Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

64. Endometriosis

Deborah A. Sturpe and Kathleen J. Pincus


KEY CONCEPTS

 Images Endometriosis should be suspected in any woman of reproductive age with recurring cyclic or acyclic pelvic pain and/or subfertility, especially if pain does not improve with nonsteroidal antiinflammatory drugs and hormonal contraceptives.

 Images The etiology of endometriosis is likely multifactorial and requires a genetic or immunologic predisposition. Retrograde menstruation is the most widely accepted theory to account for displacement of endometrial tissue, although alternative theories have been proposed.

 Images Treatment goals include improvement of painful symptoms and maintenance or improvement of fertility. Therapy is considered successful based on resolution of the patient’s symptoms or achievement of pregnancy.

 Images Both drug therapy and surgery may treat endometriosis-related pain, but infertility can only be treated with surgery or assisted reproductive techniques.

 Images No medical therapy has been proven to be more effective than another; thus, the choice among agents is determined primarily by side effect profile, cost, and individual patient response.

 Images For endometriosis pain, surgical therapy is typically reserved for medical therapy failure.

 Images Diagnosis of endometriosis can be made only via surgical visualization of lesions, not by physical examination or laboratory testing. Empiric treatment without confirmation of diagnosis is acceptable in most cases.

 Images To help avoid loss of bone mineral density, add-back therapy should be strongly considered in any woman receiving a gonadotropin-releasing hormone agonist.


INTRODUCTION

Images Endometriosis causes secondary dysmenorrhea and is associated with infertility. Presence of endometrial tissue outside the uterus is chronic and relapsing. Endometriosis treatment targets pain relief and fertility improvement.

EPIDEMIOLOGY

The prevalence of endometriosis is estimated at 5% to 10% of the general female population.14 Four percent of premenopausal women presenting to primary care for nongynecologic problems have endometriosis, and up to 80% of adult women and 50% of adolescents with chronic pelvic pain are diagnosed with the disorder.1,48 The incidence is 10-fold higher in women with infertility (20% to 50%) compared with that in fertile women (0.5% to 5%).1,47,9 A genetic predisposition for endometriosis has also been noted.2

ETIOLOGY

Endometriosis is characterized by findings of endometrial tissue outside of the normal uterine cavity. It may be diagnosed at any age, but is most commonly found during the reproductive years (range 12 to 80 years old, average 28 years).1,7 Risk of developing endometriosis increases with early menarche (≤11 years), shorter menstrual cycles (<27 days), and heavy, prolonged menstruation.4,7 Taller, thinner women are more likely to develop endometriosis than patients with higher body weights, body mass indexes, or waist-to-hip ratios potentially due to higher follicular-phase estradiol levels.7 Altered pelvic anatomy, such as Müllerian duct anomalies and cervical or vaginal outlet obstruction, also increases risk of developing endometriosis, as does in utero exposure to environmental toxins or potent estrogens.2,3,7Conversely, higher parity, increased duration of lactation, regular exercise (>4 h/wk), greater birth weight, and breast-feeding decrease the risk of endometriosis.4,7

Gene mutation studies suggest genes regulating inflammation, sex steroid regulation, metabolism, biosynthesis, detoxification, vascular function, and tissue remodeling may contribute to endometriosis, but no validated associations have been confirmed.10 Alterations on chromosomes 7 and 10 have been identified in clusters of women with endometriosis.2 It is most likely that a multitude of genetic mutations are involved with the development of endometriosis.

PATHOPHYSIOLOGY

Images Multiple theories exist to explain why endometrial tissue is present outside the uterine cavity, and the true pathophysiology is likely multifactorial.13,5 The most widely accepted theory proposes that endometrial tissue is deposited in the peritoneal cavity by retrograde menstruation through the fallopian tubes.3 However, retrograde menstruation occurs in up to 90% of women while only 10% to 15% develop endometriosis, indicating that additional factors are necessary for endometrial lesions to attach, survive, and proliferate.1,2,4 Alternative theories include the inappropriate differentiation of mesothelial cells into endometrium-like tissue (coelomic metaplasia), the differentiation of stem cells from either bone marrow or the endometrial basalis layer into endometrial-like tissues (stem cell theory), and the spread of menstrual tissue to distant sites through veins or lymphatic vessels (lymphatic or hematogenous spread).2,3

Endometriosis is a chronic inflammatory disorder that exhibits cellular proliferation, cellular invasion, and angiogenesis not unlike solid tumor malignancies.11 Genetic alterations may predispose endometrial lesion survival in certain women, and immunologic abnormalities may decrease the clearance of displaced endometrial tissue.1,2,4 Findings of abnormal B- and T-cell function, decreased apoptosis, and altered levels of prostanoids, cytokines, growth factors, interleukins, and aromatase in endometrial lesions and peritoneal fluid of affected women support this theory.1,2,12


CLINICAL PRESENTATION

Symptoms

    • Most common are dysmenorrhea and infertility.

    • Other symptoms include dyspareunia, menorrhagia, chronic pelvic pain (cyclic or acyclic), ovulation pain, sacral back pain, cyclic or perimenstrual bowel and bladder complaints (e.g., GI disturbances, painful defecation, tenesmus dysuria, and/or hematuria), chronic fatigue, or rarely neuropathic pain.

    • Some patients may be asymptomatic.

Signs

    • Findings on physical examination are best observed during menstruation and may include pelvic tenderness, tender uterosacral ligaments, enlarged ovaries, pelvic masses or nodules, or a fixed, retroverted uterus.

    • Findings on laparoscopic examination may range from a few small lesions located on the ovaries, serosal surfaces, or peritoneum to large cysts called endometriomas. Lesions are often described as: “powder burn” or “gunshot” lesions; dark brown, black, or blue lesions, nodules, and cysts; and “chocolate cysts” (endometriomas containing blood).

Diagnosis

    • Definitive diagnosis can be made only by direct surgical visualization of endometrial lesions; however, treatment guidelines allow for nondefinitive diagnosis in patients presenting with chronic pelvic pain provided that other causes of pain are ruled out and that pain responds to empiric therapies.

    • Ultrasonography, magnetic resonance imaging, and computed tomography have much lower sensitivity for endometrial lesions, but have utility in assessing for pelvic or adnexal masses.

Disease Staging

    • Severity of disease can be classified according to the American Society of Reproductive Medicine staging system (stage I [mild] to stage IV [severe]), but clinical utility of this staging system is limited because findings do not correlate with painful symptoms, nor does the staging system predict pregnancy rates. Staging may be useful in guiding decisions regarding prognosis and treatment for infertility.

Data from references 4 and 20.

Pain associated with endometriosis results from increased concentrations of inflammatory markers, including prostaglandins, and increased nerve density at lesion sites. Proinflammatory cytokines found in endometrial lesions, including tumor necrosis factor-α and interleukins 1, 6, and 8, promote lesion formation, adhesion, and infiltration and induce pain through pelvic nerve stimulation.2,4 Prostaglandin Finduces vasoconstriction and can cause uterine contractions, a component of dysmenorrhea, while prostaglandin E2 can induce pain through direct actions on nerves.2 Increased density of sensory, cholinergic, and adrenergic nerves and an overexpression of nerve growth factors near lesions in endometrial tissue also cause pain.3 Researchers have demonstrated that these nerve fibers are found significantly more often in patients with endometriosis than in those without endometriosis, in greater density in patients with higher pain scores (≥3 vs. ≤20), and in greater density in patients with deep infiltrating lesions.11,1315 The interplay between increased density of nerve fibers in endometrial lesions and increased concentrations of cytokines and prostaglandins in peritoneal fluid combines to confer significant pelvic pain in many patients.

The pathophysiology for infertility in endometriosis is less well defined, especially in mild disease. In advanced endometriosis, inflammation and anatomic abnormalities such as ovarian cysts and adhesions may physically block fallopian tubes and decrease receptivity of the endometrium, thus hindering oocyte and embryo development.2,4 The same inflammatory cytokines that lead to pain also create a hostile peritoneal environment leading to damage of sperm DNA and cell membranes.16 Hormonal dysregulation resulting from the disease also leads to decreased ovarian reserve, altered follicular morphology, oocyte dysfunction, and decreased efficacy of fertility treatments.17

TREATMENT

Endometriosis is a chronic, relapsing disease. Lifelong treatment plans must consider individual patient symptoms, goals for fertility, and impact on quality of life.18 Various organizations, including the American Congress of Obstetricians and Gynecologists, the American Society for Reproductive Medicine, the Society of Obstetricians and Gynaecologists of Canada, and the European Society of Human Reproduction and Embryology, have published recent evidence-based and/or expert opinion-based guidelines for treating endometriosis.4,6,1820 These guidelines should be used to help inform treatment choice.

Desired Outcomes

Identification of endometriosis treatment goals depends on individual patient presentation and needs. Images Images Typical outcomes include minimization of associated pain, improved quality of life, and correction of associated infertility. The first two outcomes can often be achieved through use of pharmacologic therapy and surgery.4,6,18 Infertility is nonresponsive to medical therapies; thus, surgical intervention to remove endometrial lesions coupled with various assisted reproductive techniques must be employed.4,19 Even with such efforts, not all women with endometriosis will be able to conceive, and exact success rates are unknown due to a paucity of well-designed clinical studies.

General Approach to Treatment

Treatment of the asymptomatic patient consists of expectant management (watchful waiting). For symptomatic patients, the foundation of therapy includes medical treatment, surgical treatment, or both. To date, no studies have directly compared medical and surgical treatment as first-line therapy. Furthermore, determining the optimal medical or surgical approach is difficult secondary to a paucity of well-designed, randomized controlled trials comparing options. Images All commonly prescribed medical therapies relieve endometriosis-related pain by regressing lesions via induction of a pseudopregnancy or pseudomenopausal state, but medications do not eradicate lesions or improve fertility. The choice of initial therapy depends on factors such as the patient’s primary complaint, the location and extent of disease, desire for future fertility, cost of therapy, contraindications to therapy, and potential side effects.4,6,18,20 Information regarding drugs commonly prescribed for endometriosis, their dosing, side effects, and special monitoring parameters are listed in Tables 64-1 and 64-2. No endometriosis treatments are guaranteed to provide full relief of symptoms; consequently, analgesics such as nonsteroidal antiinflammatory drugs or opioids are often used as adjunctive therapy for pain relief.

TABLE 64-1 Dosing of Drugs Used in Treatment of Endometriosis

Images

TABLE 64-2 Monitoring Drug Therapy for Endometriosis

Images

Nonpharmacologic Therapy

Surgery, generally performed via laparoscopy, is used in endometriosis as both a diagnostic and a therapeutic tool.19,20 Images Images Due to lack of data supporting superiority of surgery over medical therapies in relieving endometriosis pain, surgical therapy is typically reserved for patients experiencing medication failure or who suffer from infertility. Women with continuing pain symptoms who do not desire pregnancy may be offered the option of hysterectomy with or without oophorectomy. In one long-term followup study conducted at the Cleveland Clinic, surgery-free rates 7 years after initial surgery were lower with laparotomy alone versus hysterectomy (45.7% vs. 84.6% surgery free).21 In both groups, ovary removal did not improve surgery-free rates regardless of baseline ovarian disease involvement.21


Clinical Controversy…

The optimal use of medical therapy after laparoscopy or hysterectomy remains ill-defined. It is known that pain recurrence after surgery is high, yet the optimal dose and duration for postoperative medications are unknown. Some experts advocate avoidance of drug therapy unless pain symptoms recur, while others recommend immediate use of medications in order to extend the pain-free interval. Medications studied for these indications include combined oral contraceptives (both continuous and cyclic dosing), GnRH agonists, and the levonorgestrel intrauterine system.

Other nonpharmacologic methods that have been investigated in the treatment of endometriosis pain include acupuncture and dietary therapy, but data for both are sparse.

Effectiveness of acupuncture has been investigated in a small, crossover study that compared targeted site acupuncture (treatment arm that was specific for the pelvic region) with nontargeted acupuncture (control arm that was for generalized pain conditions).22 Despite the inclusion of this potentially effective control arm, a significant decrease in endometriosis pain was noted by all patients when receiving the targeted site acupuncture as compared with nontargeted treatments.

Interest in using dietary therapy to treat endometriosis stems from the observation that supplements may be able to modify some of the inflammatory processes that lead to dysmenorrhea.23 In a randomized, placebo-controlled trial, women with severe endometriosis were randomized to 6 months of postsurgical treatment with one of the following three treatments: hormone therapy (combined oral contraceptive or gonadotropin-releasing hormone [GnRH] agonist); dietary therapy consisting of vitamins (B6, A, C, E), mineral salts (calcium, magnesium, selenium, zinc, and iron), lactic ferments, and omega-3 and omega-6 fatty acids; or placebo.24 Results revealed statistically significant decreases in dysmenorrhea and nonmenstrual pelvic pain in all active groups compared with placebo. Although the results of this study must still be confirmed by additional research, the relative safety of such dietary supplementation makes its use intriguing.

Pharmacologic Therapy

Images Pharmacologic therapy is typically the first choice for treatment of endometriosis-related pain to minimize risks from multiple surgeries such as scarring and tissue adhesions (see Fig. 64-1).

Images

FIGURE 64-1 Treatment algorithm for chronic pelvic pain and suspected endometriosis. (CHC, combined hormonal contraceptive; GnRH-a, gonadotropin-releasing hormone agonist.) (Data from references 4, 6, 18, and 20.)

Drug Treatments of First Choice

First-line therapy for endometriosis-associated pain includes oral, transdermal, or vaginal combined hormonal contraception (CHC) or progestins (norethindrone or depot medroxyprogesterone) since both drug classes are as effective as, but less costly and toxic than, other pharmacologic options.4,6,18,20 Choice among these agents depends on patient characteristics such as the desire for contraception, pain patterns, and contraindications as no direct comparisons are available in the literature. Long-term maintenance therapy with these agents should be considered for women achieving a good therapeutic response.4 Images These drugs may be used empirically for suspected endometriosis prior to laparoscopy in patients of any age.4,6,18,20

Alternative Drug Treatments

Patients whose endometriosis pain does not respond to CHCs or progestins may next be empirically treated with GnRH agonists or the levonorgestrel intrauterine system provided the patient is older than 16 years.4,18,20,25 ImagesSelection is again driven primarily by side effect profile, available dosage forms, and medication costs, since no method has been proven superior to another.4,6,18 Unlike the first-line agents, the safety of long-term use of these options is unknown. Most clinical trials have only examined use of GnRH agonists for up to 6 months duration, yet recurrence of painful symptoms after drug cessation is high, thus necessitating off-label extended treatment or retreatment.1,6 One of the biggest concerns with such extension of therapy is bone mineral density loss, but add-back therapy with a progestin and/or estrogen and progestin combination minimizes this loss along with mitigation of other bothersome side effects.26 Images Consequently, practice guidelines now recommend use of add-back therapy on immediate initiation of GnRH agonist treatments.4,18

Pharmacologic options for endometriosis pain refractory to the aforementioned drug and nondrug methods include danazol or the aromatase inhibitors. Danazol was once the mainstay of endometriosis treatment, but its side effect profile has caused the drug to fall out of favor for most clinicians.4,6,18 Data on use of aromatase inhibitors for endometriosis pain are still sparse enough that these medications are not yet recommended within practice guidelines, but this class of medications is often the focus of current research efforts.

Special Populations

Treatment of the adolescent patient with endometriosis presents a unique challenge, as these patients often present with normal physical findings and laparoscopic findings that are atypical for endometriosis; thus, endometriosis must be strongly suspected in any patient whose dysmenorrhea fails to respond to first-line agents.18 Treatment algorithms for such patients are extrapolated from adult recommendations and expert opinion, but generally follow the same recommendations as for adult patients.18,25 Pertinent differences include less aggressive use of GnRH agonist therapy prior to laparoscopy in patients younger than age 18 and avoidance (if possible) of this medication class in patients younger than age 16 due to concerns over the potential long-term detrimental effects of bone loss.18,25 Despite these limitations, early recognition and treatment of endometriosis in the adolescent population may be critical for maintenance of quality of life in this age group.27

Drug Class Information

No single drug therapy has been shown to be superior to another for the treatment of endometriosis pain. Therefore, the choice of drug between and within classes is often dependent on patient factors and clinician experience.

Combined Hormonal Contraception Effectiveness of oral CHCs in treating endometriosis pain has been demonstrated in numerous observational, placebo-controlled, and active-comparator trials.2834 More recently, effectiveness of the CHC patch and vaginal ring has also been demonstrated.35 There is no evidence to suggest superiority of any of these contraceptive methods over another, although most available studies used monophasic oral pills. Thus, the choice between CHCs should be guided by patient preference, likelihood of adherence, and cost.

Administration of CHCs may be cyclic (includes a placebo or nondrug week) or continuous. In one randomized, placebo-controlled trial comparing cyclic and continuous dosing of a low-dose monophasic oral contraceptive pill after laparoscopy, the continuous dosing strategy provided statistically superior improvement in pain and disease recurrence compared with both the cyclic dosing and placebo groups at 6, 12, 18, and 24 months postoperatively, while the cyclic dosing group demonstrated superiority only over placebo after 12 months of therapy.36 One theory that may explain these findings is prevention of retrograde menstruation through induction of an amenorrheic state with continuous dosing. At least one practice guideline specifically recommends that CHC dosing be continuous in all endometriosis patients.18

Progestins Various progestins have been studied for the treatment of endometriosis. The largest body of data support use of oral norethindrone, oral dienogest (not available in the United States), and depot medroxyprogesterone. The only well designed, active-comparator trials of progestins involved the subcutaneous form of depot medroxyprogesterone, and both of those studies revealed equivalent pain relief compared with pain relief with a GnRH agonist.37,38As with the CHCs, there are no trials that directly compare the progestins with one another; thus, selection of an agent must consider its dosage form, cost, and potential side effects.

One concern over use of depot medroxyprogesterone is its potential to cause bone mineral density loss, and for this reason both the intramuscular and the subcutaneous products carry FDA black box warnings against use for more than 2 years.39,40 In the two comparator studies of depot medroxyprogesterone and GnRH agonist, the extent and degree of bone loss was less severe with the progestin.37,38 One limitation to these findings, however, is that add-back therapy was not used with the GnRH agonist. Prolonged delays in return to ovulation after cessation of therapy is also concerning; thus, depot medroxyprogesterone may not be optimal for use in women desiring future pregnancy.18

Gonadotropin-Releasing Hormone Agonists GnRH agonists create a functional oophorectomy via inhibition of follicle-stimulating hormone and luteinizing hormone secretion. When first initiated, GnRH agonists create a gonadotropin flare prior to receptor downregulation that may cause a temporary increase in pain. Initiating therapy during the mid-luteal phase may minimize such effects, and use of analgesics during this time frame is also critical. Of the four agents available for use in the United States (goserelin, leuprolide, nafarelin, and triptorelin), route of administration and cost is the primary distinguishing factor that determines choice of drug.

Pain relief with GnRH agonists is superior to placebo and comparable to other therapies such as danazol, CHCs, depot medroxyprogesterone, and intrauterine progestins.41 Although typically used for only a 6-month treatment duration, recurrence of pain is high after cessation of therapy.6 Thus, therapy may be extended beyond 6 months to maintain efficacy, although data regarding such extended usage are limited.

Side effects are the primary limitation of GnRH agonist use. The pharmacologically induced hypoestrogenic environment results in bone mineral density loss and vasomotor symptoms such as hot flashes, vaginal dryness, and insomnia. Loss of bone mineral density is estimated at 4% to 6% over a 6-month treatment course, but this loss is partially to fully recoverable on cessation of the drug.1 Extended use up to 12 months duration results in continuing and progressive loss that is not fully reversed on drug cessation; thus, add-back therapy is especially critical when these drugs are used as extended regimens.26

Cost of the GnRH agonists is high. In one study, every 6-week dosing of intramuscular triptorelin was compared with its usual every 4-week dosing regimen.42 Pain relief and serum hormone levels were equivalent between groups, suggesting that an extended interval strategy may be an option for cost savings.

Women receiving GnRH agonist therapy should be encouraged to take supplemental calcium and to exercise as these strategies may assist with recovery of bone mineral density after cessation of therapy.43

Add-Back Therapy Images Add-back therapy refers to use of pharmacologic agents in addition to GnRH agonists in order to minimize side effects and improve adherence.26 Regimens investigated for this purpose are an estrogen, progestin, or combination of the two.26,44 Although it may seem counterintuitive to use such therapy in endometriosis patients, the doses of add-back hormones are low enough to prevent GnRH agonist side effects while still preventing growth of new endometrial tissue.18 Add-back regimens that have been successfully studied as part of both 6-month and 12-month GnRH agonist regimens include norethindrone alone (2.5 to 5 mg) or in combination with either conjugated equine estrogens (0.625 mg) or estradiol (1 mg).26

Levonorgestrel Intrauterine System The levonorgestrel intrauterine system is an intriguing option for treating endometriosis due to its ability to locally deliver progestin to the uterine cavity without significant systemic absorption, but studies of the method have revealed mixed results.4548 In a small, direct comparison with depot medroxyprogesterone, the intrauterine system demonstrated equivalent pain relief and better adherence.46 But in a different comparison to an “every 6-month” formulation of a GnRH analogue, statistically significant pain relief was noted only in the GnRH analogue group, and intrauterine system users reported lower satisfaction with treatment.47

Disadvantages of the levonorgestrel intrauterine system include potential difficulty of inserting the device into nulliparous women, a 5% expulsion rate, and the potential for growth of ovarian endometriomas since the method does not inhibit ovulation.18

Danazol Danazol has been shown to be effective both empirically and after surgery compared with placebo.49 Formerly the “gold standard” of endometriosis treatment, the popularity of danazol has decreased with the development of agents with more favorable side effect profiles. Danazol should not be initiated in women with hyperlipidemia or liver disease. It is teratogenic; thus, barrier forms of contraception must be used.

In an effort to diminish the high rate of androgenic side effects noted with danazol while maintaining effectiveness, vaginal danazol formulations (100 to 200 mg/day) have been investigated in three small studies.50-52 Each study was a nonrandomized, prospective trial in women who had failed other therapies such as surgery, GnRH agonists, and the levonorgestrel intrauterine system. In each, improvements in dysmenorrhea, deep dyspareunia, and pelvic pain were noted without incidence of systemic side effects; thus, vaginal delivery of this drug may prove to be a viable method. Unfortunately, a vaginal formulation is not yet available in the United States.

Aromatase Inhibitors Although practice guidelines currently make no specific recommendations for the use of aromatase inhibitors to treat endometriosis, the body of literature supporting use of these agents is growing. Numerous case reports and retrospective, nonrandomized and noncomparative, as well as randomized comparative studies support the effectiveness of both letrozole and anastrozole in decreasing pain, improving quality of life, and reducing postoperative recurrence of disease.5358 In all cases, the aromatase inhibitor was used in combination with a progestin, a combined oral contraceptive, or a GnRH agonist. Because most safety information for the aromatase inhibitors is derived from use in postmenopausal women with cancer, it is unknown if similar issues will be experienced by premenopausal women using these agents for endometriosis. Based on available data, it does appear that use of progestins and combined oral contraceptives in combination with the aromatase inhibitors helps to limit side effects and bone mineral density loss.55

Personalized Pharmacotherapy

At this point in time, no evidence exists to suggest how to select or dose therapy for endometriosis based on pharmacogenomic, pharmacogenetic, or pharmacokinetic differences between patients. As additional understanding of the pathogenesis of endometriosis emerges, such personalized pharmacotherapy options might be realized.

Evaluation of Therapeutic Outcomes

Size, number, and distribution of endometrial lesions do not correlate with pain symptoms or fertility potential; thus, therapeutic outcome monitoring should focus solely on subjective relief of symptoms.4Although traditional measures such as visual pain scales and symptom diaries have been utilized to measure treatment effectiveness, such measures do not capture overall patient satisfaction with treatment, a factor which has been correlated to treatment adherence.59 Recently, a patient-reported outcome instrument, the Endometriosis Treatment Satisfaction Questionnaire, has been developed and validated.59 The tool includes six items (pain before and/or during periods, pain during and/or after sex, endometriosis pain, bleeding/spotting, tolerability, overall satisfaction) that are rated by patients on a 7-point Likert scale.59

Images Endometriosis-related pain should be relieved within 2 months of initiating medical therapy. If symptoms persist, consideration should be given to different medical and/or surgical therapy. For endometriosis-related infertility, most experts recommend 6 months of watchful waiting after surgical intervention. If pregnancy is not achieved within that time, assisted reproductive techniques can be considered.


Clinical Controversy…

Numerous medications used to treat endometriosis are known to diminish bone mineral density, yet the optimal method for monitoring this effect is unknown. Although some clinicians may select to routinely measure bone mineral density through dual-energy x-ray absorptiometry before, during, or after treatment, no data exist to support this practice. What is known is that add-back therapy effectively mitigates most bone mineral density loss and that any loss is generally recovered on cessation of therapy. Consequently, use of bone mineral density testing may be best reserved for the clinical trial environment until more information is known about the predictive utility of such testing in routine practice.

ABBREVIATIONS

Images

REFERENCES

    1. Olive DL. Gonadotropin-releasing hormone agonists for endometriosis. N Engl J Med 2008;359(11):1136–1142.

    2. Bulun SE. Endometriosis. N Engl J Med 2009;360(3):268–279.

    3. Sasson IE, Taylor HS. Stem cells and the pathogenesis of endometriosis. Ann N Y Acad Sci 2008;1127:106–115.

    4. Committee on Gynecologic Practice. Management of endometriosis. Obstet Gynecol 2010;116(1):223–236.

    5. Farquhar C. Endometriosis. BMJ 2007;334(7587):249–253.

    6. Practice Committee of American Society for Reproductive Medicine. Treatment of pelvic pain associated with endometriosis. Fertil Steril 2008;90(5 Suppl):S260–S269.

    7. Ozkan S, Murk W, Arici A. Endometriosis and infertility: Epidemiology and evidence-based treatments. Ann N Y Acad Sci 2008;1127:92–100.

    8. Ferrero S, Arena E, Morando A, Remorgida V. Prevalence of newly diagnosed endometriosis in women attending the general practitioner. Int J Gynaecol Obstet 2010;110(3):203–207.

    9. Meuleman C, Vandenabeele B, Fieuws S, et al. High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners. Fertil Steril 2009;92(1):68–74.

   10. Tempfer CB, Simoni M, Destenaves B, Fauser BC. Functional genetic polymorphisms and female reproductive disorders: Part II—Endometriosis. Hum Reprod Update 2009;15(1):97–118.

   11. Tokushige N, Markham R, Russell P, Fraser IS. Nerve fibres in peritoneal endometriosis. Hum Reprod 2006;21(11):3001–3007.

   12. Committee on Gynecologic Practice. Aromatase inhibitors in gynecologic practice. Obstet Gynecol 2008;112(2):405–407.

   13. Tokushige N, Markham R, Russell P, Fraser IS. High density of small nerve fibres in the functional layer of the endometrium in women with endometriosis. Hum Reprod 2006;21(3):782–787.

   14. Wang G, Tokushige N, Markham R, Fraser IS. Rich innervation of deep infiltrating endometriosis. Hum Reprod 2009;24(4):827–834.

   15. Mechsner S, Kaiser A, Kopf A, et al. A pilot study to evaluate the clinical relevance of endometriosis-associated nerve fibers in peritoneal endometriotic lesions. Fertil Steril 2009;92(6):1856–1861.

   16. Mansour G, Aziz N, Sharma R, et al. The impact of peritoneal fluid from healthy women and from women with endometriosis on sperm DNA and its relationship to the sperm deformity index. Fertil Steril 2009;92(1):61–67.

   17. Lemos NA, Arbo E, Scalco R, et al. Decreased anti-mullerian hormone and altered ovarian follicular cohort in infertile patients with mild/minimal endometriosis. Fertil Steril 2008;89(5):1064–1068.

   18. Leyland N, Casper R, Laberge P, Singh SS. Endometriosis: Diagnosis and management. J Obstet Gynaecol Can 2010; 32(7 Suppl 2):S1-S32.

   19. Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility. Fertil Steril 2006;86(5 Suppl):S156-S160.

   20. ESHRE Guideline for the Diagnosis and Treatment of Endometriosis. 2007, http://guidelines.endometriosis.org/index.html.

   21. 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.

   22. Rubi-Klein K, Kucera-Sliutz E, Nissel H, et al. Is acupuncture in addition to conventional medicine effective as pain treatment for endometriosis? A randomised controlled cross-over trial. Eur J Obstet Gynecol Reprod Biol 2010;153(1):90–93.

   23. Proctor M, Murphy PA. Herbal and dietary therapies for primary and secondary dysmenorrhoea. Cochrane Database Syst Rev 2001;(3):CD002124.

   24. Sesti F, Pietropolli A, Capozzolo T, et al. Hormonal suppression treatment or dietary therapy versus placebo in the control of painful symptoms after conservative surgery for endometriosis stage III-IV. A randomized comparative trial. Fertil Steril 2007;88(6):1541–1547.

   25. Dovey S, Sanfilippo J. Endometriosis and the adolescent. Clin Obstet Gynecol 2010;53(2):420–428.

   26. Surrey ES. Gonadotropin-releasing hormone agonist and add-back therapy: What do the data show? Curr Opin Obstet Gynecol 2010;22(4):283–288.

   27. Ballweg ML. Treating endometriosis in adolescents: Does it matter? J Pediatr Adolesc Gynecol 2011;24(5 Suppl):S2-S6.

   28. Hughes E, Brown J, Collins JJ, et al. Ovulation suppression for endometriosis. Cochrane Database Syst Rev 2007;(3):CD000155.

   29. Guzick DS, Huang LS, Broadman BA, et al. Randomized trial of leuprolide versus continuous oral contraceptives in the treatment of endometriosis-associated pelvic pain. Fertil Steril 2011;95(5):1568–1573.

   30. Mabrouk M, Frasca C, Geraci E, et al. Combined oral contraceptive therapy in women with posterior deep infiltrating endometriosis. J Minim Invasive Gynecol 2011;18(4):470–474.

   31. Roman H. Oral contraceptives and endometriosis. Hum Reprod 2011;26(6):1600–1601.

   32. Fedele L, Bianchi S, Montefusco S, et al. A gonadotropin-releasing hormone agonist versus a continuous oral contraceptive pill in the treatment of bladder endometriosis. Fertil Steril 2008;90(1):183–184.

   33. Harada T, Momoeda M, Taketani Y, et al. Low-dose oral contraceptive pill for dysmenorrhea associated with endometriosis: A placebo-controlled, double-blind, randomized trial. Fertil Steril 2008;90(5):1583–1588.

   34. Vercellini P, Trespidi L, Colombo A, et al. A gonadotropin-releasing hormone agonist versus a low-dose oral contraceptive for pelvic pain associated with endometriosis. Fertil Steril 1993;60(1):75–79.

   35. Vercellini P, Barbara G, Somigliana E, et al. Comparison of contraceptive ring and patch for the treatment of symptomatic endometriosis. Fertil Steril 2010;93(7):2150–2161.

   36. Seracchioli R, Mabrouk M, Frasca C, et al. Long-term oral contraceptive pills and postoperative pain management after laparoscopic excision of ovarian endometrioma: A randomized controlled trial. Fertil Steril 2010;94(2):464–471.

   37. Schlaff WD, Carson SA, Luciano A, et al. Subcutaneous injection of depot medroxyprogesterone acetate compared with leuprolide acetate in the treatment of endometriosis-associated pain. Fertil Steril 2006;85(2):314–325.

   38. Crosignani PG, Luciano A, Ray A, Bergqvist A. Subcutaneous depot medroxyprogesterone acetate versus leuprolide acetate in the treatment of endometriosis-associated pain. Hum Reprod 2006;21(1):248–256.

   39. Depo-Provera Prescribing Information. 2011, http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020246s035lbl.pdf.

   40. Depo-SubQ Provera 104 Prescribing Information. 2009, http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021583s011lbl.pdf.

   41. Brown J, Pan A, Hart RJ. Gonadotropin hormone releasing analogues for pain associated with endometriosis. Cochrane Database Syst Rev 2010;(12):CD008475.

   42. Kang JL, Wang XX, Nie ML, Huang XH. Efficacy of gonadotropin-releasing hormone agonist and an extended-interval dosing regimen in the treatment of patients with adenomyosis and endometriosis. Gynecol Obstet Invest 2010;69(2):73–77.

   43. Bergstrom I, Freyschuss B, Jacobsson H, Landgren B. The effect of physical training on bone mineral density in women with endometriosis treated with GnRH analogs: A pilot study. Acta Obstet Gynecol Scand 2005;84(4):380–383.

   44. Kim NY, Ryoo U, Lee DY, et al. The efficacy and tolerability of short-term low-dose estrogen-only add-back therapy during post-operative GnRH agonist treatment for endometriosis. Eur J Obstet Gynecol Reprod Biol 2011;154(1):85–89.

   45. Petta CA, Ferriani RA, Abrao MS, et al. Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis. Hum Reprod 2005;20(7):1993–1998.

   46. Wong AY, Tang LC, Chin RK. Levonorgestrel-releasing intrauterine system (Mirena) and depot medroxyprogesterone acetate (Depo-Provera) as long-term maintenance therapy for patients with moderate and severe endometriosis: A randomised controlled trial. Aust N Z J Obstet Gynaecol 2010;50(3):273–279.

   47. Bayoglu Tekin Y, Dilbaz B, Altinbas SK, Dilbaz S. Postoperative medical treatment of chronic pelvic pain related to severe endometriosis: Levonorgestrel-releasing intrauterine system versus gonadotropin-releasing hormone analogue. Fertil Steril 2011;95(2):492–496.

   48. Abou-Setta AM, Al-Inany HG, Farquhar C. Levonorgestrel-releasing intrauterine device (LNG-IUD) for symptomatic endometriosis following surgery. Cochrane Database Syst Rev 2013;(1):CD005072.

   49. Selak V, Farquhar C, Prentice A, Singla AA. Danazol for pelvic pain associated with endometriosis. Cochrane Database Syst Rev 2007;(4):CD000068.

   50. Razzi S, Luisi S, Calonaci F, et al. Efficacy of vaginal danazol treatment in women with recurrent deeply infiltrating endometriosis. Fertil Steril 2007;88(4):789–794.

   51. Bhattacharya SM, Tolasaria A, Khan B. Vaginal danazol for the treatment of endometriosis-related pelvic pain. Int J Gynaecol Obstet 2011;115(3):294–295.

   52. Ferrero S, Tramalloni D, Venturini PL, Remorgida V. Vaginal danazol for women with rectovaginal endometriosis and pain symptoms persisting after insertion of a levonorgestrel-releasing intrauterine device. Int J Gynaecol Obstet 2011;113(2):116–119.

   53. Abushahin F, Goldman KN, Barbieri E, et al. Aromatase inhibition for refractory endometriosis-related chronic pelvic pain. Fertil Steril 2011;96(4):939–942.

   54. Colette S, Donnez J. Are aromatase inhibitors effective in endometriosis treatment? Expert Opin Investig Drugs 2011;20(7):917–931.

   55. Ferrero S, Gillott DJ, Venturini PL, Remorgida V. Use of aromatase inhibitors to treat endometriosis-related pain symptoms: A systematic review. Reprod Biol Endocrinol 2011;9:89.

   56. Nothnick WB. The emerging use of aromatase inhibitors for endometriosis treatment. Reprod Biol Endocrinol 2011;9:87.

   57. Nawathe A, Patwardhan S, Yates D, et al. Systematic review of the effects of aromatase inhibitors on pain associated with endometriosis. BJOG 2008;115(7):818–822.

   58. Alborzi S, Hamedi B, Omidvar A, et al. A comparison of the effect of short-term aromatase inhibitor (letrozole) and GnRH agonist (triptorelin) versus case control on pregnancy rate and symptom and sign recurrence after laparoscopic treatment of endometriosis. Arch Gynecol Obstet 2011;284(1):105–110.

   59. Deal LS, Williams VS, DiBenedetti DB, Fehnel SE. Development and psychometric evaluation of the endometriosis treatment satisfaction questionnaire. Qual Life Res 2010;19(6):899–905.