Therapy for endometriosis depends on a woman’s specific complaints, symptom severity, location of endometriotic lesions, goals for treatment, and desire to conserve future fertility. As shown in Figure 10-8, determining whether a patient is seeking treatment for infertility or pain is essential, as therapy for these two is different.
Diagnostic and treatment algorithm for women with presumptive or proven endometriosis.
COCs = combination oral contraceptive pills; GnRH = gonadotropin-releasing hormone; IUI = intrauterine insemination; NSAIDs = nonsteroidal antiinflammatory drugs. aAgents not recommended for adolescents younger than 16 years.
If pain is prominent and conception is not currently desired, then medical therapy is typically selected. Treatment strives to atrophy ectopic endometrium and diminish disease-associated inflammation. Available agents include NSAIDs, sex steroid hormones, GnRH agents, and aromatase inhibitors. In general, suitable starting regimens are NSAIDS alone or combined with oral contraceptive pills or with a progestin. These agents may be initiated if endometriosis is suspected in a woman with CPP or may be started following diagnostic laparoscopy. If initial therapy fails to control pain following laparoscopy, then use of a different medication is reasonable. If initial empiric therapy is ineffective, then either diagnostic laparoscopy or medication change is suitable (American College of Obstetricians and Gynecologists, 2014b). Of note, although medical treatment improves pain, relapse rates are high with therapy discontinuation.
If infertility is the presenting symptom, then fertility-preserving treatment without ovulation suppression will be required, as outlined on page 243. In contrast, if the patient has severe, recalcitrant pain and has completed childbearing, definitive surgery may be warranted, as described on page 243.
Medical Treatment of Pain
For many women, symptoms will preclude them from choosing expectant management. However, for those with mild symptoms or for asymptomatic women diagnosed incidentally, expectant management may be appropriate (Moen, 2002). Sutton and associates (1997) expectantly managed patients initially diagnosed by laparoscopy with minimal to moderate endometriosis. At second-look laparoscopy after 1 year, 29 percent of women had disease regression, 42 percent remained unchanged, and 29 percent had disease progression. Other investigators have shown similar rates of disease regression with expectant management (Thomas, 1987). These studies are confined to patients with minimal to moderate endometriosis. There are no well-designed trials examining the effect of expectant management on severe endometriosis.
Nonsteroidal Antiinflammatory Drugs
Both COX-1 and -2 enzymes promote synthesis of prostaglandins involved in the pain and inflammation associated with endometriosis. Specifically, endometriotic tissue expresses COX-2 at greater levels than eutopic endometrium (Cho, 2010). Accordingly, therapy aimed at lowering these prostaglandin levels plays a role in alleviating endometriosis-associated pain. As such, NSAIDs are often first-line therapy in women with primary dysmenorrhea or pelvic pain with suspected or known endometriosis. That said, study evidence supporting NSAIDs for this disease is scant and is extrapolated from efficacy data in primary dysmenorrhea (Kauppila, 1985; Marjoribanks, 2010).
The NSAIDs listed in Table 10-1 nonselectively inhibit both COX-1 and COX-2 enzymes. In contrast, selective COX-2 inhibitors specifically inhibit the COX-2 isoenzyme. Due to the cardiovascular risks with long-term use of selective COX-2 inhibitors, these medications are used at the lowest possible dose and for the shortest duration necessary (Jones, 2005). Thus, drugs in Table 10-1 are primarily selected.
TABLE 10-1Commonly Used Oral Nonsteroidal Antiinflammatory Drugs (NSAIDs) in the Treatment of Endometriosis-Associated Dysmenorrhea ||Download (.pdf) TABLE 10-1 Commonly Used Oral Nonsteroidal Antiinflammatory Drugs (NSAIDs) in the Treatment of Endometriosis-Associated Dysmenorrhea
|Generic Name ||Trade Name ||Dosage |
|Ibuprofen ||Motrin, Advil, Nuprin ||400 mg every 4–6 hr |
|Naproxen ||Naprosyn, Aleve ||500 mg initially, then 250 mg every 6–8 hr |
|Naproxen sodium ||Anaprox ||550 mg initially, then 275 mg every 6–8 hr |
|Mefenamic acid ||Ponstel ||500 mg initially, then 250 mg every 6 hr |
|Ketoprofen ||Orudis, Oruvail ||50 mg every 6–8 hr |
Combination Hormonal Contraceptives
These agents are a mainstay for the treatment of endometriosis-related pain. They inhibit gonadotropin release, decrease menstrual flow, and decidualize implants. As such, abundant study evidence supports use of combination oral contraceptive (COC) pills or the contraceptive patch or ring to relieve endometriosis-related pain (Harada, 2008; Vercellini, 1993, 2010). These provide contraception and other noncontraceptive benefits, which are balanced against risks enumerated in Chapter 5.
COCs can be used conventionally in a cyclic regimen or may be used continuously, without a break for withdrawal menses. The continuous regimen decreases the frequency of painful menses and improves CPP (Guzick, 2011). For endometriosis-related pain, monophasic or multiphasic COCs are both suitable. Additionally, low-dose COCs (containing ≤20 μg ethinyl estradiol) have not proved superior to conventional-dose COCs for endometriosis treatment, but lower doses may lead to higher rates of abnormal uterine bleeding (Gallo, 2013).
This family of hormones is often used for endometriosis therapy. Progestational agents are known to antagonize estrogenic effects on the endometrium, causing initial decidualization and subsequent endometrial atrophy. For endometriosis treatment, progestins can be administered as an oral progestin pill, depot medroxyprogesterone acetate (DMPA) (Depo-Provera), norethindrone acetate (NETA), or a levonorgestrel-releasing intrauterine system.
As supporting evidence, one randomized trial compared the effect of oral medroxyprogesterone acetate (MPA) 100 mg daily given for 6 months and placebo. At second-look laparoscopy, partial or total resolution of peritoneal implants was noted in 60 percent of progestin-treated women compared with 18 percent of the placebo group. Furthermore, pelvic pain and defecatory pain were significantly reduced (Telimaa, 1987). Side effects of high-dose MPA included acne, edema, weight gain, and irregular menstrual bleeding. In practice, MPA is prescribed in oral dosages ranging from 20 to 100 mg daily.
Alternatively, MPA may be given intramuscularly in depot form in a dosage of 150 mg every 3 months. In depot form, MPA may delay resumption of normal menses and ovulation and thus is less suitable for women contemplating imminent pregnancy. Subcutaneous formulation of MPA, marketed as Depo-SubQ Provera 104, is also effective (Schlaff, 2006).
As discussed in Chapter 5, the Depo-Provera package insert carries a “black box warning.” This describes that prolonged DMPA use may result in bone density loss, that this loss is greater with increasing duration of use, and that the loss may not be completely reversible. Labeling recommends limiting use to 2 years unless other contraceptive methods are inadequate. Thus, the risks and benefits of treatment are weighed if contemplating long-term DMPA therapy. Bone density surveillance with dual energy x-ray absorptiometry (DEXA) scanning is not recommended (American College of Obstetricians and Gynecologists, 2014a).
NETA is a 19-nortestosterone synthetic progestin that has been used to treat endometriosis. In one study, investigators administered an initial oral dosage of NETA, 5 mg daily, with increases of 2.5 mg daily until amenorrhea or a maximal dosage of 20 mg daily was reached. They found an approximately 90-percent reduction in dysmenorrhea and pelvic pain (Muneyyirci-Delale, 1998). As discussed on page in the next section, NETA is also used as adjunct therapy with GnRH agents to blunt the bone loss linked with those drugs.
Dienogest is another 19-nortestosterone synthetic progestin suitable for endometriosis. In one randomized study, it was significantly more effective than placebo for reducing endometriosis-associated pain when used orally at a dosage of 2 mg daily (Strowitzki, 2010a). Other trials show efficacy equivalent to that of GnRH agonists (Harada, 2009; Strowitzki, 2010b). Currently, this progestin as a sole agent is not available in the United States.
The levonorgestrel-releasing intrauterine system (LNG-IUS) (Mirena) delivers levonorgestrel directly to the endometrium and is effective for up to 5 years. This intrauterine device has traditionally been used for contraception, but data are accruing for endometriosis treatment. One small randomized trial that incorporated second-look laparoscopy showed improved endometriosis stage with both LNG-IUS and the comparator GnRH treatment. Other small randomized trials have shown symptom improvement when compared against expectant management, DMPA, or GnRH agonists (Petta, 2005; Tanmahasamut, 2012; Vercellini, 2003b; Wong, 2010). However, in patients with bowel endometriosis, the LNG-IUS may be ineffective for symptom control (Hinterholzer, 2007). Contraindications to LNG-IUS use are listed in Chapter 5.
Intuitively, the implant that chronically releases the progestin etonogestrel might be considered for endometriosis. Data regarding its efficacy for this indication are limited. One small randomized study comparing the implant and the LNG-IUS reported comparable efficacy (Walch, 2009).
Endogenous pulsatile release of GnRH prompts secretory activity of the gonadotropes within the anterior pituitary. Gonadotropin release from the pituitary then leads to ovarian steroidogenesis and ovulation. However, continuous, nonpulsatile GnRH administration results in pituitary desensitization and subsequent loss of ovarian steroidogenesis. These features allow pharmacologic use of GnRH agonists for endometriosis treatment. With loss of ovarian estradiol production, the hypoestrogenic environment removes the stimulation normally provided to the endometriotic implants and creates a pseudomenopausal state during treatment. In addition to their direct effect on estrogen production, GnRH agonists also reduce COX-2 levels in patients with endometriosis, providing another mechanism of treatment (Kim, 2009).
GnRH agonists are inactive if taken orally, but intramuscular, subcutaneous, and intranasal preparations are available. Leuprolide acetate (Lupron Depot) is available in a 3.75-mg monthly dose or an 11.25-mg 3-month dose, both given IM. Less frequently used GnRH agonists include goserelin (Zoladex) administered as a 3.6-mg monthly or a 10.8-mg 3-month subcutaneous depot implant; triptorelin (Trelstar) given as a 3.75-mg monthly IM injection; and nafarelin (Synarel) used in a 200-mg twice-daily nasal spray regimen. All of these except triptorelin carry specific Food and Drug Administration (FDA) approval for endometriosis treatment.
Empirically, GnRH agonists may be used prior to laparoscopy in women with CPP and clinical suspicion of endometriosis. In a study by Ling and associates (1999), after 3 months of GnRH agonist treatment, pain scores significantly declined compared with those after placebo. Subsequent laparoscopy revealed that 93 percent of these women had surgically diagnosed endometriosis. Similarly, in suspected cases, depot leuprolide acetate may be used empirically in lieu of laparoscopy for satisfactory symptom improvement. That said, an empiric GnRH trial is not routinely offered to patients younger than 16 years because GnRH agonist effects on long-term bone mineral density (BMD) have not been adequately studied in this age group.
In those with surgically confirmed endometriosis, numerous studies demonstrate the effectiveness of GnRH agonist therapy to improve pain symptoms (Brown, 2010). The GnRH agonists provide greater relief when administered for 6 months compared with 3 months (Hornstein, 1995b). As noted in the prior sections, GnRH agonists compares favorably with other drugs used for endometriosis treatment. Although GnRH is effective, its cost and side effects often favor trials of COCs or progestins first.
Concerns regarding the effects of prolonged hypoestrogenism preclude extended treatment with GnRH agonists. Hypoestrogenic symptoms include hot flushes, insomnia, reduced libido, vaginal dryness, and headaches. Moreover, both spine and hip BMD decrease at 3 and 6 months of GnRH agonist therapy, with only partial recovery at 12 to 15 months after treatment (Orwoll, 1994). Because of the increased osteoporosis risk, therapy is usually limited to the shortest possible duration—usually no greater than 6 months.
Estrogen may be added to GnRH agonist therapy to counteract bone loss and is termed add-back therapy. With the addition of such hormonal add-back therapy, a GnRH agonist may occasionally be used longer than 6 months (American College of Obstetricians and Gynecologists, 2014b). The goal of add-back therapy is to supply enough estrogen to minimize GnRH agonist side effects while still maintaining a hypoestrogenic state sufficient to suppress endometriosis. Barbieri (1992) explained that tissues have varied sensitivity to estrogen, and a concentration of estrogen that will partially prevent bone loss may not stimulate endometrial growth. This “estrogen threshold” has not been established but is thought to approximate 30 to 40 pg/mL of estradiol.
Several regimens are suitable and appear equally efficacious (Wu, 2014). In one study, NETA 5 mg orally given daily, with or without conjugated equine estrogen (Premarin) 0.625 mg orally daily, for 12 months provided extended pain relief beyond the duration of treatment and preserved BMD (Hornstein, 1998). Another regimen of transdermal estradiol 25 μg plus daily 5 mg oral MPA showed that the GnRH agonist remained effective in reducing endometriosis pain (Edmonds, 1996). In addition, traditional COCs may be used effectively as add-back agents.
The extent of BMD decline has been evaluated with add-back therapy. Although bone loss was noted in all patients undergoing GnRH agonist treatment, the extent of loss was lower in the add-back group (Edmonds, 1994). Quality of life is also improved with add-back therapy (Zupi, 2004).
Such therapy can be initiated either immediately with the GnRH agonist or after 3 to 6 months of agonist therapy. However, little benefit is gained by deferring add-back therapy, and patients who receive add-back concurrently with agonist therapy have reduced bone loss (Al-Azemi, 2009; Kiesel, 1996). Supplemental calcium as a 1000-mg total daily dose is recommended along with add-back regimens (American College of Obstetricians and Gynecologists, 2014b).
GnRH antagonists are a newer category of GnRH analogues capable of suppressing gonadotropin production. Unlike GnRH agonists, GnRH antagonists do not produce an initial release or flare of gonadotropins. Thus, suppression of gonadotropins and sex steroid hormones is immediate.
GnRH antagonists are mainly used for suppression of premature ovulation during IVF cycles. They have not been well studied for endometriosis treatment. Küpker and colleagues (2002) evaluated the effect of the antagonist cetrorelix in 15 endometriosis patients. They administered subcutaneous injections of cetrorelix at a dosage of 3 mg weekly for 8 weeks. Patients were symptom free during treatment, and second-look laparoscopy revealed disease regression in 60 percent of study participants. That said, long-term depot forms are not currently available.
Of newer agents, a nonpeptide, orally bioactive GnRH antagonist, elagolix, is undergoing evaluation. One 24-week randomized trial showed similar efficacy between elagolix and DMPA for endometriosis-associated pain (Carr, 2014).
As noted earlier, in endometriotic tissue, estrogen may be produced locally through aromatization of circulating androgens. This may clarify postmenopausal endometriosis or may explain cases in which symptoms persist despite conventional treatment. Hormonal strategies described in prior sections target ovarian estrogen production but have little effect on estrogens produced from other sources. In contrast, the aromatase inhibitors (AIs) block aromatase action and estradiol production in both the ovary and extraovarian sites. As a result, estrogen levels are dramatically suppressed, and AIs have hypoestrogenic side-effect profiles similar to those of GnRH agonists (Pavone, 2012). AIs used clinically include anastrozole (Arimidex) and letrozole (Femara).
In addition to hypoestrogenic side effects, a second concern is ovarian cyst formation. As explanation and shown in Figure 20-3, by blocking the conversion of androgens to estrogens in ovarian granulosa cells, AIs reduce the negative feedback at the pituitary–hypothalamus level. This leads to increased GnRH secretion. Resulting elevations in luteinizing hormone (LH) and follicle-stimulating hormone promote increased ovarian follicular development. Therefore, combining AI with a progestins or COCs helps blunt this side effect (Shippen, 2004).
Small studies that combined aromatase inhibitors with NETA or with COCs support this approach for pain relief (Amsterdam, 2005; Ferrero, 2009). However, due to side effects and limited data, such AI combinations are usually prescribed to women after other options for medical or surgical treatment have been exhausted (Dunselman, 2014).
Selective Progesterone-Receptor Modulators
Progestins produce agonist effects upon binding to progesterone receptors. In contrast, progesterone antagonists and selective progesterone-receptor modulators (SPRMs) are agents that vary in their progesterone-receptor binding. Progesterone antagonists universally bind to and inactivate these receptors. SPRMS, depending on their individual pharmacologic profile, may activate or inactive progesterone receptors variably within different tissue types (Chap. 15). Currently, these are not used in the United States to treat endometriosis.
Of progesterone antagonists, mifepristone (RU-486; Mifeprex) is FDA-approved solely for early pregnancy termination. Studied in women with endometriosis, mifepristone reduced pelvic pain and extent of endometriosis (Kettel, 1996). However, as a side effect, its antiprogestational effects expose the endometrium to chronic unopposed estrogen. Resulting endometrial changes range from simple endometrial hyperplasia to a new category described as progesterone-receptor-modulator–associated endometrial changes (PAEC) (Mutter, 2008). The clinical significance of PAEC is still unclear.
Of SPRMs, ulipristal acetate is available in the United States for emergency contraception as Ella and in Europe for presurgical treatment of leiomyomas as Esmya. Again, long-term endometrial safety for both eutopic and ectopic endometria is unclear with this SPRM, and this limits its chronic use at this time. Most other SPRMs are still experimental.
These drugs are now used as second-line agents for endometriosis due to their androgenic side effects. Of these, danazol is a synthetic 17α-ethinyl testosterone derivative. Its predominant action suppresses the midcycle LH surge to promote chronic anovulation (Floyd, 1980). Danazol occupies receptor sites on sex hormone-binding globulin (SHBG) and thereby increases serum free testosterone levels. It also binds directly to androgen and progesterone receptors. As a result, danazol creates a hypoestrogenic, hyperandrogenic state that induces endometrial atrophy in endometriotic implants (Fedele, 1990). Regarding efficacy, danazol given orally at dosages of 200 mg three times daily proved superior to placebo to diminish endometriotic implants and pelvic pain symptoms after 6 months of therapy (Telimaa, 1987).
The recommended dosage of danazol is 600 to 800 mg orally daily. Unfortunately, significant androgenic side effects develop and include acne, hot flushes, hirsutism, adverse serum lipid profiles, voice deepening (possibly irreversible), elevation of liver enzyme levels, and mood changes. Moreover, due to possible teratogenicity, this medication should be taken in conjunction with effective contraception. Because of its adverse side-effect profile, danazol is prescribed less frequently, and if administered, its duration is limited.
Gestrinone (ethylnorgestrienone; R2323) is an antiprogestational agent prescribed in Europe for endometriosis. It has antiprogestational, antiestrogenic, and androgenic effects. Gestrinone equals the effectiveness of danazol and of GnRH agonists for relief of endometriosis-related pain (Prentice, 2000). Furthermore, during 6 months of treatment, gestrinone was not associated with the bone density loss commonly seen with GnRH agonist use and was more effective in persistently decreasing moderate to severe pelvic pain (Gestrinone Italian Study Group, 1996). Disadvantageously, gestrinone appears to lower high-density lipoprotein (HDL) levels. Gestrinone is administered orally, 2.5 to 10 mg weekly, given daily or three times weekly.
Surgical Treatment of Endometriosis-Related Pain
Lesion Removal and Adhesiolysis
Because laparoscopy is the primary method for endometriosis diagnosis, surgical treatment at the time of diagnosis is an attractive option. Numerous studies have examined removal of endometriotic lesions, through either excision or ablation. In one randomized trial, diagnostic laparoscopy alone was compared with laparoscopic endometriotic lesion ablation plus uterine nerve ablation. In the ablation group, 63 percent of women attained significant symptom relief compared with 23 percent in the expectant management group (Jones, 2001).
The optimal method to address endometriotic implants for maximal symptom relief is controversial. First, laser ablation does not appear to be more effective than conventional electrosurgical ablation of endometriosis (Blackwell, 1991). Second, ablation and excision both appear to perform suitably. In one randomized trial, ablation was compared with excision of lesions in women with stage I or II endometriosis. At 6 months, similar reductions in pain scores were found (Wright, 2005). Another study showed no significant difference between ablation and excision at 12 months (Healey, 2010). However, at 5 years, the need for further hormonal or analgesic treatment was greater in the ablation group (Healey, 2014). For deeply infiltrative endometriosis, some authors have advocated radical surgical excision, although well-designed trials are lacking (Chapron, 2004).
Unfortunately, recurrence is common following surgical excision. Jones and associates (2001) demonstrated pain recurrence in 74 percent of patients at a mean time of 73 months postoperatively. The median time for recurrence was 20 months. After surgery for pain-related endometriosis, postoperative medical treatment may be elected to extend pain relief or treat residual pain. For this, the most rigorous evidence supports COCs or the LNG-IUS (Somigliana, 2014).
Adhesiolysis is postulated to effectively treat pain symptoms in women with endometriosis by restoring normal anatomy. However, most studies are poorly designed and retrospective. As a result, a definitive link between adhesions and pelvic pain is unclear (Hammoud, 2004). For example, one randomized trial demonstrated no overall pain relief from adhesiolysis compared with expectant management (Peters, 1992). However, within this study, one woman with severe, dense vascularized bowel adhesions experienced pain relief following adhesiolysis.
Adhesion prevention during endometriosis surgery emphasizes sound surgical techniques described in Chapter 40. Of adhesion-prevention agents available in the United States, small studies show lower adhesions reformation rates with use of the cellulose barrier Interceed in endometriosis cases (Mais, 1995a; Sekiba, 1992). But, as noted by the American Society for Reproductive Medicine (2013), although peritoneal instillates and barriers may reduce postoperative adhesions, this has not translated clinically into improved pain, fertility, or bowel obstruction rates.
Endometriomas are typically treated surgically to exclude malignancy or treat associated pain. To determine the best technique, total ovarian cystectomy compared against aspiration coupled with cyst wall ablation has been studied. Findings note that cystectomy lowers endometrioma recurrence rates and pain symptoms and improves subsequent spontaneous pregnancy rates (Dan, 2013; Hart, 2008). During surgery, ideally normal ovarian tissue is preserved. Toward this goal, electrosurgical coagulation of bleeding sites should be limited. As alternatives, some have described use of dilute vasopressin or suture (Pergialiotis, 2015; Qiong-Zhen, 2014). Other technical steps are described in Chapter 44. Despite cystectomy, endometriomas may recur. Liu and coworkers (2007) found an approximately 15 percent recurrence rate at 2 years following initial surgery.
Importantly, women who undergo endometrioma excision may subsequently have a reduced ovarian reserve, that is, the capacity to provide ova capable of fertilization (Somigliana, 2012). Additionally, surgery increases risks for adhesion formation. Both effects may diminish future fertility. Accordingly, in a woman who is asymptomatic, has a small endometrioma that displays classic findings, has a known endometriosis diagnosis, and has normal or stable CA125 levels, surveillance is an option (American College of Obstetricians and Gynecologists, 2013, 2014b). This approach may benefit asymptomatic women with recurrent endometriomas, as repeat surgery can again diminish reserve (Ferrero, 2015). Following initial diagnosis of an endometrioma, repeat TVS is recommended 6 to 12 weeks later to exclude a hemorrhagic cyst. Endometriomas may then be sonographically surveilled in asymptomatic women yearly or sooner, at the clinician’s discretion (Levine, 2010). The main disadvantage to observation is an inability to exclude ovarian malignancy, and thus patient counseling is essential.
For some women, transection of presacral nerves lying within the presacral space may provide relief of chronic pelvic pain (Fig. 38-23). Results from a randomized trial revealed significantly greater pain relief at 12 months postoperatively in women treated with presacral neurectomy (PSN) and endometriotic excision compared with that from endometriotic excision alone (86 percent versus 57 percent) (Zullo, 2003). However, all of these women had midline pain. One metaanalysis demonstrated a significant decrease in pelvic pain after PSN compared with that following more conservative procedures, but only in those with midline pain (Proctor, 2005). Neurectomy may be performed laparoscopically, but it is technically challenging. Due to involved nerve disruption, postoperative constipation and voiding dysfunction are common (Huber, 2015). For these reasons, PSN is used in a limited manner and not recommended routinely for management of endometriosis-related pain.
Laparoscopic Uterosacral Nerve Ablation
There is no evidence that laparoscopic uterosacral nerve ablation (LUNA) is effective in treating endometriosis-related pain (Vercellini, 2003a). In a randomized trial of 487 women with chronic pelvic pain lasting longer than 6 months, with or without minimal endometriosis, LUNA did not improve pain, dysmenorrhea, dyspareunia, or quality-of-life scores compared with laparoscopy without pelvic denervation (Daniels, 2009).
Abdominal versus Laparoscopic Approach
All of the surgical procedures listed above can be completed through open or laparoscopic approaches. First, for benign ovarian masses such as endometriomas, strong evidence supports laparoscopy (Mais, 1995b; Yuen, 1997). Laparoscopic treatment of endometrioma carries an associated 5-percent risk for conversion to laparotomy. However, because of its efficacy and low rates of postoperative morbidity, laparoscopy is a preferred route when feasible (Canis, 2003).
For excision of endometriotic implants, studies also demonstrate effectiveness and low morbidity rates with laparoscopy. Moreover, adhesiolysis is preferred via laparoscopy when safe, and laparoscopy leads to less de novo adhesion formation than laparotomy (Gutt, 2004). Laparoscopic presacral neurectomy appears to be as effective as laparotomy (Nezhat, 1992; Redwine, 1991).
This procedure is the definitive and most effective therapy for women with endometriosis who do not wish to retain fertility. It is appropriate for women with intractable pain, adnexal masses, or multiple previous conservative therapies or surgeries (American College of Obstetricians and Gynecologists, 2014b). Hysterectomy for patients with endometriosis may suitably be completed laparoscopically, abdominally, or vaginally. However, adhesions and distorted anatomy secondary to endometriosis often makes a laparoscopic or vaginal approach difficult. In addition, the need to remove ovaries may make a vaginal approach less feasible. Accordingly, the choice of procedure will depend on equipment availability, operator experience, and extent of disease.
Prior to hysterectomy for endometriosis, oophorectomy is discussed. A general discussion of risks and benefits is found in Chapter 43. Specific to endometriosis, the benefits of pain relief and reoperation risks are measured against complications of hypoestrogenism. In one study, of those with hysterectomy and bilateral salpingo-oophorectomy (BSO), 10 percent had recurrent chronic pelvic pain and 4 percent required reoperation. Compared with these women, those choosing ovarian conservation had a sixfold greater risk of recurrent pain and an eightfold greater risk of requiring additional surgery (Namnoum, 1995). In a second study, among all those choosing hysterectomy, ovarian conservation doubled the reoperation rate compared with those undergoing BSO (Shakiba, 2008). Moreover, in a subanalysis of those older than 40, ovary conservation lead to a sevenfold greater reoperation rate than BSO. However, in those younger than 40, reoperation rates did not differ whether ovaries were retained or removed. The American College of Obstetricians and Gynecologists (2014b) notes that ovarian conservation can be considered in patients undergoing hysterectomy if ovaries appear normal.
In epidemiologic studies, women with prior endometriosis have slightly increased ovarian cancer rates and higher proportions of clear cell and endometrioid subtypes (Kim, 2014; Pearce, 2012; Somigliana, 2006). That said, consensus guidelines do not recommend management changes in relation to this cancer risk (Dunselman, 2014).
Postoperative Hormone Replacement
Women with surgical menopause are usually younger and would likely benefit from estrogen replacement. Options are discussed in Chapter 22. Although evidence is lacking, some suggest that treatment in these women continue until the time of expected natural menopause.
Unopposed estrogen is appropriate for hypoestrogenic women without a uterus, but disease recurrence has been reported with this therapy in women with severe endometriosis first treated with hysterectomy and BSO (Taylor, 1999). Symptoms required repeat surgery and did not recur with adjuvant combined estrogen and progestin regimens. Additionally, cases of endometrial carcinoma have been reported in women with endometriosis who were treated with unopposed estrogen after hysterectomy and BSO (Reimnitz, 1988; Soliman, 2006). This is rare and may arise from incompletely resected pelvic endometriosis. Therefore, adding a progestin to estrogen replacement therapy can be considered in women with severe endometriosis treated surgically (Moen, 2010). Again, the risks of malignancy are balanced against the adverse lipid changes and breast cancer risks associated with adding progesterone to hormone replacement therapy.
The optimal timing for hormone replacement initiation following hysterectomy with BSO is support by limited data. One small study showed no significant differences in postoperative recurrent pain rates whether hormones were initiated immediately after surgery or were delayed (Hickman, 1998).
Treatment of Endometriosis-Related Infertility
For an asymptomatic woman with infertility, laparoscopy solely to exclude endometriosis is unwarranted (American Society for Reproductive Medicine, 2012). For those with endometriosis-related pain undergoing medical therapy, treatment does not raise fecundity (Hughes, 2007).
For women with infertility and minimal to mild endometriosis, surgical ablation has been suggested to be beneficial, although the effect appears small (Marcoux, 1997). However, other researchers did not report a fertility benefit to surgical ablation for mild to moderate endometriosis (Parazzini, 1999). A metaanalysis of these two studies did demonstrate an advantage for laparoscopic surgery compared with diagnostic laparoscopy (Jacobson, 2010).
Moderate to severe endometriosis may be treated with surgery to restore normal anatomy and tubal function. However, well-designed trials examining the role of surgery for subfertility in women with severe endometriosis are limited (Crosignani, 1996). In infertile women with stage III/IV endometriosis, clinicians can consider operative laparoscopy, instead of expectant management, to increase spontaneous pregnancy rates (Dunselman, 2014). However, after initial unsuccessful surgery for infertility, IVF is preferable to reoperation (Pagidas, 1996).
Alternatively, patients with endometriosis and infertility are candidates for fertility treatments such as controlled ovarian hyperstimulation, intrauterine insemination, and IVF (Chap. 20). Logically, age and disease stage factor into treatment decisions.