pain,” Dr. Stratton says. “Thus, obtaining a history about current symptoms or prior diagnosis of irritable bowel syndrome, interstitial cystitis/painful bladder, migraines, fibromyalgia, or chronic fatigue syndrome is beneficial.^10,15-17 Facilitating treatment for these comorbidities is a key principle in helping women with endometriosis-associated pain, as any condition that triggers or perpetuates pain warrants treatment.”

Continue for what the physical exam entails >>

4. WHAT SHOULD THE PHYSICAL EXAM ENTAIL?
“An abdominal exam and a pelvic exam are essential in evaluating pain in a ­woman when endometriosis is suspected,” says Dr. Giudice. “Sometimes the latter is challenging in young teens and can be deferred.” Overall, however, “the pelvic exam can give insight into pain triggers, adnexal masses (possible endometriomas), and mobility of pelvic organs. A rectovaginal exam is important in evaluating deep infiltrating disease and to gauge the pelvic pain landscape overall. In addition, palpating the pelvic floor musculature is important to distinguish pelvic floor muscle spasm from endometriosis pain.”

“The challenge for clinicians is to think beyond the endometrial implants, taking into account multiple factors that influence pain perception,” says Dr. Stratton. During the examination, the clinician should begin by mapping the regions of pain in the abdomen and back, “distinguishing musculoskeletal pain from deep pain. Determining whether pains are focused or diffuse is also important.”

Dr. Stratton recommends that the routine pelvic exam be modified because a standard bimanual exam “confuses pain signals from the pelvic floor, abdominal wall, bladder, and other viscera. For this reason, a pain-oriented assessment is mandatory.”

Begin with a single digital examination to map tender areas, Dr. Stratton advises. Then consider the size, shape, and mobility of reproductive and pelvic organs. “A bimanual exam will help identify adnexal masses like endometriomas,” she says.

Endometriomas usually are not associated with pain, she adds, but “they are associated with deep infiltrating lesions. Nodularity along the uterosacral ligaments, limited reproductive organ mobility, and thickening of the rectovaginal septum also suggest deep infiltrating lesions. Importantly, deep infiltrating lesions are the lesion type most associated with pain.”^18,19

Continue to learn if imaging is useful in the diagnosis of endometriosis >>

5. IS IMAGING USEFUL IN THE DIAGNOSIS OF ENDOMETRIOSIS?
Laparoscopy remains the gold standard for diagnosis of endometriosis, observes Steven R. Goldstein, MD. Visualization of ­endometriotic implants at the time of surgery—with histologic assessment—offers definitive confirmation of the diagnosis. The physical examination, too, can offer a strong suggestion of endometriosis, he says.

“In the past, the pelvic examination and history often were the sine qua non for patients with pain,” Dr. Goldstein says. “Extreme dysmenorrhea and pain between periods, especially with intercourse, defecation, and exercise, all increased the suspicion of endometriosis. People used to talk about feeling nodularity in the uterosacral ligaments and finding decreased mobility of pelvic structures—but I don’t have any question that the skill of today’s gynecologists in doing a bimanual pelvic exam is a fraction of what it was in years gone by, because they haven’t had the necessity of experience. The first thing they do if there’s any question is send the patient for an ultrasound.”

Of course, ultrasound can be especially helpful in identifying endometriomas—sometimes called chocolate cysts—in the ovary. Endometriomas can have a solid appearance on ultrasound, says Dr. Goldstein, because the fluid they contain (dried blood) is sonolucent or pure black on ultrasound, similar to amniotic fluid or the fluid seen in the bladder. “This ‘chocolate’ fluid contained in endometriomas is homogeneous, particulate, and very monotonous in its appearance, in contrast to the internal echoes observed in hemorrhagic corpus lutea, which are very cobweb-like and can sometimes mimic papillary projections,” he adds.

“What’s absolutely essential when imaging a suspected endometrioma by ultrasound is that there be no evidence of any blood flow contained within that structure. Because it’s dried blood, it shouldn’t have any vascularity. If you see blood flow inside what you would call an endometrioma, you need to rethink your diagnosis,” he says.

In some cases, a supposed endometrioma lacks a black, sonolucent appearance, but “the clinician often can tell that it’s a cystic structure by the very bright posterior wall—what we call posterior wall acoustic enhancement—even though the interior of the structure may appear sort of grayish or whitish rather than the pure black of a simple cyst. It’s still fluid-filled,” Dr. Goldstein says.

In some instances, even endometriotic nodules can be imaged by ultrasound, he adds. “There’s an increasing body of literature that suggests that, if you look carefully in people with deep infiltrating endometriosis, you can often see solid-appearing nodules in the rectovaginal septum or between the uterus and bladder. With the kind of resolution that we now have with the vaginal probe, some of these nodules can be seen. That’s somewhat new, and it’s a function of two things—people looking for endometriosis and the better resolution of more modern equipment.”

Dr. Goldstein believes that MRI is “almost never” indicated in the diagnosis of endometriosis. A more helpful approach would be a consultative ultrasound with someone with more experience. However, when that is not available, or “in areas where you have excellent backup in terms of pelvic MRI, that may be the way to go. I don’t think so,” he demurs, “and some of my colleagues would be very upset at the thought of needing to use MRI to diagnose endometriosis. But in the occasional confusing or difficult case, depending on the quality of the referral pattern you have, it might make sense."

Continue to learn when diagnostic laparoscopy is clearly indicated >>

6. WHEN IS DIAGNOSTIC LAPAROSCOPY CLEARLY INDICATED?
Dr. Giudice believes that laparoscopy—with the intention to treat endometriosis, if present—“is essential when firstline medical therapy fails or when pain is acute and severe.”⁵

Dr. Stratton concurs. “Any woman with chronic pain wants to know what is causing the pain,” she says. Therefore, “women report a benefit from knowing that their pain is ­associated with endometriosis.6 However, diagnostic laparoscopy alone, with the sole purpose of determining the presence of endometriosis but not treating the lesions, is no longer performed, as it poses little benefit to the patient other than peace of mind.”

“The general trend in the US has been to first use hormonal treatments when the diagnosis of endometriosis is suspected, prior to performing surgery,” Dr. Stratton says.¹ In many cases, by using cyclic combined hormonal contraceptives to reduce menstrual flow or “suppressing menstruation with continuous combined hormonal contraceptives,” gonadotropin-releasing hormone analogues (combined with progestin to prevent bone loss) “or continuous progestin alone may be effective in decreasing pain. Not surprisingly, these hormonal approaches are effective for any chronic pelvic pain, even for women who do not have the surgical diagnosis of endometriosis.”²⁰

“When the firstline approach to chronic pelvic pain is hormonal treatment, laparoscopy is considered when these medical treatments have failed to control the pain or are poorly tolerated, or when the diagnosis of endometriosis is in question,” Dr. Stratton says.

“Laparoscopy to treat endometriomas is indicated if an endometrioma is enlarging or measures more than 4 cm in diameter, or if the diagnosis of an ovarian mass is in question,” she explains. “While surgeons have previously been aggressive in removing endometriomas, this practice may have negative consequences on ovarian function. Because endometriomas are pseudocysts, removing them completely leads to the removal of viable ovarian tissue and may diminish ovarian reserve.”^21,22

Continue for the surgical appearance of endometriosis >>

7. WHAT IS THE SURGICAL APPEARANCE OF ENDOMETRIOSIS?
Dr. Giudice returns to the enigmatic nature of endometriosis in addressing this question, mentioning its “many faces” at the time of surgery. “It is imperative that the surgeon recognize the disease in its many forms,” she says. “Also, it is especially helpful at the time of surgery if suspected lesions are biopsied and sent to pathology to have the diagnosis made unequivocally.”⁵

As for the surgical appearance of endometriosis, Dr. Stratton notes that there are three types of lesions—“superficial lesions, deep infiltrating lesions, and endometriomas. Endometriomas occur almost exclusively in the ovary and are pseudocysts without an identifiable cystic lining. They vary in dimension from a few millimeters to several centimeters.”

“Superficial peritoneal endometriosis lesions have a variable appearance, with some lesions being clear or red; some brown, blue or black; and some having a white appearance, like a scar,” says Dr. Stratton. “Endometriosis can be diagnosed on histologic examination of any of these lesion types."

“Overall, single-color lesions have similar frequencies of biopsy-confirmed endometriosis (59% to 62%),” she says.²³ “These lesion appearances likely represent different stages of development of endometriosis, with red or clear lesions occurring first, soon after endometrial tissue implantation; black, blue, or brown lesions occurring later, in response to the hormones varying in the menstrual cycle; and white lesions occurring as the lesions age. Deep infiltrating lesions generally have blue/black or white features.”

“Wide, deep, multiple-color lesions in the cul-de-sac, ovarian fossa, or uterosacral ligaments are most likely endometriosis,” Dr. Stratton adds.²³ Only lesions with multiple colors have a significantly higher percentage of positive biopsies (76%). Importantly, more than half of women with only subtle lesions (small red or white lesions) have endometriosis.

You tell the patient that endometriosis is one of the possible diagnoses for her chronic pelvic pain, and you take a focused history. During a pelvic examination, you observe that her right ovary lacks mobility, and you map a number of trigger points for her pain. Transvaginal ultrasound results suggest the presence of nodules in the rectovaginal septum. You begin empiric treatment with continuous combined hormonal contraceptives to suppress menstruation. On her next visit, M.L. reports reduced but still bothersome pain. Laparoscopy reveals a 2-cm endometrioma in the right ovary and deep infiltrating lesions in the cul-de-sac. The endometrioma is resected. Histology confirms the diagnosis of endometriosis. 

REFERENCES
1. American College of Obstetricians and Gynecologists. Practice Bulletin #114: Management of endometriosis. Obstet Gynecol. 2010; 116(1):223-236.
2. Sanfilippo JS, Wakim NG, Schikler KN, Yussman MA. Endometriosis in association with uterine anomaly. Am J Obstet Gynecol. 1986; 154(1):39-43.
3. Taylor HS, Bagot C, Kardana A. HOX gene expression is altered in the endometrium of women with endometriosis. Hum Reprod. 1999; 14(5):1328-1331.
4. Berkley KJ, Stratton P. Mechanisms: lessons from translational studies of endometriosis. In: Giamberardino MA, ed. Visceral Pain: Clinical, Pathophysiological and Therapeutic Aspects. Oxford, UK: Oxford University Press; 2009:39-50.
5. Giudice LC. Clinical practice: endometriosis. N Engl J Med. 2010;362(25): 2389-2398.
6. Ballard K, Lowton K, Wright J. What’s the delay: a qualitative study of women’s experiences of reaching a diagnosis of endometriosis. Fertil Steril. 2006;86(5):1296-1301.
7. May KE, Conduit-Hulbert SA, Villar J, et al. Peripheral biomarkers of endometriosis: a systematic review. Hum Reprod Update. 2010; 16(6):651-674.
8. May KE, Villar J, Kirtley S, et al. Endometrial alterations in endometriosis: a systematic review of putative biomarkers. Hum Reprod Update. 2011; 17(5):637-653.
9. Tamaresis JS, Irwin JC, Goldfien GA, et al. Molecular classification of endometriosis and disease stage using high-dimensional genomic data. Endocrinology. 2014;155(12):4986-4999.
10. Sinaii N, Cleary SD, Ballweg ML, et al. High rates of autoimmune and endocrine disorders, fibromyalgia, chronic fatigue syndrome and atopic diseases among women with endometriosis: a survey analysis. Hum Reprod. 2002;17(10):2715-2724.
11. De Graaff AA, D’Hooghe TM, Dunselman GA, et al. The significant effect of endometriosis on physical, mental and social wellbeing: results from an international cross-sectional survey. Hum Reprod. 2013;28(10):2677-2685.
12. Lafay Pillet MC, Huchon C, Santulli P, et al. A clinical score can predict associated deep infiltrating endometriosis before surgery for an endometrioma. Hum Reprod. 2014;29(8):1666-1676.
13. Healey M, Cheng C, Kaur H. To excise or ablate endometriosis? A prospective randomized double-blinded trial after 5-year follow-up. J Minim Invasive Gynecol. 2014;21(6):999-1004.
14. Anaf V, El Nakadi I, De Moor V, et al. Increased nerve density in deep infiltrating endometriotic nodules. Gynecol Obstet Invest. 2011;71(2):112-117.
15. Stratton P, Berkley KJ. Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications. Hum Reprod Update. 2011;17(3):327-346.
16. Karp BI, Sinaii N, Nieman LK, et al. Migraine in women with chronic pelvic pain with and without endometriosis. Fertil Steril. 2011;95(3):895-899.
17. Berkley KJ. A life of pelvic pain. Physiol Behav. 2005;86(3):272-280.
18. Fauconnier A, Chapron C. Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications. Hum Reprod Update. 2005;11(6):595-606.
19. Vercellini P, Fedele L, Aimi G, et al. Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: a multivariate analysis of over 1000 patients. Hum Reprod. 2007;22(1):266-271.
20. Ling FW. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Pelvic Pain Study Group. Obstet Gynecol. 1999;93(1):51-58.
21. Muzii L, Di Tucci C, Di Feliciantonio M, et al. The effect of surgery for endometrioma on ovarian reserve evaluated by antral follicle count: a systematic review and meta-analysis. Hum Reprod. 2014;29(10):2190-2198.
22. Muzii L, Luciano AA, Zupi E, Panici PB. Effect of surgery for endometrioma on ovarian function: a different point of view. J Minim Invasive Gynecol. 2014;21(4):531-533.
23. Stegmann BJ, Sinaii N, Liu S, et al. Using location, color, size, and depth to characterize and identify endometriosis lesions in a cohort of 133 women. Fertil Steril. 2008;89(6):1632-1636.

IN THIS ARTICLE
• The “why” of endometriosis
• Environmental factors, estrogen, and endometriosis
• Is imaging useful?
• When is diagnostic laparoscopy clearly indicated?

CASE M.L. is a 32-year-old nulliparous woman who is referred to your office by her primary care provider for chronic pelvic pain. She reports severe dysmenorrhea as her main symptom, but she also mentions dyspareunia. She says these symptoms have been present for several years but have increased in intensity gradually. She asks what you consider to be the most likely diagnosis.

What potential diagnoses do you mention to her? And how do you identify the cause of her pain?

Although endometriosis—the presence of endometrial tissue outside the uterus—affects at least 5 million women of reproductive age in the United States alone, it can be a challenging diagnosis for several reasons.

“Endometriosis is a great masquerader,” says Linda Giudice, MD, PhD. “It presents with a variety of pain patterns, intensities, and triggers. It can also involve symptoms that overlap those of other disorders, including disorders of the gastrointestinal and urinary tracts.”

Although endometriosis falls within the differential diagnosis of chronic pelvic pain, “it is usually not high on the list in the primary care setting (adult and adolescent),” adds Dr. Giudice.

John R. Lue, MD, MPH, an author of the most recent practice bulletin on endometriosis from the American College of Obstetricians and Gynecologists,¹ sees the situation similarly.

“The main challenge in the diagnosis of endometriosis is that its presentation mimics other causes of chronic pelvic pain,” he says. “Pelvic pain due to endometriosis is usually chronic (lasting ≥ 6 months). It is associated with dysmenorrhea in 50% to 90% of cases, as well as with dyspareunia, deep pelvic pain, and lower abdominal pain with or without back and loin pain. The pain can occur unpredictably and intermittently throughout the menstrual cycle or it can be continuous. In addition, it can be dull, throbbing, or sharp and may be exacerbated by physical activity.^2,3 Up to 20% of women with endometriosis have concurrent pain conditions.”⁴

There are three types of endometriosis lesions—endometriomas, which affect the ovary; superficial lesions; and deep infiltrating endometriosis. Peritoneal lesions may vary widely in appearance. Some may be clear or red; others brown, blue, or black; and some may have a white, scar-like appearance. To identify this elusive disease, it is critical that the clinician be able to recognize its “many faces.”

Among other diseases of the female pelvis that have a relatively similar presentation, Dr. Lue adds, are pathologies of the
• Uterus (adenomyosis, fibroids)
• Fallopian tube (hydrosalpinx)
• Ovaries (ovarian cysts)
• Bladder (interstitial cystitis)
• Bowel (irritable bowel syndrome)
• Musculoskeletal system (piriformis syndrome).
Before pelvic pain is attributed to endometriosis, he says, the provider should rule out bowel, bladder, musculoskeletal, and psychiatric causes.

This article focuses on seven questions, the answers to which are critical to narrowing in on the diagnosis of endometriosis, including essential factors to consider in the patient history, imaging and other diagnostic tools, and considerations in surgical exploration.

1. WHY SUCH A LONG DELAY IN DIAGNOSIS?
Investigators exploring the length of time from a patient’s presentation with symptoms to diagnosis have found it to be particularly long for endometriosis, ranging from six 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, NSAIDs, 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.

Continue to learn any biomarkers proved to be useful diagnostic tools >>

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 past 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.”

Continue for key aspects of patient history >>

3. WHAT ASPECTS OF THE PATIENT HISTORY ARE KEY?
Dr. Stratton recommends that clinicians begin their evaluation of the patient with pain by asking her to describe that pain: how long she has had it, when it occurs, and which areas are affected.

“Most women with endometriosis-associated pain have chronic pelvic pain,” Dr. Stratton continues.⁵ “Up to 90% of those have dysmenorrhea or cyclic pain with menses.”¹⁰ In addition, women with endometriosis “commonly report having pain with any bleeding or spotting. About 30% of women diagnosed with endometriosis initially present to their gynecologist with dyspareunia.”¹¹

“Episodic pain with menses may become more constant, lasting for many days of the month,” says Dr. Stratton. “Women with dyschezia or dysuria may have endometriosis lesions associated with the bowel or bladder, respectively.¹² When women with these symptoms do not have lesions on the bowel or bladder, these pain symptoms may occur because of higher peritoneal hormone and inflammatory factor levels or because adjacent organs share the neural networks.”

Dr. Giudice views the history similarly: “I believe listening to the patient is essential in evaluating the possibility of her having endometriosis. This involves asking her to describe where her pain is, grading it on a scale of 1 to 10, identifying when in her cycle it occurs, and learning what makes it better or worse.”

“It also is important to assess the quality of the pain,” she adds. “Does it radiate, does it limit her daily activities, does it interfere with her relationships, intercourse, work, school? Is it associated with bowel movements, urination, other pain syndromes?”

“Having a pain questionnaire is a great help so that patients have a chance to reflect on these and other questions that help to frame the pain associated with endometriosis when they come for consultation,” she adds.

By determining if pain is associated with menstruation or spotting, the clinician is better informed about the value of menstrual suppression, says Dr. Stratton. “Determining what makes the pain better or worse can help define triggers which, if treated, can decrease the likelihood of episodes of pain.”

“A detailed history of any medical or surgical treatments and their outcome is helpful in guiding future treatment,” she adds. “While hormonal therapy has been a mainstay of treatment, in some women, some hormonal treatments may worsen pain or have unacceptable adverse effects, such as worsening depression or anxiety. In addition, some pain—especially that associated with deep lesions—may be relieved by surgical treatment;^13,14 pain that worsened after surgery may suggest neural damage.”

“As there is an engagement of the central nervous system, endometriosis is considered a central sensitivity syndrome in which women may also have other sites of pain,” Dr. Stratton says. “Thus, obtaining a history about current symptoms or prior diagnosis of irritable bowel syndrome, interstitial cystitis/painful bladder, migraines, fibromyalgia, or chronic fatigue syndrome is beneficial.^10,15-17 Facilitating treatment for these comorbidities is a key principle in helping women with endometriosis-associated pain, as any condition that triggers or perpetuates pain warrants treatment.”

Continue for what the physical exam entails >>

4. WHAT SHOULD THE PHYSICAL EXAM ENTAIL?
“An abdominal exam and a pelvic exam are essential in evaluating pain in a ­woman when endometriosis is suspected,” says Dr. Giudice. “Sometimes the latter is challenging in young teens and can be deferred.” Overall, however, “the pelvic exam can give insight into pain triggers, adnexal masses (possible endometriomas), and mobility of pelvic organs. A rectovaginal exam is important in evaluating deep infiltrating disease and to gauge the pelvic pain landscape overall. In addition, palpating the pelvic floor musculature is important to distinguish pelvic floor muscle spasm from endometriosis pain.”

“The challenge for clinicians is to think beyond the endometrial implants, taking into account multiple factors that influence pain perception,” says Dr. Stratton. During the examination, the clinician should begin by mapping the regions of pain in the abdomen and back, “distinguishing musculoskeletal pain from deep pain. Determining whether pains are focused or diffuse is also important.”

Dr. Stratton recommends that the routine pelvic exam be modified because a standard bimanual exam “confuses pain signals from the pelvic floor, abdominal wall, bladder, and other viscera. For this reason, a pain-oriented assessment is mandatory.”

Begin with a single digital examination to map tender areas, Dr. Stratton advises. Then consider the size, shape, and mobility of reproductive and pelvic organs. “A bimanual exam will help identify adnexal masses like endometriomas,” she says.

Endometriomas usually are not associated with pain, she adds, but “they are associated with deep infiltrating lesions. Nodularity along the uterosacral ligaments, limited reproductive organ mobility, and thickening of the rectovaginal septum also suggest deep infiltrating lesions. Importantly, deep infiltrating lesions are the lesion type most associated with pain.”^18,19

Continue to learn if imaging is useful in the diagnosis of endometriosis >>

5. IS IMAGING USEFUL IN THE DIAGNOSIS OF ENDOMETRIOSIS?
Laparoscopy remains the gold standard for diagnosis of endometriosis, observes Steven R. Goldstein, MD. Visualization of ­endometriotic implants at the time of surgery—with histologic assessment—offers definitive confirmation of the diagnosis. The physical examination, too, can offer a strong suggestion of endometriosis, he says.

“In the past, the pelvic examination and history often were the sine qua non for patients with pain,” Dr. Goldstein says. “Extreme dysmenorrhea and pain between periods, especially with intercourse, defecation, and exercise, all increased the suspicion of endometriosis. People used to talk about feeling nodularity in the uterosacral ligaments and finding decreased mobility of pelvic structures—but I don’t have any question that the skill of today’s gynecologists in doing a bimanual pelvic exam is a fraction of what it was in years gone by, because they haven’t had the necessity of experience. The first thing they do if there’s any question is send the patient for an ultrasound.”

Of course, ultrasound can be especially helpful in identifying endometriomas—sometimes called chocolate cysts—in the ovary. Endometriomas can have a solid appearance on ultrasound, says Dr. Goldstein, because the fluid they contain (dried blood) is sonolucent or pure black on ultrasound, similar to amniotic fluid or the fluid seen in the bladder. “This ‘chocolate’ fluid contained in endometriomas is homogeneous, particulate, and very monotonous in its appearance, in contrast to the internal echoes observed in hemorrhagic corpus lutea, which are very cobweb-like and can sometimes mimic papillary projections,” he adds.

“What’s absolutely essential when imaging a suspected endometrioma by ultrasound is that there be no evidence of any blood flow contained within that structure. Because it’s dried blood, it shouldn’t have any vascularity. If you see blood flow inside what you would call an endometrioma, you need to rethink your diagnosis,” he says.

In some cases, a supposed endometrioma lacks a black, sonolucent appearance, but “the clinician often can tell that it’s a cystic structure by the very bright posterior wall—what we call posterior wall acoustic enhancement—even though the interior of the structure may appear sort of grayish or whitish rather than the pure black of a simple cyst. It’s still fluid-filled,” Dr. Goldstein says.

In some instances, even endometriotic nodules can be imaged by ultrasound, he adds. “There’s an increasing body of literature that suggests that, if you look carefully in people with deep infiltrating endometriosis, you can often see solid-appearing nodules in the rectovaginal septum or between the uterus and bladder. With the kind of resolution that we now have with the vaginal probe, some of these nodules can be seen. That’s somewhat new, and it’s a function of two things—people looking for endometriosis and the better resolution of more modern equipment.”

Dr. Goldstein believes that MRI is “almost never” indicated in the diagnosis of endometriosis. A more helpful approach would be a consultative ultrasound with someone with more experience. However, when that is not available, or “in areas where you have excellent backup in terms of pelvic MRI, that may be the way to go. I don’t think so,” he demurs, “and some of my colleagues would be very upset at the thought of needing to use MRI to diagnose endometriosis. But in the occasional confusing or difficult case, depending on the quality of the referral pattern you have, it might make sense."

Continue to learn when diagnostic laparoscopy is clearly indicated >>

6. WHEN IS DIAGNOSTIC LAPAROSCOPY CLEARLY INDICATED?
Dr. Giudice believes that laparoscopy—with the intention to treat endometriosis, if present—“is essential when firstline medical therapy fails or when pain is acute and severe.”⁵

Dr. Stratton concurs. “Any woman with chronic pain wants to know what is causing the pain,” she says. Therefore, “women report a benefit from knowing that their pain is ­associated with endometriosis.6 However, diagnostic laparoscopy alone, with the sole purpose of determining the presence of endometriosis but not treating the lesions, is no longer performed, as it poses little benefit to the patient other than peace of mind.”

“The general trend in the US has been to first use hormonal treatments when the diagnosis of endometriosis is suspected, prior to performing surgery,” Dr. Stratton says.¹ In many cases, by using cyclic combined hormonal contraceptives to reduce menstrual flow or “suppressing menstruation with continuous combined hormonal contraceptives,” gonadotropin-releasing hormone analogues (combined with progestin to prevent bone loss) “or continuous progestin alone may be effective in decreasing pain. Not surprisingly, these hormonal approaches are effective for any chronic pelvic pain, even for women who do not have the surgical diagnosis of endometriosis.”²⁰

“When the firstline approach to chronic pelvic pain is hormonal treatment, laparoscopy is considered when these medical treatments have failed to control the pain or are poorly tolerated, or when the diagnosis of endometriosis is in question,” Dr. Stratton says.

“Laparoscopy to treat endometriomas is indicated if an endometrioma is enlarging or measures more than 4 cm in diameter, or if the diagnosis of an ovarian mass is in question,” she explains. “While surgeons have previously been aggressive in removing endometriomas, this practice may have negative consequences on ovarian function. Because endometriomas are pseudocysts, removing them completely leads to the removal of viable ovarian tissue and may diminish ovarian reserve.”^21,22

Continue for the surgical appearance of endometriosis >>

7. WHAT IS THE SURGICAL APPEARANCE OF ENDOMETRIOSIS?
Dr. Giudice returns to the enigmatic nature of endometriosis in addressing this question, mentioning its “many faces” at the time of surgery. “It is imperative that the surgeon recognize the disease in its many forms,” she says. “Also, it is especially helpful at the time of surgery if suspected lesions are biopsied and sent to pathology to have the diagnosis made unequivocally.”⁵

As for the surgical appearance of endometriosis, Dr. Stratton notes that there are three types of lesions—“superficial lesions, deep infiltrating lesions, and endometriomas. Endometriomas occur almost exclusively in the ovary and are pseudocysts without an identifiable cystic lining. They vary in dimension from a few millimeters to several centimeters.”

“Superficial peritoneal endometriosis lesions have a variable appearance, with some lesions being clear or red; some brown, blue or black; and some having a white appearance, like a scar,” says Dr. Stratton. “Endometriosis can be diagnosed on histologic examination of any of these lesion types."

“Overall, single-color lesions have similar frequencies of biopsy-confirmed endometriosis (59% to 62%),” she says.²³ “These lesion appearances likely represent different stages of development of endometriosis, with red or clear lesions occurring first, soon after endometrial tissue implantation; black, blue, or brown lesions occurring later, in response to the hormones varying in the menstrual cycle; and white lesions occurring as the lesions age. Deep infiltrating lesions generally have blue/black or white features.”

“Wide, deep, multiple-color lesions in the cul-de-sac, ovarian fossa, or uterosacral ligaments are most likely endometriosis,” Dr. Stratton adds.²³ Only lesions with multiple colors have a significantly higher percentage of positive biopsies (76%). Importantly, more than half of women with only subtle lesions (small red or white lesions) have endometriosis.

You tell the patient that endometriosis is one of the possible diagnoses for her chronic pelvic pain, and you take a focused history. During a pelvic examination, you observe that her right ovary lacks mobility, and you map a number of trigger points for her pain. Transvaginal ultrasound results suggest the presence of nodules in the rectovaginal septum. You begin empiric treatment with continuous combined hormonal contraceptives to suppress menstruation. On her next visit, M.L. reports reduced but still bothersome pain. Laparoscopy reveals a 2-cm endometrioma in the right ovary and deep infiltrating lesions in the cul-de-sac. The endometrioma is resected. Histology confirms the diagnosis of endometriosis. 

REFERENCES
1. American College of Obstetricians and Gynecologists. Practice Bulletin #114: Management of endometriosis. Obstet Gynecol. 2010; 116(1):223-236.
2. Sanfilippo JS, Wakim NG, Schikler KN, Yussman MA. Endometriosis in association with uterine anomaly. Am J Obstet Gynecol. 1986; 154(1):39-43.
3. Taylor HS, Bagot C, Kardana A. HOX gene expression is altered in the endometrium of women with endometriosis. Hum Reprod. 1999; 14(5):1328-1331.
4. Berkley KJ, Stratton P. Mechanisms: lessons from translational studies of endometriosis. In: Giamberardino MA, ed. Visceral Pain: Clinical, Pathophysiological and Therapeutic Aspects. Oxford, UK: Oxford University Press; 2009:39-50.
5. Giudice LC. Clinical practice: endometriosis. N Engl J Med. 2010;362(25): 2389-2398.
6. Ballard K, Lowton K, Wright J. What’s the delay: a qualitative study of women’s experiences of reaching a diagnosis of endometriosis. Fertil Steril. 2006;86(5):1296-1301.
7. May KE, Conduit-Hulbert SA, Villar J, et al. Peripheral biomarkers of endometriosis: a systematic review. Hum Reprod Update. 2010; 16(6):651-674.
8. May KE, Villar J, Kirtley S, et al. Endometrial alterations in endometriosis: a systematic review of putative biomarkers. Hum Reprod Update. 2011; 17(5):637-653.
9. Tamaresis JS, Irwin JC, Goldfien GA, et al. Molecular classification of endometriosis and disease stage using high-dimensional genomic data. Endocrinology. 2014;155(12):4986-4999.
10. Sinaii N, Cleary SD, Ballweg ML, et al. High rates of autoimmune and endocrine disorders, fibromyalgia, chronic fatigue syndrome and atopic diseases among women with endometriosis: a survey analysis. Hum Reprod. 2002;17(10):2715-2724.
11. De Graaff AA, D’Hooghe TM, Dunselman GA, et al. The significant effect of endometriosis on physical, mental and social wellbeing: results from an international cross-sectional survey. Hum Reprod. 2013;28(10):2677-2685.
12. Lafay Pillet MC, Huchon C, Santulli P, et al. A clinical score can predict associated deep infiltrating endometriosis before surgery for an endometrioma. Hum Reprod. 2014;29(8):1666-1676.
13. Healey M, Cheng C, Kaur H. To excise or ablate endometriosis? A prospective randomized double-blinded trial after 5-year follow-up. J Minim Invasive Gynecol. 2014;21(6):999-1004.
14. Anaf V, El Nakadi I, De Moor V, et al. Increased nerve density in deep infiltrating endometriotic nodules. Gynecol Obstet Invest. 2011;71(2):112-117.
15. Stratton P, Berkley KJ. Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications. Hum Reprod Update. 2011;17(3):327-346.
16. Karp BI, Sinaii N, Nieman LK, et al. Migraine in women with chronic pelvic pain with and without endometriosis. Fertil Steril. 2011;95(3):895-899.
17. Berkley KJ. A life of pelvic pain. Physiol Behav. 2005;86(3):272-280.
18. Fauconnier A, Chapron C. Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications. Hum Reprod Update. 2005;11(6):595-606.
19. Vercellini P, Fedele L, Aimi G, et al. Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: a multivariate analysis of over 1000 patients. Hum Reprod. 2007;22(1):266-271.
20. Ling FW. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Pelvic Pain Study Group. Obstet Gynecol. 1999;93(1):51-58.
21. Muzii L, Di Tucci C, Di Feliciantonio M, et al. The effect of surgery for endometrioma on ovarian reserve evaluated by antral follicle count: a systematic review and meta-analysis. Hum Reprod. 2014;29(10):2190-2198.
22. Muzii L, Luciano AA, Zupi E, Panici PB. Effect of surgery for endometrioma on ovarian function: a different point of view. J Minim Invasive Gynecol. 2014;21(4):531-533.
23. Stegmann BJ, Sinaii N, Liu S, et al. Using location, color, size, and depth to characterize and identify endometriosis lesions in a cohort of 133 women. Fertil Steril. 2008;89(6):1632-1636.

IN THIS ARTICLE
• The “why” of endometriosis
• Environmental factors, estrogen, and endometriosis
• Is imaging useful?
• When is diagnostic laparoscopy clearly indicated?

CASE M.L. is a 32-year-old nulliparous woman who is referred to your office by her primary care provider for chronic pelvic pain. She reports severe dysmenorrhea as her main symptom, but she also mentions dyspareunia. She says these symptoms have been present for several years but have increased in intensity gradually. She asks what you consider to be the most likely diagnosis.

What potential diagnoses do you mention to her? And how do you identify the cause of her pain?

Although endometriosis—the presence of endometrial tissue outside the uterus—affects at least 5 million women of reproductive age in the United States alone, it can be a challenging diagnosis for several reasons.

“Endometriosis is a great masquerader,” says Linda Giudice, MD, PhD. “It presents with a variety of pain patterns, intensities, and triggers. It can also involve symptoms that overlap those of other disorders, including disorders of the gastrointestinal and urinary tracts.”

Although endometriosis falls within the differential diagnosis of chronic pelvic pain, “it is usually not high on the list in the primary care setting (adult and adolescent),” adds Dr. Giudice.

John R. Lue, MD, MPH, an author of the most recent practice bulletin on endometriosis from the American College of Obstetricians and Gynecologists,¹ sees the situation similarly.

“The main challenge in the diagnosis of endometriosis is that its presentation mimics other causes of chronic pelvic pain,” he says. “Pelvic pain due to endometriosis is usually chronic (lasting ≥ 6 months). It is associated with dysmenorrhea in 50% to 90% of cases, as well as with dyspareunia, deep pelvic pain, and lower abdominal pain with or without back and loin pain. The pain can occur unpredictably and intermittently throughout the menstrual cycle or it can be continuous. In addition, it can be dull, throbbing, or sharp and may be exacerbated by physical activity.^2,3 Up to 20% of women with endometriosis have concurrent pain conditions.”⁴

There are three types of endometriosis lesions—endometriomas, which affect the ovary; superficial lesions; and deep infiltrating endometriosis. Peritoneal lesions may vary widely in appearance. Some may be clear or red; others brown, blue, or black; and some may have a white, scar-like appearance. To identify this elusive disease, it is critical that the clinician be able to recognize its “many faces.”

Among other diseases of the female pelvis that have a relatively similar presentation, Dr. Lue adds, are pathologies of the
• Uterus (adenomyosis, fibroids)
• Fallopian tube (hydrosalpinx)
• Ovaries (ovarian cysts)
• Bladder (interstitial cystitis)
• Bowel (irritable bowel syndrome)
• Musculoskeletal system (piriformis syndrome).
Before pelvic pain is attributed to endometriosis, he says, the provider should rule out bowel, bladder, musculoskeletal, and psychiatric causes.

This article focuses on seven questions, the answers to which are critical to narrowing in on the diagnosis of endometriosis, including essential factors to consider in the patient history, imaging and other diagnostic tools, and considerations in surgical exploration.

1. WHY SUCH A LONG DELAY IN DIAGNOSIS?
Investigators exploring the length of time from a patient’s presentation with symptoms to diagnosis have found it to be particularly long for endometriosis, ranging from six 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, NSAIDs, 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.

Continue to learn any biomarkers proved to be useful diagnostic tools >>

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 past 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.”

Continue for key aspects of patient history >>

3. WHAT ASPECTS OF THE PATIENT HISTORY ARE KEY?
Dr. Stratton recommends that clinicians begin their evaluation of the patient with pain by asking her to describe that pain: how long she has had it, when it occurs, and which areas are affected.

“Most women with endometriosis-associated pain have chronic pelvic pain,” Dr. Stratton continues.⁵ “Up to 90% of those have dysmenorrhea or cyclic pain with menses.”¹⁰ In addition, women with endometriosis “commonly report having pain with any bleeding or spotting. About 30% of women diagnosed with endometriosis initially present to their gynecologist with dyspareunia.”¹¹

“Episodic pain with menses may become more constant, lasting for many days of the month,” says Dr. Stratton. “Women with dyschezia or dysuria may have endometriosis lesions associated with the bowel or bladder, respectively.¹² When women with these symptoms do not have lesions on the bowel or bladder, these pain symptoms may occur because of higher peritoneal hormone and inflammatory factor levels or because adjacent organs share the neural networks.”

Dr. Giudice views the history similarly: “I believe listening to the patient is essential in evaluating the possibility of her having endometriosis. This involves asking her to describe where her pain is, grading it on a scale of 1 to 10, identifying when in her cycle it occurs, and learning what makes it better or worse.”

“It also is important to assess the quality of the pain,” she adds. “Does it radiate, does it limit her daily activities, does it interfere with her relationships, intercourse, work, school? Is it associated with bowel movements, urination, other pain syndromes?”

“Having a pain questionnaire is a great help so that patients have a chance to reflect on these and other questions that help to frame the pain associated with endometriosis when they come for consultation,” she adds.

By determining if pain is associated with menstruation or spotting, the clinician is better informed about the value of menstrual suppression, says Dr. Stratton. “Determining what makes the pain better or worse can help define triggers which, if treated, can decrease the likelihood of episodes of pain.”

“A detailed history of any medical or surgical treatments and their outcome is helpful in guiding future treatment,” she adds. “While hormonal therapy has been a mainstay of treatment, in some women, some hormonal treatments may worsen pain or have unacceptable adverse effects, such as worsening depression or anxiety. In addition, some pain—especially that associated with deep lesions—may be relieved by surgical treatment;^13,14 pain that worsened after surgery may suggest neural damage.”

“As there is an engagement of the central nervous system, endometriosis is considered a central sensitivity syndrome in which women may also have other sites of pain,” Dr. Stratton says. “Thus, obtaining a history about current symptoms or prior diagnosis of irritable bowel syndrome, interstitial cystitis/painful bladder, migraines, fibromyalgia, or chronic fatigue syndrome is beneficial.^10,15-17 Facilitating treatment for these comorbidities is a key principle in helping women with endometriosis-associated pain, as any condition that triggers or perpetuates pain warrants treatment.”

Continue for what the physical exam entails >>

4. WHAT SHOULD THE PHYSICAL EXAM ENTAIL?
“An abdominal exam and a pelvic exam are essential in evaluating pain in a ­woman when endometriosis is suspected,” says Dr. Giudice. “Sometimes the latter is challenging in young teens and can be deferred.” Overall, however, “the pelvic exam can give insight into pain triggers, adnexal masses (possible endometriomas), and mobility of pelvic organs. A rectovaginal exam is important in evaluating deep infiltrating disease and to gauge the pelvic pain landscape overall. In addition, palpating the pelvic floor musculature is important to distinguish pelvic floor muscle spasm from endometriosis pain.”

“The challenge for clinicians is to think beyond the endometrial implants, taking into account multiple factors that influence pain perception,” says Dr. Stratton. During the examination, the clinician should begin by mapping the regions of pain in the abdomen and back, “distinguishing musculoskeletal pain from deep pain. Determining whether pains are focused or diffuse is also important.”

Dr. Stratton recommends that the routine pelvic exam be modified because a standard bimanual exam “confuses pain signals from the pelvic floor, abdominal wall, bladder, and other viscera. For this reason, a pain-oriented assessment is mandatory.”

Begin with a single digital examination to map tender areas, Dr. Stratton advises. Then consider the size, shape, and mobility of reproductive and pelvic organs. “A bimanual exam will help identify adnexal masses like endometriomas,” she says.

Endometriomas usually are not associated with pain, she adds, but “they are associated with deep infiltrating lesions. Nodularity along the uterosacral ligaments, limited reproductive organ mobility, and thickening of the rectovaginal septum also suggest deep infiltrating lesions. Importantly, deep infiltrating lesions are the lesion type most associated with pain.”^18,19

Continue to learn if imaging is useful in the diagnosis of endometriosis >>

5. IS IMAGING USEFUL IN THE DIAGNOSIS OF ENDOMETRIOSIS?
Laparoscopy remains the gold standard for diagnosis of endometriosis, observes Steven R. Goldstein, MD. Visualization of ­endometriotic implants at the time of surgery—with histologic assessment—offers definitive confirmation of the diagnosis. The physical examination, too, can offer a strong suggestion of endometriosis, he says.

“In the past, the pelvic examination and history often were the sine qua non for patients with pain,” Dr. Goldstein says. “Extreme dysmenorrhea and pain between periods, especially with intercourse, defecation, and exercise, all increased the suspicion of endometriosis. People used to talk about feeling nodularity in the uterosacral ligaments and finding decreased mobility of pelvic structures—but I don’t have any question that the skill of today’s gynecologists in doing a bimanual pelvic exam is a fraction of what it was in years gone by, because they haven’t had the necessity of experience. The first thing they do if there’s any question is send the patient for an ultrasound.”

Of course, ultrasound can be especially helpful in identifying endometriomas—sometimes called chocolate cysts—in the ovary. Endometriomas can have a solid appearance on ultrasound, says Dr. Goldstein, because the fluid they contain (dried blood) is sonolucent or pure black on ultrasound, similar to amniotic fluid or the fluid seen in the bladder. “This ‘chocolate’ fluid contained in endometriomas is homogeneous, particulate, and very monotonous in its appearance, in contrast to the internal echoes observed in hemorrhagic corpus lutea, which are very cobweb-like and can sometimes mimic papillary projections,” he adds.

“What’s absolutely essential when imaging a suspected endometrioma by ultrasound is that there be no evidence of any blood flow contained within that structure. Because it’s dried blood, it shouldn’t have any vascularity. If you see blood flow inside what you would call an endometrioma, you need to rethink your diagnosis,” he says.

In some cases, a supposed endometrioma lacks a black, sonolucent appearance, but “the clinician often can tell that it’s a cystic structure by the very bright posterior wall—what we call posterior wall acoustic enhancement—even though the interior of the structure may appear sort of grayish or whitish rather than the pure black of a simple cyst. It’s still fluid-filled,” Dr. Goldstein says.

In some instances, even endometriotic nodules can be imaged by ultrasound, he adds. “There’s an increasing body of literature that suggests that, if you look carefully in people with deep infiltrating endometriosis, you can often see solid-appearing nodules in the rectovaginal septum or between the uterus and bladder. With the kind of resolution that we now have with the vaginal probe, some of these nodules can be seen. That’s somewhat new, and it’s a function of two things—people looking for endometriosis and the better resolution of more modern equipment.”

Dr. Goldstein believes that MRI is “almost never” indicated in the diagnosis of endometriosis. A more helpful approach would be a consultative ultrasound with someone with more experience. However, when that is not available, or “in areas where you have excellent backup in terms of pelvic MRI, that may be the way to go. I don’t think so,” he demurs, “and some of my colleagues would be very upset at the thought of needing to use MRI to diagnose endometriosis. But in the occasional confusing or difficult case, depending on the quality of the referral pattern you have, it might make sense."

Continue to learn when diagnostic laparoscopy is clearly indicated >>

6. WHEN IS DIAGNOSTIC LAPAROSCOPY CLEARLY INDICATED?
Dr. Giudice believes that laparoscopy—with the intention to treat endometriosis, if present—“is essential when firstline medical therapy fails or when pain is acute and severe.”⁵

Dr. Stratton concurs. “Any woman with chronic pain wants to know what is causing the pain,” she says. Therefore, “women report a benefit from knowing that their pain is ­associated with endometriosis.6 However, diagnostic laparoscopy alone, with the sole purpose of determining the presence of endometriosis but not treating the lesions, is no longer performed, as it poses little benefit to the patient other than peace of mind.”

“The general trend in the US has been to first use hormonal treatments when the diagnosis of endometriosis is suspected, prior to performing surgery,” Dr. Stratton says.¹ In many cases, by using cyclic combined hormonal contraceptives to reduce menstrual flow or “suppressing menstruation with continuous combined hormonal contraceptives,” gonadotropin-releasing hormone analogues (combined with progestin to prevent bone loss) “or continuous progestin alone may be effective in decreasing pain. Not surprisingly, these hormonal approaches are effective for any chronic pelvic pain, even for women who do not have the surgical diagnosis of endometriosis.”²⁰

“When the firstline approach to chronic pelvic pain is hormonal treatment, laparoscopy is considered when these medical treatments have failed to control the pain or are poorly tolerated, or when the diagnosis of endometriosis is in question,” Dr. Stratton says.

“Laparoscopy to treat endometriomas is indicated if an endometrioma is enlarging or measures more than 4 cm in diameter, or if the diagnosis of an ovarian mass is in question,” she explains. “While surgeons have previously been aggressive in removing endometriomas, this practice may have negative consequences on ovarian function. Because endometriomas are pseudocysts, removing them completely leads to the removal of viable ovarian tissue and may diminish ovarian reserve.”^21,22

Continue for the surgical appearance of endometriosis >>

7. WHAT IS THE SURGICAL APPEARANCE OF ENDOMETRIOSIS?
Dr. Giudice returns to the enigmatic nature of endometriosis in addressing this question, mentioning its “many faces” at the time of surgery. “It is imperative that the surgeon recognize the disease in its many forms,” she says. “Also, it is especially helpful at the time of surgery if suspected lesions are biopsied and sent to pathology to have the diagnosis made unequivocally.”⁵

As for the surgical appearance of endometriosis, Dr. Stratton notes that there are three types of lesions—“superficial lesions, deep infiltrating lesions, and endometriomas. Endometriomas occur almost exclusively in the ovary and are pseudocysts without an identifiable cystic lining. They vary in dimension from a few millimeters to several centimeters.”

“Superficial peritoneal endometriosis lesions have a variable appearance, with some lesions being clear or red; some brown, blue or black; and some having a white appearance, like a scar,” says Dr. Stratton. “Endometriosis can be diagnosed on histologic examination of any of these lesion types."

“Overall, single-color lesions have similar frequencies of biopsy-confirmed endometriosis (59% to 62%),” she says.²³ “These lesion appearances likely represent different stages of development of endometriosis, with red or clear lesions occurring first, soon after endometrial tissue implantation; black, blue, or brown lesions occurring later, in response to the hormones varying in the menstrual cycle; and white lesions occurring as the lesions age. Deep infiltrating lesions generally have blue/black or white features.”

“Wide, deep, multiple-color lesions in the cul-de-sac, ovarian fossa, or uterosacral ligaments are most likely endometriosis,” Dr. Stratton adds.²³ Only lesions with multiple colors have a significantly higher percentage of positive biopsies (76%). Importantly, more than half of women with only subtle lesions (small red or white lesions) have endometriosis.

You tell the patient that endometriosis is one of the possible diagnoses for her chronic pelvic pain, and you take a focused history. During a pelvic examination, you observe that her right ovary lacks mobility, and you map a number of trigger points for her pain. Transvaginal ultrasound results suggest the presence of nodules in the rectovaginal septum. You begin empiric treatment with continuous combined hormonal contraceptives to suppress menstruation. On her next visit, M.L. reports reduced but still bothersome pain. Laparoscopy reveals a 2-cm endometrioma in the right ovary and deep infiltrating lesions in the cul-de-sac. The endometrioma is resected. Histology confirms the diagnosis of endometriosis. 

REFERENCES
1. American College of Obstetricians and Gynecologists. Practice Bulletin #114: Management of endometriosis. Obstet Gynecol. 2010; 116(1):223-236.
2. Sanfilippo JS, Wakim NG, Schikler KN, Yussman MA. Endometriosis in association with uterine anomaly. Am J Obstet Gynecol. 1986; 154(1):39-43.
3. Taylor HS, Bagot C, Kardana A. HOX gene expression is altered in the endometrium of women with endometriosis. Hum Reprod. 1999; 14(5):1328-1331.
4. Berkley KJ, Stratton P. Mechanisms: lessons from translational studies of endometriosis. In: Giamberardino MA, ed. Visceral Pain: Clinical, Pathophysiological and Therapeutic Aspects. Oxford, UK: Oxford University Press; 2009:39-50.
5. Giudice LC. Clinical practice: endometriosis. N Engl J Med. 2010;362(25): 2389-2398.
6. Ballard K, Lowton K, Wright J. What’s the delay: a qualitative study of women’s experiences of reaching a diagnosis of endometriosis. Fertil Steril. 2006;86(5):1296-1301.
7. May KE, Conduit-Hulbert SA, Villar J, et al. Peripheral biomarkers of endometriosis: a systematic review. Hum Reprod Update. 2010; 16(6):651-674.
8. May KE, Villar J, Kirtley S, et al. Endometrial alterations in endometriosis: a systematic review of putative biomarkers. Hum Reprod Update. 2011; 17(5):637-653.
9. Tamaresis JS, Irwin JC, Goldfien GA, et al. Molecular classification of endometriosis and disease stage using high-dimensional genomic data. Endocrinology. 2014;155(12):4986-4999.
10. Sinaii N, Cleary SD, Ballweg ML, et al. High rates of autoimmune and endocrine disorders, fibromyalgia, chronic fatigue syndrome and atopic diseases among women with endometriosis: a survey analysis. Hum Reprod. 2002;17(10):2715-2724.
11. De Graaff AA, D’Hooghe TM, Dunselman GA, et al. The significant effect of endometriosis on physical, mental and social wellbeing: results from an international cross-sectional survey. Hum Reprod. 2013;28(10):2677-2685.
12. Lafay Pillet MC, Huchon C, Santulli P, et al. A clinical score can predict associated deep infiltrating endometriosis before surgery for an endometrioma. Hum Reprod. 2014;29(8):1666-1676.
13. Healey M, Cheng C, Kaur H. To excise or ablate endometriosis? A prospective randomized double-blinded trial after 5-year follow-up. J Minim Invasive Gynecol. 2014;21(6):999-1004.
14. Anaf V, El Nakadi I, De Moor V, et al. Increased nerve density in deep infiltrating endometriotic nodules. Gynecol Obstet Invest. 2011;71(2):112-117.
15. Stratton P, Berkley KJ. Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications. Hum Reprod Update. 2011;17(3):327-346.
16. Karp BI, Sinaii N, Nieman LK, et al. Migraine in women with chronic pelvic pain with and without endometriosis. Fertil Steril. 2011;95(3):895-899.
17. Berkley KJ. A life of pelvic pain. Physiol Behav. 2005;86(3):272-280.
18. Fauconnier A, Chapron C. Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications. Hum Reprod Update. 2005;11(6):595-606.
19. Vercellini P, Fedele L, Aimi G, et al. Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: a multivariate analysis of over 1000 patients. Hum Reprod. 2007;22(1):266-271.
20. Ling FW. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Pelvic Pain Study Group. Obstet Gynecol. 1999;93(1):51-58.
21. Muzii L, Di Tucci C, Di Feliciantonio M, et al. The effect of surgery for endometrioma on ovarian reserve evaluated by antral follicle count: a systematic review and meta-analysis. Hum Reprod. 2014;29(10):2190-2198.
22. Muzii L, Luciano AA, Zupi E, Panici PB. Effect of surgery for endometrioma on ovarian function: a different point of view. J Minim Invasive Gynecol. 2014;21(4):531-533.
23. Stegmann BJ, Sinaii N, Liu S, et al. Using location, color, size, and depth to characterize and identify endometriosis lesions in a cohort of 133 women. Fertil Steril. 2008;89(6):1632-1636.

Although endometriosis and infertility are clearly linked—in life as well as the medical literature—no causal relationship has been established. Nevertheless, data suggest that 25% to 50% of infertile women have endometriosis, and that as many as 30% to 50% of women who have endometriosis are infertile.¹

Among the mechanisms that have been proposed to explain this link are:

Recent studies by Kao and colleagues and Giudice and colleagues have led to new findings in regard to endometriosis and infertility, says Ceana Nezhat, MD.^3,4 Dr. ­Nezhat is Director of the Nezhat Medical Center in Atlanta, Georgia, and Medical Director of Training and Education at ­Northside ­Hospital in Atlanta. “These researchers have discovered that endometriosis causes changes to the endometrium that contribute to infertility.”

“There are no studies that have specifically assessed whether one anatomic site is associated with increased infertility over another,” says Tommaso Falcone, MD. “However, it is assumed that disease that involves the tubes and ovaries would impede fertility the most. Adhesive disease and endometriomas around the tubes and ovaries are associated with a worsening prognosis. Although peritoneal disease probably influences fertility solely on the basis of inflammation, disease around the tubes and ovaries is thought to have a mechanical effect as well.” Dr. Falcone is Professor and Chair of Obstetrics and Gynecology at the Cleveland Clinic in Cleveland, Ohio.

“Endometriosis is a chronic and hetero­geneous disease process,” says ­Stephanie J. Estes, MD, Director of Robotic Surgical Services and Associate Professor, Division of Reproductive Endocrinology and ­Infertility, Department of Obstetrics and Gynecology, at Penn State Hershey Medical Center in Hershey, Pennsylvania.

“It is likely that no single site is the causative factor,” Dr. Estes says. “Endometriosis alters prostaglandins, cytokines, and proteases that may adversely affect eggs, sperm, or embryo development. In addition, altered endometrial receptivity may play a role. It has been shown that, when donor oocytes from women with endometriosis are transferred to women without endometriosis, there are lower implantation rates and poorer embryo quality.”⁵

Does it follow, then, that eradication of endometriosis improves fertility?

The answer is not clear. Rather, it depends on a number of variables, including the stage of the disease, its location, the presence of symptoms, and more.

“The approach for endometiosis-­associated infertility is completely different from the approach for pain,” says Dr. Nezhat. “In a patient with pain, complete eradication of endometriosis is necessary. However, when addressing infertility, a surgeon must be cautious in the vicinity of the reproductive organs, even if a multistage approach is required. Fertility preservation is the goal.^6,7 However, thorough treatment of endometriosis improves fertility rates even in cases of failed in vitro fertilization” (IVF).⁸

In this article, the focus is on 6 critical questions concerning endometriosis and infertility, including the role of medical therapy, when surgery is indicated, and whether an endometrioma warrants removal or referral for IVF.

In Part 1 of this 3-part series, which appeared in the April 2015 issue of OBG Management, the subject was diagnosis of endometriosis. In Part 2, which appeared in May 2015, the focus was endometriosis and pain.

1. Is there a role for medical therapy?
In women who have endometriosis-related infertility, medical therapy does not appear to produce any benefit. In its committee opinion on the subject, the American Society for Reproductive Medicine (ASRM) states as much: “There is no evidence that medical treatment of endometriosis improves fertility.”²

In fact, observes Dr. Estes, trials of medical treatment, involving such medications as combined estrogen-­progestin therapy, danazol, progestins, or ­gonadotropin-releasing hormone (GnRH) agonists, may cause an unnecessary “delay in the use of more effective treatments that could result in pregnancy.”

Dr. Nezhat believes that medical therapy is effective in patients who have adenomyosis in addition to endometriosis. “Three months of treatment with a GnRH agonist will improve fertility rates in these patients,” he says.

“Medical treatments inhibit ovulation,” notes Dr. Estes. “These therapies have no role in pretreatment of patients with endometriosis prior to infertility treatment. On the other hand, medical therapy with GnRH agonists for 3 to 6 months prior to an IVF cycle does result in increased pregnancy rates.”⁹

2. What is the role of clomiphene and intrauterine insemination?
Should women who have endometriosis, open fallopian tubes, and infertility be treated with clomiphene and intrauterine insemination (IUI) prior to a cycle of IVF?

“This is a complex question,” says Dr. ­Estes, “as clinical parameters such as age, symptoms, duration of infertility, and the ability to proceed with IVF are important, as well as stage of disease.”

“Overall, in patients younger than 35 years, clomiphene-IUI is an option and has an increased pregnancy rate over timed intercourse” (9% vs 3%), she says.¹⁰ “How­ever, clearly IVF is much more successful and is the most effective treatment, with pregnancy rates of approximately 46% for women younger than 35 years (3% of whom have a ‘diagnosis’ of endometriosis, and 13% of whom have an ‘unknown’ infertility factor).¹¹ Women who are older than 35 or who have additional infertility factors, such as male factor, should consider IVF first.”

3. When is surgery indicated?
“Patients who have significant pain associated with their infertility will benefit from surgery, which offers both pain relief and an improvement in the spontaneous pregnancy rate,” says Dr. Falcone. “Patients who are infertile and desire spontaneous pregnancy without pharmacologic intervention or assisted reproductive technology (ART) also benefit from surgery.”

The benefit of surgery in asymptomatic women with minimal to mild endometriosis is unclear. In a randomized controlled trial of 341 women (aged 20–39 years) with infertility and minimal to mild endometriosis, laparoscopic resection or ablation of visible lesions resulted in pregnancy in 30.7% of women, compared with 17.7% of women who underwent diagnostic laparoscopy only.¹²

Another randomized study of 96 women with minimal to mild endometriosis who underwent resection/ablation or diagnostic laparoscopy found no difference in the birth rate at 1 year.¹³

When the results of these 2 studies are combined, the number needed to treat is 12 laparoscopies in women with endometriosis, says Dr. Falcone. “So 1 additional pregnancy would be gained from performing endometriosis surgery in 12 patients. If we assume a prevalence of 30% in asymptomatic women with infertility, then you need to perform 40 diagnostic laparoscopies to achieve an extra pregnancy.”

For women with infertility and severe endometriosis, a nonrandomized study found cumulative pregnancy rates of 45% and 63% after laparoscopy and laparotomy, respectively, in 216 women followed for up to 2 years.¹⁴ The difference in rates was not statistically significant.

“Although surgery is indicated to diagnose endometriosis, multiple repeat procedures are not an effective treatment for infertility,” says Dr. Estes. “Plus, especially for stage I and II endometriosis [according to the ASRM classification system], approximately 12 patients will need surgery for 1 additional pregnancy—and many more will have needed the procedure to even get to those who have endometriosis. While patients often want us to ‘do something’—­often a covered service such as surgery—we need to consider that surgery for early disease does not provide a significant or long-lasting enhancement to women’s ability to conceive.”

In the absence of male-factor infertility, surgical diagnosis with conservative and precise treatment of endometriosis at the same time is better than going directly to IVF, says Dr. Nezhat. Younger patients who undergo surgical treatment have a better chance of achieving more than 1 spontaneous pregnancy than they do with IVF. And older patients also will have an improved conception rate with ART when they are treated surgically, he says.⁸

Coding and reimbursement 

For endometriosis, the correct diagnostic code helps establish the medical necessity of later treatments
Several diagnostic codes are available to describe the location of endometriotic implants, but the fact remains that these codes can be reported only after a definitive diagnosis is made, which generally comes after confirmatory surgery has been performed. When the patient is in the diagnostic phase, she may present with complaints of pelvic pain, dyspareunia, dysmenorrhea, or infertility. Knowing which codes to use at the time of evaluation goes a long way toward establishing medical necessity for any later surgery or medical treatment.

In the TABLE, you will find common diagnostic codes that can be reported during evaluation of endometriosis, including both International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and ICD-10-CM equivalents. Note that, with ICD-10-CM, payers are looking for a more specific type of dysmenorrhea in the documentation. In the case of painful menstruation suspected to arise from endometriosis, the code for secondary dysmenorrhea should be reported.

Diagnostic coding in cases in which the patient first presents with a complaint of infertility in the absence of other symptoms can be problematic, as many insurers still do not cover the treatment of infertility. However, in the diagnostic stage, codes for fertility testing can be reported instead of codes that confirm infertility when no other symptoms are present. Once the clinician has verified that endometriosis is the source of the infertility and begins treatment, the primary code for the type of endometriosis would be reported, not a diagnosis of infertility.

The procedure performed to diagnose endometriosis would be diagnostic laparoscopy (Current Procedure Terminology [CPT] code 49320, Laparoscopy, abdomen, peritoneum, and omentum, diagnostic, with or without collection of specimen[s] by brushing or washing [separate procedure]) if medical treatment is being pursued. If the plan is to confirm and then immediately remove the implants, the CPT codes would be either 58662, Laparoscopy, surgical; with fulguration or excision of lesions of the ovary, pelvic viscera, or peritoneal surface by any method, or 49203–49205, Excision or destruction, open, intra-abdominal tumors, cysts or endometriomas, 1 or more peritoneal, mesenteric, or retroperitoneal primary or secondary tumors, based on the largest tumor diameter, if they are removed via an abdominal incision.

—Melanie Witt, RN, CPC, COBGC, MA

Ms. Witt is an independent coding and documentation consultant and former program manager, department of coding and nomenclature, American Congress of Obstetricians and Gynecologists.

4. Surgery or IVF for endometriomas?
When an endometrioma is present, should it be surgically treated or should the patient go straight to IVF? And does the optimal approach depend on the size of the endometrioma?

“The answer to this question ultimately depends on the skill and experience of the surgeon and the type of endometrioma,” says Dr. Nezhat, “because improper removal of an endometrioma may compromise the function of the ovary.”

“I recommend removal of the endometrioma by a skilled surgeon experienced in the management of ovarian cysts and preservation of ovarian function, especially in patients who have failed IVF,” he says.^6,15

According to the ASRM committee opinion on endometriosis and infertility, laparoscopic cystectomy for endometriomas larger than 4 cm improves fertility, compared with cyst drainage and coagulation, which is associated with a high risk of cyst recurrence.² However, no randomized trials have compared laparoscopic excision of an endometrioma to expectant management prior to IVF/intracytoplasmic sperm injection (ICSI). One case-control study found that laparoscopic cystectomy prior to IVF had no effect on fertility outcomes.¹⁶ At the same time, however, “conservative surgical treatment in symptomatic patients did not impair the success rates of IVF or ICSI,” notes the ASRM.² Therefore, “evidence suggests that surgery does not benefit asymptomatic women with an endometrioma prior to scheduled IVF/ICSI,” the ASRM concludes.²

Dr. Nezhat cautions against the practice of indiscriminate IVF in the setting of ovarian endometriomas because he has seen patients who developed tubo-ovarian abscess and infected endometriomas after transvaginal egg retrieval. He notes that there are additional case reports of similar findings from other surgeons.

As far as excision versus ablation is concerned, all studies have shown some effect on ovarian function after excision, says Dr. Falcone. “The studies assessed this parameter using several endpoints, such as the number of oocytes retrieved at IVF. Recently, anti-Müllerian hormone has been used and has confirmed this observation. The decreased ovarian reserve is especially problematic with bilateral ovarian disease. The extent of the decreased ovarian function is dependent on several parameters, especially how much energy is used to achieve hemostasis. Several techniques have been proposed to reduce damage, including less traumatic ways of achieving hemostasis in the ovarian hilus.”

“The dilemma is that, if we excise the disease, the pregnancy rates are better than with ablation, but if we excise, there is more damage to the ovary. In my practice, I excise if there is minimal associated disease, such as adhesions, because the pregnancy rate after surgery is good. If, however, there are extensive adhesions with a low chance of spontaneous pregnancy, I minimize excision,” Dr. Falcone says.

As for going straight to IVF, “many patients cannot afford IVF; therefore, surgery is their only option. Furthermore, many patients have severe associated pain; therefore, surgery is required to improve quality of life. However, if the decision is made to proceed to IVF, there is no evidence that cystectomy prior to treatment with ART improves the pregnancy rate,” Dr. Falcone says.

“Basically, if a woman has no pain and no endometrioma, and infertility alone is the issue, I treat her in the same manner as I would a patient with idiopathic infertility—no surgery,” Dr. Falcone says. “If a patient has severe pain and infertility, I treat her surgically but conservatively, especially when an endometrioma is present. The patient will get pain relief but also derive fertility benefit. If a patient has had previous surgery for ­endometriosis-associated infertility, additional surgery is not the next step—as our study has shown that pregnancy rates are better with IVF than repeat surgery.”¹⁷

5. Is surgery ever effective after failed IVF?
To answer this question, Dr. Nezhat points to a retrospective case series by Littman and colleagues in which 29 women with a history of failed IVF underwent laparoscopic evaluation and treatment of endometriosis (by the same surgeon).⁸ Of 29 patients, 22 conceived after laparoscopic treatment of ­endometriosis, including 15 “non-IVF” pregnancies and 7 IVF pregnancies, the study results show.⁸

“It is not unusual for patients and health care providers to perceive IVF as the final treatment for infertility,” Littman and colleagues write. “When this definitive therapy fails repeatedly, clinicians and patients may be inclined to pursue oocyte donation or elect to forego further treatment altogether. This is especially true in women of advanced age and in patients with borderline embryo quality. Presently, as a result of our clinical observation in patients with failed IVF, before egg donation or adoption, we offer the option to have meticulous laparoscopic evaluation and treatment by a skilled surgeon. Furthermore, we would not classify an infertility condition as unexplained without confirming the absence of endometriosis by a thorough laparoscopy. In our experience, patients under 35 years old with unexplained infertility who are found to have endometriosis at the time of laparoscopy have an excellent chance of pregnancy following surgical treatment without ART.”⁸

6. Is repeat surgery ever helpful?
In the treatment of endometriosis-­associated infertility, repeat surgery should be avoided if no symptoms are present, says Dr. Estes. “In women with continued symptoms, the benefits of repeat surgery are small, with known risks, including the potential for adhesive disease and the iatro­genic detrimental effect on ovarian ­function—often in a setting of already-present decreased ovarian reserve.”

Dr. Nezhat agrees that multiple surgeries carry the potential for harm. “However, there is one caveat,” he says. “What was done at the previous surgery and how? The skill and experience of the surgeon and proper technique are of paramount importance to the surgical outcome.”

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Although endometriosis and infertility are clearly linked—in life as well as the medical literature—no causal relationship has been established. Nevertheless, data suggest that 25% to 50% of infertile women have endometriosis, and that as many as 30% to 50% of women who have endometriosis are infertile.¹

Among the mechanisms that have been proposed to explain this link are:

Recent studies by Kao and colleagues and Giudice and colleagues have led to new findings in regard to endometriosis and infertility, says Ceana Nezhat, MD.^3,4 Dr. ­Nezhat is Director of the Nezhat Medical Center in Atlanta, Georgia, and Medical Director of Training and Education at ­Northside ­Hospital in Atlanta. “These researchers have discovered that endometriosis causes changes to the endometrium that contribute to infertility.”

“There are no studies that have specifically assessed whether one anatomic site is associated with increased infertility over another,” says Tommaso Falcone, MD. “However, it is assumed that disease that involves the tubes and ovaries would impede fertility the most. Adhesive disease and endometriomas around the tubes and ovaries are associated with a worsening prognosis. Although peritoneal disease probably influences fertility solely on the basis of inflammation, disease around the tubes and ovaries is thought to have a mechanical effect as well.” Dr. Falcone is Professor and Chair of Obstetrics and Gynecology at the Cleveland Clinic in Cleveland, Ohio.

“Endometriosis is a chronic and hetero­geneous disease process,” says ­Stephanie J. Estes, MD, Director of Robotic Surgical Services and Associate Professor, Division of Reproductive Endocrinology and ­Infertility, Department of Obstetrics and Gynecology, at Penn State Hershey Medical Center in Hershey, Pennsylvania.

“It is likely that no single site is the causative factor,” Dr. Estes says. “Endometriosis alters prostaglandins, cytokines, and proteases that may adversely affect eggs, sperm, or embryo development. In addition, altered endometrial receptivity may play a role. It has been shown that, when donor oocytes from women with endometriosis are transferred to women without endometriosis, there are lower implantation rates and poorer embryo quality.”⁵

Does it follow, then, that eradication of endometriosis improves fertility?

The answer is not clear. Rather, it depends on a number of variables, including the stage of the disease, its location, the presence of symptoms, and more.

“The approach for endometiosis-­associated infertility is completely different from the approach for pain,” says Dr. Nezhat. “In a patient with pain, complete eradication of endometriosis is necessary. However, when addressing infertility, a surgeon must be cautious in the vicinity of the reproductive organs, even if a multistage approach is required. Fertility preservation is the goal.^6,7 However, thorough treatment of endometriosis improves fertility rates even in cases of failed in vitro fertilization” (IVF).⁸

In this article, the focus is on 6 critical questions concerning endometriosis and infertility, including the role of medical therapy, when surgery is indicated, and whether an endometrioma warrants removal or referral for IVF.

In Part 1 of this 3-part series, which appeared in the April 2015 issue of OBG Management, the subject was diagnosis of endometriosis. In Part 2, which appeared in May 2015, the focus was endometriosis and pain.

1. Is there a role for medical therapy?
In women who have endometriosis-related infertility, medical therapy does not appear to produce any benefit. In its committee opinion on the subject, the American Society for Reproductive Medicine (ASRM) states as much: “There is no evidence that medical treatment of endometriosis improves fertility.”²

In fact, observes Dr. Estes, trials of medical treatment, involving such medications as combined estrogen-­progestin therapy, danazol, progestins, or ­gonadotropin-releasing hormone (GnRH) agonists, may cause an unnecessary “delay in the use of more effective treatments that could result in pregnancy.”

Dr. Nezhat believes that medical therapy is effective in patients who have adenomyosis in addition to endometriosis. “Three months of treatment with a GnRH agonist will improve fertility rates in these patients,” he says.

“Medical treatments inhibit ovulation,” notes Dr. Estes. “These therapies have no role in pretreatment of patients with endometriosis prior to infertility treatment. On the other hand, medical therapy with GnRH agonists for 3 to 6 months prior to an IVF cycle does result in increased pregnancy rates.”⁹

2. What is the role of clomiphene and intrauterine insemination?
Should women who have endometriosis, open fallopian tubes, and infertility be treated with clomiphene and intrauterine insemination (IUI) prior to a cycle of IVF?

“This is a complex question,” says Dr. ­Estes, “as clinical parameters such as age, symptoms, duration of infertility, and the ability to proceed with IVF are important, as well as stage of disease.”

“Overall, in patients younger than 35 years, clomiphene-IUI is an option and has an increased pregnancy rate over timed intercourse” (9% vs 3%), she says.¹⁰ “How­ever, clearly IVF is much more successful and is the most effective treatment, with pregnancy rates of approximately 46% for women younger than 35 years (3% of whom have a ‘diagnosis’ of endometriosis, and 13% of whom have an ‘unknown’ infertility factor).¹¹ Women who are older than 35 or who have additional infertility factors, such as male factor, should consider IVF first.”

3. When is surgery indicated?
“Patients who have significant pain associated with their infertility will benefit from surgery, which offers both pain relief and an improvement in the spontaneous pregnancy rate,” says Dr. Falcone. “Patients who are infertile and desire spontaneous pregnancy without pharmacologic intervention or assisted reproductive technology (ART) also benefit from surgery.”

The benefit of surgery in asymptomatic women with minimal to mild endometriosis is unclear. In a randomized controlled trial of 341 women (aged 20–39 years) with infertility and minimal to mild endometriosis, laparoscopic resection or ablation of visible lesions resulted in pregnancy in 30.7% of women, compared with 17.7% of women who underwent diagnostic laparoscopy only.¹²

Another randomized study of 96 women with minimal to mild endometriosis who underwent resection/ablation or diagnostic laparoscopy found no difference in the birth rate at 1 year.¹³

When the results of these 2 studies are combined, the number needed to treat is 12 laparoscopies in women with endometriosis, says Dr. Falcone. “So 1 additional pregnancy would be gained from performing endometriosis surgery in 12 patients. If we assume a prevalence of 30% in asymptomatic women with infertility, then you need to perform 40 diagnostic laparoscopies to achieve an extra pregnancy.”

For women with infertility and severe endometriosis, a nonrandomized study found cumulative pregnancy rates of 45% and 63% after laparoscopy and laparotomy, respectively, in 216 women followed for up to 2 years.¹⁴ The difference in rates was not statistically significant.

“Although surgery is indicated to diagnose endometriosis, multiple repeat procedures are not an effective treatment for infertility,” says Dr. Estes. “Plus, especially for stage I and II endometriosis [according to the ASRM classification system], approximately 12 patients will need surgery for 1 additional pregnancy—and many more will have needed the procedure to even get to those who have endometriosis. While patients often want us to ‘do something’—­often a covered service such as surgery—we need to consider that surgery for early disease does not provide a significant or long-lasting enhancement to women’s ability to conceive.”

In the absence of male-factor infertility, surgical diagnosis with conservative and precise treatment of endometriosis at the same time is better than going directly to IVF, says Dr. Nezhat. Younger patients who undergo surgical treatment have a better chance of achieving more than 1 spontaneous pregnancy than they do with IVF. And older patients also will have an improved conception rate with ART when they are treated surgically, he says.⁸

Coding and reimbursement 

For endometriosis, the correct diagnostic code helps establish the medical necessity of later treatments
Several diagnostic codes are available to describe the location of endometriotic implants, but the fact remains that these codes can be reported only after a definitive diagnosis is made, which generally comes after confirmatory surgery has been performed. When the patient is in the diagnostic phase, she may present with complaints of pelvic pain, dyspareunia, dysmenorrhea, or infertility. Knowing which codes to use at the time of evaluation goes a long way toward establishing medical necessity for any later surgery or medical treatment.

In the TABLE, you will find common diagnostic codes that can be reported during evaluation of endometriosis, including both International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and ICD-10-CM equivalents. Note that, with ICD-10-CM, payers are looking for a more specific type of dysmenorrhea in the documentation. In the case of painful menstruation suspected to arise from endometriosis, the code for secondary dysmenorrhea should be reported.

Diagnostic coding in cases in which the patient first presents with a complaint of infertility in the absence of other symptoms can be problematic, as many insurers still do not cover the treatment of infertility. However, in the diagnostic stage, codes for fertility testing can be reported instead of codes that confirm infertility when no other symptoms are present. Once the clinician has verified that endometriosis is the source of the infertility and begins treatment, the primary code for the type of endometriosis would be reported, not a diagnosis of infertility.

The procedure performed to diagnose endometriosis would be diagnostic laparoscopy (Current Procedure Terminology [CPT] code 49320, Laparoscopy, abdomen, peritoneum, and omentum, diagnostic, with or without collection of specimen[s] by brushing or washing [separate procedure]) if medical treatment is being pursued. If the plan is to confirm and then immediately remove the implants, the CPT codes would be either 58662, Laparoscopy, surgical; with fulguration or excision of lesions of the ovary, pelvic viscera, or peritoneal surface by any method, or 49203–49205, Excision or destruction, open, intra-abdominal tumors, cysts or endometriomas, 1 or more peritoneal, mesenteric, or retroperitoneal primary or secondary tumors, based on the largest tumor diameter, if they are removed via an abdominal incision.

—Melanie Witt, RN, CPC, COBGC, MA

Ms. Witt is an independent coding and documentation consultant and former program manager, department of coding and nomenclature, American Congress of Obstetricians and Gynecologists.

4. Surgery or IVF for endometriomas?
When an endometrioma is present, should it be surgically treated or should the patient go straight to IVF? And does the optimal approach depend on the size of the endometrioma?

“The answer to this question ultimately depends on the skill and experience of the surgeon and the type of endometrioma,” says Dr. Nezhat, “because improper removal of an endometrioma may compromise the function of the ovary.”

“I recommend removal of the endometrioma by a skilled surgeon experienced in the management of ovarian cysts and preservation of ovarian function, especially in patients who have failed IVF,” he says.^6,15

According to the ASRM committee opinion on endometriosis and infertility, laparoscopic cystectomy for endometriomas larger than 4 cm improves fertility, compared with cyst drainage and coagulation, which is associated with a high risk of cyst recurrence.² However, no randomized trials have compared laparoscopic excision of an endometrioma to expectant management prior to IVF/intracytoplasmic sperm injection (ICSI). One case-control study found that laparoscopic cystectomy prior to IVF had no effect on fertility outcomes.¹⁶ At the same time, however, “conservative surgical treatment in symptomatic patients did not impair the success rates of IVF or ICSI,” notes the ASRM.² Therefore, “evidence suggests that surgery does not benefit asymptomatic women with an endometrioma prior to scheduled IVF/ICSI,” the ASRM concludes.²

Dr. Nezhat cautions against the practice of indiscriminate IVF in the setting of ovarian endometriomas because he has seen patients who developed tubo-ovarian abscess and infected endometriomas after transvaginal egg retrieval. He notes that there are additional case reports of similar findings from other surgeons.

As far as excision versus ablation is concerned, all studies have shown some effect on ovarian function after excision, says Dr. Falcone. “The studies assessed this parameter using several endpoints, such as the number of oocytes retrieved at IVF. Recently, anti-Müllerian hormone has been used and has confirmed this observation. The decreased ovarian reserve is especially problematic with bilateral ovarian disease. The extent of the decreased ovarian function is dependent on several parameters, especially how much energy is used to achieve hemostasis. Several techniques have been proposed to reduce damage, including less traumatic ways of achieving hemostasis in the ovarian hilus.”

“The dilemma is that, if we excise the disease, the pregnancy rates are better than with ablation, but if we excise, there is more damage to the ovary. In my practice, I excise if there is minimal associated disease, such as adhesions, because the pregnancy rate after surgery is good. If, however, there are extensive adhesions with a low chance of spontaneous pregnancy, I minimize excision,” Dr. Falcone says.

As for going straight to IVF, “many patients cannot afford IVF; therefore, surgery is their only option. Furthermore, many patients have severe associated pain; therefore, surgery is required to improve quality of life. However, if the decision is made to proceed to IVF, there is no evidence that cystectomy prior to treatment with ART improves the pregnancy rate,” Dr. Falcone says.

“Basically, if a woman has no pain and no endometrioma, and infertility alone is the issue, I treat her in the same manner as I would a patient with idiopathic infertility—no surgery,” Dr. Falcone says. “If a patient has severe pain and infertility, I treat her surgically but conservatively, especially when an endometrioma is present. The patient will get pain relief but also derive fertility benefit. If a patient has had previous surgery for ­endometriosis-associated infertility, additional surgery is not the next step—as our study has shown that pregnancy rates are better with IVF than repeat surgery.”¹⁷

5. Is surgery ever effective after failed IVF?
To answer this question, Dr. Nezhat points to a retrospective case series by Littman and colleagues in which 29 women with a history of failed IVF underwent laparoscopic evaluation and treatment of endometriosis (by the same surgeon).⁸ Of 29 patients, 22 conceived after laparoscopic treatment of ­endometriosis, including 15 “non-IVF” pregnancies and 7 IVF pregnancies, the study results show.⁸

“It is not unusual for patients and health care providers to perceive IVF as the final treatment for infertility,” Littman and colleagues write. “When this definitive therapy fails repeatedly, clinicians and patients may be inclined to pursue oocyte donation or elect to forego further treatment altogether. This is especially true in women of advanced age and in patients with borderline embryo quality. Presently, as a result of our clinical observation in patients with failed IVF, before egg donation or adoption, we offer the option to have meticulous laparoscopic evaluation and treatment by a skilled surgeon. Furthermore, we would not classify an infertility condition as unexplained without confirming the absence of endometriosis by a thorough laparoscopy. In our experience, patients under 35 years old with unexplained infertility who are found to have endometriosis at the time of laparoscopy have an excellent chance of pregnancy following surgical treatment without ART.”⁸

6. Is repeat surgery ever helpful?
In the treatment of endometriosis-­associated infertility, repeat surgery should be avoided if no symptoms are present, says Dr. Estes. “In women with continued symptoms, the benefits of repeat surgery are small, with known risks, including the potential for adhesive disease and the iatro­genic detrimental effect on ovarian ­function—often in a setting of already-present decreased ovarian reserve.”

Dr. Nezhat agrees that multiple surgeries carry the potential for harm. “However, there is one caveat,” he says. “What was done at the previous surgery and how? The skill and experience of the surgeon and proper technique are of paramount importance to the surgical outcome.”

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Although endometriosis and infertility are clearly linked—in life as well as the medical literature—no causal relationship has been established. Nevertheless, data suggest that 25% to 50% of infertile women have endometriosis, and that as many as 30% to 50% of women who have endometriosis are infertile.¹

Among the mechanisms that have been proposed to explain this link are:

Recent studies by Kao and colleagues and Giudice and colleagues have led to new findings in regard to endometriosis and infertility, says Ceana Nezhat, MD.^3,4 Dr. ­Nezhat is Director of the Nezhat Medical Center in Atlanta, Georgia, and Medical Director of Training and Education at ­Northside ­Hospital in Atlanta. “These researchers have discovered that endometriosis causes changes to the endometrium that contribute to infertility.”

“There are no studies that have specifically assessed whether one anatomic site is associated with increased infertility over another,” says Tommaso Falcone, MD. “However, it is assumed that disease that involves the tubes and ovaries would impede fertility the most. Adhesive disease and endometriomas around the tubes and ovaries are associated with a worsening prognosis. Although peritoneal disease probably influences fertility solely on the basis of inflammation, disease around the tubes and ovaries is thought to have a mechanical effect as well.” Dr. Falcone is Professor and Chair of Obstetrics and Gynecology at the Cleveland Clinic in Cleveland, Ohio.

“Endometriosis is a chronic and hetero­geneous disease process,” says ­Stephanie J. Estes, MD, Director of Robotic Surgical Services and Associate Professor, Division of Reproductive Endocrinology and ­Infertility, Department of Obstetrics and Gynecology, at Penn State Hershey Medical Center in Hershey, Pennsylvania.

“It is likely that no single site is the causative factor,” Dr. Estes says. “Endometriosis alters prostaglandins, cytokines, and proteases that may adversely affect eggs, sperm, or embryo development. In addition, altered endometrial receptivity may play a role. It has been shown that, when donor oocytes from women with endometriosis are transferred to women without endometriosis, there are lower implantation rates and poorer embryo quality.”⁵

Does it follow, then, that eradication of endometriosis improves fertility?

The answer is not clear. Rather, it depends on a number of variables, including the stage of the disease, its location, the presence of symptoms, and more.

“The approach for endometiosis-­associated infertility is completely different from the approach for pain,” says Dr. Nezhat. “In a patient with pain, complete eradication of endometriosis is necessary. However, when addressing infertility, a surgeon must be cautious in the vicinity of the reproductive organs, even if a multistage approach is required. Fertility preservation is the goal.^6,7 However, thorough treatment of endometriosis improves fertility rates even in cases of failed in vitro fertilization” (IVF).⁸

In this article, the focus is on 6 critical questions concerning endometriosis and infertility, including the role of medical therapy, when surgery is indicated, and whether an endometrioma warrants removal or referral for IVF.

In Part 1 of this 3-part series, which appeared in the April 2015 issue of OBG Management, the subject was diagnosis of endometriosis. In Part 2, which appeared in May 2015, the focus was endometriosis and pain.

1. Is there a role for medical therapy?
In women who have endometriosis-related infertility, medical therapy does not appear to produce any benefit. In its committee opinion on the subject, the American Society for Reproductive Medicine (ASRM) states as much: “There is no evidence that medical treatment of endometriosis improves fertility.”²

In fact, observes Dr. Estes, trials of medical treatment, involving such medications as combined estrogen-­progestin therapy, danazol, progestins, or ­gonadotropin-releasing hormone (GnRH) agonists, may cause an unnecessary “delay in the use of more effective treatments that could result in pregnancy.”

Dr. Nezhat believes that medical therapy is effective in patients who have adenomyosis in addition to endometriosis. “Three months of treatment with a GnRH agonist will improve fertility rates in these patients,” he says.

“Medical treatments inhibit ovulation,” notes Dr. Estes. “These therapies have no role in pretreatment of patients with endometriosis prior to infertility treatment. On the other hand, medical therapy with GnRH agonists for 3 to 6 months prior to an IVF cycle does result in increased pregnancy rates.”⁹

2. What is the role of clomiphene and intrauterine insemination?
Should women who have endometriosis, open fallopian tubes, and infertility be treated with clomiphene and intrauterine insemination (IUI) prior to a cycle of IVF?

“This is a complex question,” says Dr. ­Estes, “as clinical parameters such as age, symptoms, duration of infertility, and the ability to proceed with IVF are important, as well as stage of disease.”

“Overall, in patients younger than 35 years, clomiphene-IUI is an option and has an increased pregnancy rate over timed intercourse” (9% vs 3%), she says.¹⁰ “How­ever, clearly IVF is much more successful and is the most effective treatment, with pregnancy rates of approximately 46% for women younger than 35 years (3% of whom have a ‘diagnosis’ of endometriosis, and 13% of whom have an ‘unknown’ infertility factor).¹¹ Women who are older than 35 or who have additional infertility factors, such as male factor, should consider IVF first.”

3. When is surgery indicated?
“Patients who have significant pain associated with their infertility will benefit from surgery, which offers both pain relief and an improvement in the spontaneous pregnancy rate,” says Dr. Falcone. “Patients who are infertile and desire spontaneous pregnancy without pharmacologic intervention or assisted reproductive technology (ART) also benefit from surgery.”

The benefit of surgery in asymptomatic women with minimal to mild endometriosis is unclear. In a randomized controlled trial of 341 women (aged 20–39 years) with infertility and minimal to mild endometriosis, laparoscopic resection or ablation of visible lesions resulted in pregnancy in 30.7% of women, compared with 17.7% of women who underwent diagnostic laparoscopy only.¹²

Another randomized study of 96 women with minimal to mild endometriosis who underwent resection/ablation or diagnostic laparoscopy found no difference in the birth rate at 1 year.¹³

When the results of these 2 studies are combined, the number needed to treat is 12 laparoscopies in women with endometriosis, says Dr. Falcone. “So 1 additional pregnancy would be gained from performing endometriosis surgery in 12 patients. If we assume a prevalence of 30% in asymptomatic women with infertility, then you need to perform 40 diagnostic laparoscopies to achieve an extra pregnancy.”

For women with infertility and severe endometriosis, a nonrandomized study found cumulative pregnancy rates of 45% and 63% after laparoscopy and laparotomy, respectively, in 216 women followed for up to 2 years.¹⁴ The difference in rates was not statistically significant.

“Although surgery is indicated to diagnose endometriosis, multiple repeat procedures are not an effective treatment for infertility,” says Dr. Estes. “Plus, especially for stage I and II endometriosis [according to the ASRM classification system], approximately 12 patients will need surgery for 1 additional pregnancy—and many more will have needed the procedure to even get to those who have endometriosis. While patients often want us to ‘do something’—­often a covered service such as surgery—we need to consider that surgery for early disease does not provide a significant or long-lasting enhancement to women’s ability to conceive.”

In the absence of male-factor infertility, surgical diagnosis with conservative and precise treatment of endometriosis at the same time is better than going directly to IVF, says Dr. Nezhat. Younger patients who undergo surgical treatment have a better chance of achieving more than 1 spontaneous pregnancy than they do with IVF. And older patients also will have an improved conception rate with ART when they are treated surgically, he says.⁸

Coding and reimbursement 

For endometriosis, the correct diagnostic code helps establish the medical necessity of later treatments
Several diagnostic codes are available to describe the location of endometriotic implants, but the fact remains that these codes can be reported only after a definitive diagnosis is made, which generally comes after confirmatory surgery has been performed. When the patient is in the diagnostic phase, she may present with complaints of pelvic pain, dyspareunia, dysmenorrhea, or infertility. Knowing which codes to use at the time of evaluation goes a long way toward establishing medical necessity for any later surgery or medical treatment.

In the TABLE, you will find common diagnostic codes that can be reported during evaluation of endometriosis, including both International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and ICD-10-CM equivalents. Note that, with ICD-10-CM, payers are looking for a more specific type of dysmenorrhea in the documentation. In the case of painful menstruation suspected to arise from endometriosis, the code for secondary dysmenorrhea should be reported.

Diagnostic coding in cases in which the patient first presents with a complaint of infertility in the absence of other symptoms can be problematic, as many insurers still do not cover the treatment of infertility. However, in the diagnostic stage, codes for fertility testing can be reported instead of codes that confirm infertility when no other symptoms are present. Once the clinician has verified that endometriosis is the source of the infertility and begins treatment, the primary code for the type of endometriosis would be reported, not a diagnosis of infertility.

The procedure performed to diagnose endometriosis would be diagnostic laparoscopy (Current Procedure Terminology [CPT] code 49320, Laparoscopy, abdomen, peritoneum, and omentum, diagnostic, with or without collection of specimen[s] by brushing or washing [separate procedure]) if medical treatment is being pursued. If the plan is to confirm and then immediately remove the implants, the CPT codes would be either 58662, Laparoscopy, surgical; with fulguration or excision of lesions of the ovary, pelvic viscera, or peritoneal surface by any method, or 49203–49205, Excision or destruction, open, intra-abdominal tumors, cysts or endometriomas, 1 or more peritoneal, mesenteric, or retroperitoneal primary or secondary tumors, based on the largest tumor diameter, if they are removed via an abdominal incision.

—Melanie Witt, RN, CPC, COBGC, MA

Ms. Witt is an independent coding and documentation consultant and former program manager, department of coding and nomenclature, American Congress of Obstetricians and Gynecologists.

4. Surgery or IVF for endometriomas?
When an endometrioma is present, should it be surgically treated or should the patient go straight to IVF? And does the optimal approach depend on the size of the endometrioma?

“The answer to this question ultimately depends on the skill and experience of the surgeon and the type of endometrioma,” says Dr. Nezhat, “because improper removal of an endometrioma may compromise the function of the ovary.”

“I recommend removal of the endometrioma by a skilled surgeon experienced in the management of ovarian cysts and preservation of ovarian function, especially in patients who have failed IVF,” he says.^6,15

According to the ASRM committee opinion on endometriosis and infertility, laparoscopic cystectomy for endometriomas larger than 4 cm improves fertility, compared with cyst drainage and coagulation, which is associated with a high risk of cyst recurrence.² However, no randomized trials have compared laparoscopic excision of an endometrioma to expectant management prior to IVF/intracytoplasmic sperm injection (ICSI). One case-control study found that laparoscopic cystectomy prior to IVF had no effect on fertility outcomes.¹⁶ At the same time, however, “conservative surgical treatment in symptomatic patients did not impair the success rates of IVF or ICSI,” notes the ASRM.² Therefore, “evidence suggests that surgery does not benefit asymptomatic women with an endometrioma prior to scheduled IVF/ICSI,” the ASRM concludes.²

Dr. Nezhat cautions against the practice of indiscriminate IVF in the setting of ovarian endometriomas because he has seen patients who developed tubo-ovarian abscess and infected endometriomas after transvaginal egg retrieval. He notes that there are additional case reports of similar findings from other surgeons.

As far as excision versus ablation is concerned, all studies have shown some effect on ovarian function after excision, says Dr. Falcone. “The studies assessed this parameter using several endpoints, such as the number of oocytes retrieved at IVF. Recently, anti-Müllerian hormone has been used and has confirmed this observation. The decreased ovarian reserve is especially problematic with bilateral ovarian disease. The extent of the decreased ovarian function is dependent on several parameters, especially how much energy is used to achieve hemostasis. Several techniques have been proposed to reduce damage, including less traumatic ways of achieving hemostasis in the ovarian hilus.”

“The dilemma is that, if we excise the disease, the pregnancy rates are better than with ablation, but if we excise, there is more damage to the ovary. In my practice, I excise if there is minimal associated disease, such as adhesions, because the pregnancy rate after surgery is good. If, however, there are extensive adhesions with a low chance of spontaneous pregnancy, I minimize excision,” Dr. Falcone says.

As for going straight to IVF, “many patients cannot afford IVF; therefore, surgery is their only option. Furthermore, many patients have severe associated pain; therefore, surgery is required to improve quality of life. However, if the decision is made to proceed to IVF, there is no evidence that cystectomy prior to treatment with ART improves the pregnancy rate,” Dr. Falcone says.

“Basically, if a woman has no pain and no endometrioma, and infertility alone is the issue, I treat her in the same manner as I would a patient with idiopathic infertility—no surgery,” Dr. Falcone says. “If a patient has severe pain and infertility, I treat her surgically but conservatively, especially when an endometrioma is present. The patient will get pain relief but also derive fertility benefit. If a patient has had previous surgery for ­endometriosis-associated infertility, additional surgery is not the next step—as our study has shown that pregnancy rates are better with IVF than repeat surgery.”¹⁷

5. Is surgery ever effective after failed IVF?
To answer this question, Dr. Nezhat points to a retrospective case series by Littman and colleagues in which 29 women with a history of failed IVF underwent laparoscopic evaluation and treatment of endometriosis (by the same surgeon).⁸ Of 29 patients, 22 conceived after laparoscopic treatment of ­endometriosis, including 15 “non-IVF” pregnancies and 7 IVF pregnancies, the study results show.⁸

“It is not unusual for patients and health care providers to perceive IVF as the final treatment for infertility,” Littman and colleagues write. “When this definitive therapy fails repeatedly, clinicians and patients may be inclined to pursue oocyte donation or elect to forego further treatment altogether. This is especially true in women of advanced age and in patients with borderline embryo quality. Presently, as a result of our clinical observation in patients with failed IVF, before egg donation or adoption, we offer the option to have meticulous laparoscopic evaluation and treatment by a skilled surgeon. Furthermore, we would not classify an infertility condition as unexplained without confirming the absence of endometriosis by a thorough laparoscopy. In our experience, patients under 35 years old with unexplained infertility who are found to have endometriosis at the time of laparoscopy have an excellent chance of pregnancy following surgical treatment without ART.”⁸

6. Is repeat surgery ever helpful?
In the treatment of endometriosis-­associated infertility, repeat surgery should be avoided if no symptoms are present, says Dr. Estes. “In women with continued symptoms, the benefits of repeat surgery are small, with known risks, including the potential for adhesive disease and the iatro­genic detrimental effect on ovarian ­function—often in a setting of already-present decreased ovarian reserve.”

Dr. Nezhat agrees that multiple surgeries carry the potential for harm. “However, there is one caveat,” he says. “What was done at the previous surgery and how? The skill and experience of the surgeon and proper technique are of paramount importance to the surgical outcome.”

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.