Gynecology_Novak

Gynecology_Novak. U/mL in the nonmenstrual phase), and in those with moderate to severe disease (13–95 U/mL in the non-menstrual phase). Compared with laparoscopy, measurement of serum CA125 levels has no value as a diagnostic tool (223).


Gynecology_Novak

Gynecology_Novak. The specificity of CA125 is reported to be higher than 80% in most studies. This high level of specificity is achieved in selected women with infertility or pain, who are known to be at risk for endometriosis. The low level of sensitivity of CA125 (20% to 50% in most studies) poses limitations for the clinical use of this test for diagnosis of endometriosis. Theoretically, the sensitivity might increase during the menstrual period, when the increase in CA125 level is more pronounced in women who have endometriosis. Studies using cutoff levels of 35 U/mL or 85 U/mL did not find a significant improvement in sensitivity (221,222,224). A sensitivity of 66% was found when the CA125 level was determined during both the follicular phase and the menstrual phase in each patient and when the ratio of menstrual versus follicular values (>1.5) was used instead of one CA125 level (222). Other studies reported that the value of CA125 in diagnosis of endometriosis is limited but higher for moderate


Gynecology_Novak

Gynecology_Novak. of menstrual versus follicular values (>1.5) was used instead of one CA125 level (222). Other studies reported that the value of CA125 in diagnosis of endometriosis is limited but higher for moderate to severe disease, especially if serum CA125 concentrations are measured during the midfollicular phase (223,225).


Gynecology_Novak

Gynecology_Novak. Serial CA125 determinations may be useful to predict the recurrence of endometriosis after therapy (226,227). CA125 levels decrease after combined medical and surgical therapy or during medical treatment of endometriosis with danazol, gonadotropin-releasing hormone (GnRH) analogues, or gestrinone, but not with medroxyprogesterone acetate (MPA) or placebo (228–230). Levels of CA125 are reported to increase to pretreatment levels as early as 3, 4, or 6 months after the cessation of therapy with danazol, GnRH analogues, or gestrinone (218,229– 233). Posttreatment increases in CA125 levels are reported to correlate with endometriosis recurrence (217,227,234). Other studies did not substantiate a correlation between posttreatment CA125 levels and disease recurrence (228,231,235).


Gynecology_Novak

Gynecology_Novak. Laparoscopic Findings The laparoscopic findings of endometriosis include peritoneal lesions, ovarian endometriotic cysts, and deeply infiltrative endometriosis invading the peritoneal surface with a depth of at least 5 mm. Most patients with ovarian endometriotic cysts or deeply infiltrative endometriosis also have peritoneal disease.


Gynecology_Novak

Gynecology_Novak. Characteristic findings include typical (“powder-burn” or “gunshot”) lesions on the serosal surfaces of the peritoneum. These lesions are black, dark brown, or bluish nodules or small cysts containing old hemorrhage surrounded by a variable degree of fibrosis (Fig. 17.2). Endometriosis can appear as subtle lesions, including red implants (petechial, vesicular, polypoid, hemorrhagic, red ﬂamelike), serous or clear vesicles, white plaques or scarring, yellow-brown discoloration of the peritoneum, and subovarian adhesions (Fig. 17.3) (138,139,141,240,241). Histologic confirmation of the laparoscopic impression is essential for the diagnosis of endometriosis, for subtle lesions, and for the typical lesions reported to be histologically negative in 24% of cases (242,243).


Gynecology_Novak

Gynecology_Novak. Mild forms of deep endometriosis may be detected only by palpation under an endometriotic lesion or by discovery of a palpable mass beneath visually normal peritoneum, most notably in the posterior cul-de-sac (Fig. 17.4) (200). At laparoscopy, deeply infiltrating endometriosis may have the appearance of minimal disease, resulting in an underestimation of disease severity (200). Reduced size of the cul-de-sac in women with deep endometriosis suggests that such lesions develop not in the rectovaginal septum but intraperitoneally and that burial of anterior rectal wall adhesions creates a false bottom, giving an erroneous impression of extraperitoneal origin (244). Figure 17.1 Pelvic endometriosis.


Gynecology_Novak

Gynecology_Novak. The diagnosis of ovarian endometriosis is facilitated by careful inspection of all sides of both ovaries, which may be difficult when adhesions are present in more advanced stages of disease (Fig. 17.5). With superficial ovarian endometriosis, lesions can be both typical and subtle. Larger ovarian endometriotic cysts (i.e., endometriomas) usually are located on the anterior surface of the ovary and are associated with retraction, pigmentation, and adhesions to the posterior peritoneum. These ovarian endometriotic cysts often contain a thick, viscous dark brown ﬂuid (i.e., “chocolate ﬂuid”), composed of hemosiderin derived from previous intraovarian hemorrhage. Because this ﬂuid may be found in other conditions, such as in hemorrhagic corpus luteum cysts or neoplastic cysts, biopsy and preferably removal of the ovarian cyst for histologic confirmation are necessary for the diagnosis in the revised endometriosis classification of the American Society for Reproductive Medicine (ASRM). If


Gynecology_Novak

Gynecology_Novak. removal of the ovarian cyst for histologic confirmation are necessary for the diagnosis in the revised endometriosis classification of the American Society for Reproductive Medicine (ASRM). If that is not possible, the presence of an ovarian endometriotic cyst should be confirmed by the following features: cyst diameter of less than 12 cm, adhesion to pelvic sidewall or broad ligament, endometriosis on surface of ovary, and tarry, thick, chocolate-colored ﬂuid content (245). Ovarian endometriosis appears to be a marker for more extensive pelvic and intestinal disease. Exclusive ovarian disease is found in only 1% of endometriosis patients, with the remaining patients having extensive pelvic or intestinal endometriosis (246).


Gynecology_Novak

Gynecology_Novak. Figure 17.2 Typical and subtle endometriotic lesions on peritoneum. A: Typical black-puckered lesions with hypervascularization and orange polypoid vesicles. B: Red polypoid lesions with hypervascularization. (Photographs from Dr. Christel Meuleman, Leuven University Fertility Center, Leuven University Hospitals, Leuven, Belgium.) Figure 17.3 Ovarian endometriosis. (Photographs from Dr. Christel Meuleman, Leuven University Fertility Center, Leuven University Hospitals, Leuven, Belgium.) A: Superficial ovarian endometriosis. B: Superficial ovarian endometriosis and endometrioma—laparoscopic image prior to adhesiolysis. Figure 17.3 (continued) C: Laparoscopic image of uterus and right ovary with dark endometrioma. D: Ovarian endometriotic cystectomy


Gynecology_Novak

Gynecology_Novak. Figure 17.3 (continued) C: Laparoscopic image of uterus and right ovary with dark endometrioma. D: Ovarian endometriotic cystectomy Histologic Confirmation Positive histology confirms the diagnosis of endometriosis; negative histology does not exclude it (1). Whether histology should be obtained when peritoneal disease alone is present is controversial; visual inspection is usually adequate but histological confirmation of at least one lesion is ideal (1). In cases of ovarian endometrioma (>4 cm in diameter) and in deeply infiltrating disease, histology is recommended to exclude rare instances of malignancy (1). Figure 17.3 (continued) E: Ovarian endometriotic cystectomy.


Gynecology_Novak

Gynecology_Novak. Figure 17.3 (continued) E: Ovarian endometriotic cystectomy. In a study of 44 patients with chronic pelvic pain, endometriosis was laparoscopically diagnosed in 36%, but histologic confirmation was obtained in only 18%. This approach resulted in a low diagnostic accuracy of laparoscopic inspection with a positive predictive value of only 45%, explained by a specificity of only 77% (247).


Gynecology_Novak

Gynecology_Novak. Microscopically, endometriotic implants consist of endometrial glands and stroma, with or without hemosiderin-laden macrophages (Fig. 17.6). It is suggested that using these stringent and unvalidated histologic criteria may result in significant underdiagnosis of endometriosis (5). Problems in obtaining biopsies (especially small vesicles) and variability in tissue processing (step or partial instead of serial sectioning) may contribute to false-negative results. Endometrioid stroma may be more characteristic of endometriosis than endometrioid glands (248). The presence of stromal endometriosis, which contains endometrial stroma with hemosiderin-laden macrophages or hemorrhage, was reported in women and in baboons and may represent a very early event in the pathogenesis of endometriosis (147,242,243). Isolated endometrial stromal cell nodules and immunohistochemically positive for vimentin and estrogen receptor can be found in the absence of endometrial glands along blood or lymphatic


Gynecology_Novak

Gynecology_Novak. Isolated endometrial stromal cell nodules and immunohistochemically positive for vimentin and estrogen receptor can be found in the absence of endometrial glands along blood or lymphatic vessels (249).


Gynecology_Novak

Gynecology_Novak. Different types of lesions may have different degrees of proliferative or secretory glandular activity (248). Vascularization, mitotic activity, and the three-dimensional structure of endometriosis lesions are key factors (177,250,251). Deep endometriosis is described as a specific type of pelvic endometriosis characterized by proliferative strands of glands and stroma in dense fibrous and smooth muscle tissue (19). Smooth muscles are frequent components of endometriotic lesions on the peritoneum, ovary, rectovaginal septum, and uterosacral ligaments (252).


Gynecology_Novak

Gynecology_Novak. Microscopic endometriosis is defined as the presence of endometrial glands and stroma in macroscopically normal pelvic peritoneum. It is important in the histogenesis of endometriosis and its recurrence after treatment (253,254). The clinical relevance of microscopic endometriosis is controversial because it is not observed uniformly. Using undefined criteria for what constitutes normal peritoneum, peritoneal biopsy specimens of 1 to 3 cm were obtained during laparotomy from 20 patients with moderate to severe endometriosis (254). Examination of the biopsy results with low-power scanning electron microscopy revealed unsuspected microscopic endometriosis in 25% of cases not confirmed by light microscopy. Peritoneal endometriotic foci were demonstrated by light microscopy in areas that showed no obvious evidence of disease (255).


Gynecology_Novak

Gynecology_Novak. Figure 17.4 Laparoscopic excision of deep endometriosis from the cul-de-sac. (Photographs from Dr. Christel Meuleman, Leuven University Fertility Center, Leuven University Hospitals, Leuven, Belgium.) A: Extensive endometriosis with deep nodule at the right uterosacral ligament, masked by adhesions. B: Deep nodule still present in dense adhesion between rectum and uterosacral ligaments. Figure 17.4 (continued) C: Cul-de-sac after resection of deep nodule with CO2 laser.


Gynecology_Novak

Gynecology_Novak. Figure 17.4 (continued) C: Cul-de-sac after resection of deep nodule with CO2 laser. In serial sections of laparoscopic biopsies of normal peritoneum, 10% to 15% of women had microscopic endometriosis, and endometriosis was found in 6% of those without macroscopic disease (241,256,257). Other studies were unable to detect microscopic endometriosis in 2-mm biopsy specimens of visually normal peritoneum (258–261). Examination of larger samples (5–15 mm) of visually normal peritoneum revealed microscopic endometriosis in only 1 of 55 patients studied (262). A histologic study of serial sections through the entire pelvic peritoneum of visually normal peritoneum from baboons with and without disease indicated that microscopic endometriosis is a rare occurrence (95). Macroscopically appearing normal peritoneum rarely contains microscopic endometriosis (262).


Gynecology_Novak

Gynecology_Novak. Many classification systems were proposed, but only one was accepted. This system is the revised American Fertility Society (AFS) system, which is based on the appearance, size, and depth of peritoneal and ovarian implants; the presence, extent, and type of adnexal adhesions; and the degree of cul-de-sac obliteration (185,210). In this ASRM classification system, the morphology of peritoneal and ovarian implants should be categorized as red (red, red-pink, and clear lesions), white (white, yellow-brown, and peritoneal defects), and black (black and blue lesions), according to color photographs provided by ASRM.


Gynecology_Novak

Gynecology_Novak. This system reﬂects the extent of endometriotic disease but has considerable intraobserver and interobserver variability (263,264). Like all classification systems, the ASRM classification for endometriosis is subjective and correlates poorly with pain symptoms, but may be of value in infertility prognosis and management (181). Because this ASRM revised classification of endometriosis is the only internationally accepted system, it is the best available tool to describe objectively the extent of endometriosis and relate it to spontaneous evolution. More outcome-based research is needed to discover whether it is possible to improve the standardization and positive correlation of the ASRM classification of endometriosis with symptoms (pain, infertility) and with therapeutic outcome (pain relief, enhancement of fertility) after medical or surgical treatment. More variables than only the stage of endometriosis may have to be entered in such prediction models. Evidence suggests that


Gynecology_Novak

Gynecology_Novak. relief, enhancement of fertility) after medical or surgical treatment. More variables than only the stage of endometriosis may have to be entered in such prediction models. Evidence suggests that endometriosis with an ASRM score of 16 or more, together with other variables like age, duration of infertility, and least functional score for ovaries and fallopian tubes after endometriosis surgery, is predictive of pregnancy (183).


Gynecology_Novak

Gynecology_Novak. American Society for Reproductive Medicine Revised Classification of Endometriosis Figure 17.5 Revised American Society for Reproductive Medicine Classification. (From the American Society for Reproductive Medicine. Revised American Society for Reproductive Medicine classification of endometriosis. Am Soc Reprod Med 1997;5:817–821.)


Gynecology_Novak

Gynecology_Novak. Spontaneous Evolution Endometriosis appears to be a progressive disease in a significant proportion (30% to 60%) of patients. During serial observations, deterioration (47%), improvement (30%), or elimination (23%) was documented over a 6-month period (265,266). In another study, endometriosis progressed in 64%, improved in 27%, and remained unchanged in 9% of patients over 12 months (267). A third study of 24 women reported 29% with disease progression, 29% with disease regression, and 42% with no change over 12 months. Follow-up studies in both baboons and women with spontaneous endometriosis over 24 months demonstrated disease progression in all baboons and in 6 of 7 women (268–270). Several studies reported that subtle lesions and typical implants may represent younger and older types of endometriosis, respectively. In a cross-sectional study, the incidence of subtle lesions decreased with age (271). This finding was confirmed by a 3-year prospective study that reported that the


Gynecology_Novak

Gynecology_Novak. of endometriosis, respectively. In a cross-sectional study, the incidence of subtle lesions decreased with age (271). This finding was confirmed by a 3-year prospective study that reported that the incidence, overall pelvic area involved, and volume of subtle lesions decreased with age, but in typical lesions, these parameters and the depth of infiltration increased with age (6). Remodeling of endometriotic lesions (transition between typical and subtle subtypes) is reported to occur in women and in baboons, indicating that endometriosis is a dynamic condition (272,273). Several studies in women, cynomolgus monkeys, and rodents showed that endometriosis is ameliorated after pregnancy (273–276).


Gynecology_Novak

Gynecology_Novak. Figure 17.6 Histologic appearance of endometriosis: endometrial glandular epithelium, surrounded by stroma in typical lesion and clear vesicle. The characteristics of endometriosis are variable during pregnancy, and lesions tend to enlarge during the first trimester but regress thereafter (277). Studies in baboons revealed no change in the number or surface area of endometriosis lesions during the first two trimesters of pregnancy (278). These results do not exclude a beneficial effect that may occur during the third trimester or in the immediate postpartum period. Establishment of a “pseudopregnant state” with exogenously administered estrogen and progestins is based on the belief that symptomatic improvement may result from decidualization of endometrial implants during pregnancy (279). This hypothesis is not substantiated, and it is possible that amenorrhea can explain the beneficial effect of pregnancy and lactation on endometriosis-associated pain symptoms.


Gynecology_Novak

Gynecology_Novak. Prevention No strategies to prevent endometriosis are uniformly successful. A reduced incidence of endometriosis was reported in women who engaged in aerobic activity from an early age, but the possible protective effect of exercise was not investigated thoroughly (45). There is insufficient evidence that oral contraceptive use offers protection against the development of endometriosis. One report showed an increased risk for endometriosis in a select population of women taking oral contraceptives, possibly explained by the observation that dysmenorrhea as a reason to initiate estroprogestins is significantly more common in women with endometriosis than in women without the disease (280,281). Oral contraceptives (OCs) inhibit ovulation, substantially reduce the volume of menstrual ﬂow, and may interfere with implantation of reﬂuxed endometrial cells, but the hypothesis of recommending OCs for primary prevention of endometriosis is not sufficiently substantiated (282). Although the


Gynecology_Novak

Gynecology_Novak. and may interfere with implantation of reﬂuxed endometrial cells, but the hypothesis of recommending OCs for primary prevention of endometriosis is not sufficiently substantiated (282). Although the risk of endometriosis appears reduced during OC use, it is possible that this effect results from postponement of surgical evaluation caused by temporary suppression of pain symptoms (283). Confounding by selection and indication biases may explain the trend toward an increase in risk of endometriosis observed after discontinuation, but further clarification is needed (283).


Gynecology_Novak

Gynecology_Novak. Principles of Treatment Treatment of endometriosis must be individualized, taking into consideration the clinical problem in its entirety, including the impact of the disease and the effect of its treatment on quality of life. Evidence-based recommendations that are continuously updated can be found in the ESHRE guidelines for the clinical management of endometriosis (1).


Gynecology_Novak

Gynecology_Novak. In most women with endometriosis, preservation of reproductive function is desirable (1). Many women with endometriosis have pain and subfertility at the same time or may desire children after sufficient pain relief, which complicates the choice of treatment. Endometriosis surgery should be considered as reproductive surgery, recently defined by the World Health Organization (WHO) as “all surgical procedures carried out to diagnose, conserve, correct and/or improve reproductive function” (284). The least invasive and least expensive approach that is effective with the least long-term risks should be chosen (1). Symptomatic endometriosis patients can be treated with analgesics, hormones, surgery, assisted reproduction, or a combination of these modalities (1). Regardless of the clinical profile (subfertility, pain, asymptomatic findings), treatment of endometriosis may be justified because endometriosis appears to progress in 30% to 60% of patients within a year of diagnosis and it is


Gynecology_Novak

Gynecology_Novak. (subfertility, pain, asymptomatic findings), treatment of endometriosis may be justified because endometriosis appears to progress in 30% to 60% of patients within a year of diagnosis and it is not possible to predict in which patients it will progress (267). Elimination of the endometriotic implants by surgical or medical treatment often provides only temporary relief. In addition to eliminating the endometriotic lesions, the goal should be to treat the sequelae (pain and subfertility) often associated with this disease and to prevent recurrence of endometriosis (1). Endometriosis is a chronic disease and the recurrence rate is high after both hormonal and surgical treatment (1).


Gynecology_Novak

Gynecology_Novak. It is important to involve the patient in all decisions, to be ﬂexible in considering diagnostic and therapeutic approaches, and to maintain a good relationship. It may be appropriate to seek advice from more experienced colleagues or to refer the patient to a center with the necessary expertise to offer treatments in a multidisciplinary context, including advanced laparoscopic surgery and laparotomy (1,285). Because the management of severe or deeply infiltrating endometriosis is complex, referral is strongly recommended when disease of such severity is suspected or diagnosed (1). Treatment of Endometriosis-Associated Pain Pain may persist despite seemingly adequate medical or surgical treatment of the disease. A multidisciplinary approach involving a pain clinic and counseling should be considered early in the treatment plan. The least invasive and least expensive approach that is effective should be used (1).


Gynecology_Novak

Gynecology_Novak. Surgical Treatment Depending on the severity of disease, diagnosis and removal of endometriosis should be performed simultaneously at the time of surgery, provided preoperative consent was obtained (1,286–289). The goal of surgery is to excise all visible endometriotic lesions and associated adhesions—peritoneal lesions, ovarian cysts, deep rectovaginal endometriosis—and to restore normal anatomy (1). In most women, laparoscopy can be used, and this technique decreases cost, morbidity, and the possibility of recurrence of adhesions postoperatively (1). Laparotomy should be reserved for patients with advanced-stage disease who cannot undergo a laparoscopic procedure and for those in whom fertility conservation is not necessary (1).


Gynecology_Novak

Gynecology_Novak. Peritoneal Endometriosis Endometriosis lesions can be removed during laparoscopy by surgical excision with scissors, bipolar coagulation, or laser methods (CO2 laser, potassiumtitanyl-phosphate laser, or argon laser). Some surgeons claim that the CO2 laser is superior because it causes only minimal thermal damage, but no evidence is available to show the superiority of one technique over another. Comparable cumulative pregnancy rates were reported after treatment of mild endometriosis with laparoscopic excision and electrocoagulation (290). Ablation of endometriotic peritoneal lesions plus laparoscopic uterine nerve ablation (LUNA) in minimal to moderate disease reduces endometriosis-associated pain at 6 months compared to diagnostic laparoscopy; the smallest effect is seen in patients with minimal disease (1,291). There is no evidence that LUNA is a necessary component, and LUNA by itself has no effect on dysmenorrhoea associated with endometriosis (1,292,293). The effectiveness of


Gynecology_Novak

Gynecology_Novak. minimal disease (1,291). There is no evidence that LUNA is a necessary component, and LUNA by itself has no effect on dysmenorrhoea associated with endometriosis (1,292,293). The effectiveness of surgical ablation of peritoneal endometriosis is convincingly shown in two randomized trials where the control group underwent a laparoscopy without surgical ablations of lesions. The treated group had a significant reduction of symptoms that persisted for 12 months and 18 months, respectively (268,294,295). The effectiveness of surgical treatment by laparotomy was not investigated by a randomized trial, although many published observational studies claim a high percentage of success (1).


Gynecology_Novak

Gynecology_Novak. Adhesiolysis The removal of endometriosis-related adhesions (adhesiolysis) should be performed carefully. Adhesions lysed at surgery can form again (296). Routine use of pharmacologic or liquid agents to prevent postoperative adhesions after fertility surgery cannot be recommended based on a systematic review, including 16 randomized controlled trials, with the following indications for surgery included myomectomy (five trials), ovarian surgery (five trials), pelvic adhesions (four trials), endometriosis (one trial), and mixed (one trial) (297). No studies reported pregnancy or reduction in pain as outcomes (297). The absorbable adhesion barrier Interceed reduced the incidence of adhesion formation following laparoscopy and laparotomy, but there are insufficient data to support its use to improve pregnancy rates (297). The substance expanded polytetraﬂuoroethylene (Gore-Tex Surgical Membrane, Preclude; WL Gore, Flagstaff, AZ) may be superior to Oxidised regenerated cellulose


Gynecology_Novak

Gynecology_Novak. use to improve pregnancy rates (297). The substance expanded polytetraﬂuoroethylene (Gore-Tex Surgical Membrane, Preclude; WL Gore, Flagstaff, AZ) may be superior to Oxidised regenerated cellulose (Interceed; Gynecare, Somerville, NJ) in preventing adhesion formation, but its usefulness is limited by the need for suturing and later removal (297). There was no evidence of effectiveness of chemically derived sodium hyaluronate and carboxymethylcellulose (Seprafilm, Genzyme Corporation, Cambridge, USA) or sheet-type fibrin sealant (Fibrin sheet, Tacho Comb, Tokyo, Japan) in preventing adhesion formation (297). In a randomized trial in patients with surgically treated stages I to III endometriosis without endometrioma, postoperative adnexal application of Oxiplex/AP (FzioMed, San Luis Obispo, California) gel treatment was superior to surgery alone (control group) with respect to postoperative adhesion formation (defined as secondary outcome) 6 to 8 weeks later in a subgroup of patients


Gynecology_Novak

Gynecology_Novak. California) gel treatment was superior to surgery alone (control group) with respect to postoperative adhesion formation (defined as secondary outcome) 6 to 8 weeks later in a subgroup of patients with red lesions (298). This observation needs to be confirmed in other randomized trials with postoperative adhesion formation as primary outcome. In the same study, control patients with at least 50% red lesions had a greater increase in ipsilateral adnexal adhesion scores than patients with mostly black or white and/or clear lesions (298).


Gynecology_Novak

Gynecology_Novak. Surgical Technique Superficial ovarian lesions can be vaporized. The surgical management of ovarian endometriotic cysts is controversial. The primary indication for extirpation of an endometrioma is to ensure it is not malignant (1). The laparoscopic approach to the management of endometriomata is favored over a laparotomy approach because it offers the advantage of a shorter hospital stay, faster patient recovery, and decreased hospital costs (299). The most common procedures for the treatment of ovarian endometriomas are either excision of the cyst capsule or drainage and electrocoagulation of the cyst wall. During excision, the ovarian endometrioma is aspirated, followed by incision and removal of the cyst wall from the ovarian cortex with maximal preservation of normal ovarian tissue. During drainage and electrocoagulation, the ovarian endometrioma is aspirated and irrigated, its wall can be inspected with ovarian cystoscopy for intracystic lesions, and it is vaporized to destroy


Gynecology_Novak

Gynecology_Novak. During drainage and electrocoagulation, the ovarian endometrioma is aspirated and irrigated, its wall can be inspected with ovarian cystoscopy for intracystic lesions, and it is vaporized to destroy the mucosal lining of the cyst. Small ovarian endometriomata (less than 3-cm diameter) can be treated by drainage and electrocoagulation (1). Ovarian endometriomata larger than 3 cm should be removed completely (1,300). In cases where excision is technically difficult without removing a large part of the ovary, a three-step procedure (marsupialization and rinsing followed by hormonal treatment with GnRH analogues and cyst wall electrocoagulation or laser vaporization 3 months later) should be considered (1,301).


Gynecology_Novak

Gynecology_Novak. Outcome after Cystectomy Although as little as one-tenth of an ovary may be enough to preserve function and fertility, at least for a while, there is increasing concern that ovarian cystectomy with concomitant removal or destruction of normal ovarian tissue may reduce ovarian follicle reserve and reduce fertility (302). One study reported reduced follicular response in natural and clomiphene citrate– stimulated cycles, but not in gonadotropin-stimulated cycles, in women younger than 35 years of age who underwent cystectomy compared with controls of similar age with normal ovaries (302). According to a systematic review, there is good evidence that excisional surgery for endometriomas with a diameter of 3 cm provides a more favorable outcome than drainage and ablation with regard to the recurrence of the endometrioma, recurrence of pain symptoms, and in women who were previously subfertile or had subsequent spontaneous pregnancy (299). This approach should be the favored surgical


Gynecology_Novak

Gynecology_Novak. recurrence of the endometrioma, recurrence of pain symptoms, and in women who were previously subfertile or had subsequent spontaneous pregnancy (299). This approach should be the favored surgical approach, based on two randomized studies of the laparoscopic management of ovarian endometriomata of greater than 3 cm in size for the primary symptom of pain (303,304). Laparoscopic excision of the cyst wall of the endometrioma was associated with a reduced recurrence rate of the symptoms of dysmenorrhea (odds ratio [OR] 0.15; 95% CI, 0.06–0.38), dyspareunia (OR 0.08; 95% CI, 0.01–0.51), and nonmenstrual pelvic pain (OR 0.10; 95% CI, 0.02–0.56), a reduced rate of recurrence of the endometrioma (OR 0.41; 95% CI, 0.18–0.93), and with a reduced requirement for further surgery (OR 0.21; 95% CI, 0.05–0.79) than surgery to ablate the endometrioma. For those women subsequently attempting to conceive, it was associated with an increased spontaneous pregnancy rate in women who had documented prior


Gynecology_Novak

Gynecology_Novak. than surgery to ablate the endometrioma. For those women subsequently attempting to conceive, it was associated with an increased spontaneous pregnancy rate in women who had documented prior subfertility (OR 5.21; 95% CI, 2.04–13.29).


Gynecology_Novak

Gynecology_Novak. A randomized study demonstrated an increased ovarian follicular response to gonadotrophin stimulation for women who underwent excisional surgery when compared to ablative surgery (weighted mean difference (WMD) 0.6; 95% CI, 0.04–1.16) (305). There is insufficient evidence to favor excisional surgery over ablative surgery with respect to the chance of pregnancy after controlled ovarian stimulation and intrauterine insemination (OR 1.40; 95% CI, 0.47–4.15) or treatment with assisted reproductive technology (299). It is controversial whether there is a potential negative effect of ovarian cystectomy on reproductive function. In a small prospective randomized clinical trial, 10 patients assigned to undergo laparoscopic cystectomy had a lower antral follicle count and a more pronounced reduction in serum anti-m¨ullerian hormone (AMH) levels (from 3.9 to 2.9 ng/mL) 6 months after surgery when compared to the 10 patients treated with a “three-stage procedure” as described above (reduction in


Gynecology_Novak

Gynecology_Novak. in serum anti-m¨ullerian hormone (AMH) levels (from 3.9 to 2.9 ng/mL) 6 months after surgery when compared to the 10 patients treated with a “three-stage procedure” as described above (reduction in AMH levels from 4.5 to 3.99 ng/mL) (306,307). More randomized trials are needed to assess the effect of ovarian cystectomy on ovarian reserve and on reproductive function, especially with respect to conception after treatment with medically assisted reproduction.


Gynecology_Novak

Gynecology_Novak. It is possible that the surgical techniques used to treat ovarian endometriotic cysts may inﬂuence postoperative adhesion formation and/or ovarian function. In a randomized study comparing surgical methods to achieve ovarian hemostasis after laparoscopic endometriotic ovarian cystectomy, closure of the ovary with an intraovarian suture resulted in a lower rate and extension of postsurgical ovarian adhesions at 60 to 90 days follow-up when compared to only bipolar coagulation on the internal ovarian surface (308).


Gynecology_Novak

Gynecology_Novak. Deeply infiltrating endometriosis is usually multifocal and complete surgical excision must be performed in a one-step surgical procedure in order to avoid more than one surgery, provided the patient is fully informed (1,179,287). Because management of deeply infiltrating endometriosis is complex, referral to a center with sufficient expertise to offer all available treatments in a multidisciplinary approach is strongly recommended (1). Surgical management is only for symptomatic deeply infiltrating endometriosis. Asymptomatic patients must not undergo surgery. Progression of the disease and appearance of specific symptoms rarely occurred in patients with asymptomatic rectovaginal endometriosis (288). When surgical treatment is decided, the treatment must be radical with excision of all infiltrating lesions (1). It is difficult to perform randomized studies to detect the best surgical technique to treat deeply infiltrative endometriosis because these severe cases are all managed


Gynecology_Novak

Gynecology_Novak. all infiltrating lesions (1). It is difficult to perform randomized studies to detect the best surgical technique to treat deeply infiltrative endometriosis because these severe cases are all managed individually and not all surgeons are familiar with all treatment options (1). Complete excision while preserving the uterus and ovarian tissue might include the resection of the uterosacral ligaments, the resection of the upper part of the posterior vaginal wall, and urological and bowel operations.


Gynecology_Novak

Surgical Treatment of Pain

Gynecology_Novak. Surgical Treatment of Pain


Gynecology_Novak

Gynecology_Novak. Preoperative imaging is necessary to assess bowel and urological impact of deeply infiltrative endometriosis, as described above. CT urogram to exclude ureteral endometriosis and ﬂexible sigmoidoscopy or double-contrast colon radiography to exclude transmural rectosigmoidal endometriosis, supplemented with MRI in selected cases, are preferred (285). As endometriosis sometimes involves nongynecologic organs (i.e., the bowel, the urinary tract, or pelvic bones), other surgical specialists should be consulted as appropriate. These severe cases should be handled in centers with special expertise. Preoperative intestinal preparation may be recommended. Placement of ureteric catheters may facilitate the excision of periureteral endometriosis to facilitate ureterolysis and end-to-end ureteral reanastomosis that may be needed in cases of infiltrative periureteral endometriosis causing ureteral obstruction. The pattern of pain in endometriosis is complicated and pain does not always respond to


Gynecology_Novak

Gynecology_Novak. that may be needed in cases of infiltrative periureteral endometriosis causing ureteral obstruction. The pattern of pain in endometriosis is complicated and pain does not always respond to treatment, so consultation with pain specialists may be useful.


Gynecology_Novak

Gynecology_Novak. Removal of full-thickness bladder detrusor endometriosis entails excision of the bladder dome or posterior wall, generally well above the trigone. Transurethral resection is contraindicated. A radical approach to obstructive uropathy is suggested, with resection of the stenotic ureteral tract and reimplantation with antireﬂux vesicoureteral plasty (309). Surgical excision of deep rectovaginal and rectosigmoidal endometriosis is difficult and can be associated with major complications such as bowel perforations with resulting peritonitis (310). It is debated whether this type of endometriosis is best treated by shaving, conservative excision or resection reanastomosis, by laparoscopy and laparotomy, or laparoscopically assisted vaginal technique (311).


Gynecology_Novak

Gynecology_Novak. In a randomized study comparing colorectal resection for endometriosis by laparoscopy or laparotomy, clinical outcome was similar with respect to dyschezia, bowel pain and cramping, and dysmenorrhea and dyspareunia, but laparoscopy was associated with less blood loss, fewer complications, and a higher pregnancy rate than laparotomy (312).


Gynecology_Novak

Gynecology_Novak. There are very few methodologically valid studies evaluating clinical outcome after deeply infiltrative with colorectal extension, as demonstrated in a systematic review (313). In a review on the clinical outcome of surgical treatment of deeply infiltrating endometriosis with colorectal involvement, most of the 49 reviewed studies included complications (94%) and pain (67%); few studies reported recurrence (41%), fertility (37%), and quality of life (10%); only 29% reported (loss of) follow-up. Of 3,894 patients, 71% underwent bowel resection and anastomosis, 10% had full-thickness excision, and 17% were treated with superficial surgery. Comparison of clinical outcome between different surgical techniques was not possible. Postoperative complications were present in 0% to 3% of the patients. Although pain improvement was reported in most studies, pain evaluation was patient based in less than 50% (visual analog scale [VAS] in only 18%). Although quality of life was improved in most


Gynecology_Novak

Gynecology_Novak. Although pain improvement was reported in most studies, pain evaluation was patient based in less than 50% (visual analog scale [VAS] in only 18%). Although quality of life was improved in most studies, prospective data were available for only 149 patients. Pregnancy rates were 23% to 57% with a cumulative pregnancy rate of 58% to 70% within 4 years. The overall endometriosis recurrence rate in studies (longer than 2 years follow-up) was 5% to 25%, with most of the studies reporting 10%. Owing to highly variable study design and data collection, a Consolidated Standards of Reporting Trials (CONSORT)-inspired checklist was developed for future studies (313). Prospective studies reporting standardized and well-defined clinical outcome after surgical treatment of deeply invasive endometriosis with colorectal involvement with long-term follow-up are needed (313).


Gynecology_Novak

Gynecology_Novak. The outcome of surgical therapy in patients with endometriosis and pain is inﬂuenced by many psychological factors relating to personality, depression, and marital and sexual problems. It is difficult to evaluate scientifically the objective effect of different surgical approaches because the extirpation and destruction of the pathological tissue can impact the results as can surgery per se, the doctor–patient relationship, complications, and other factors. There is a significant placebo response to surgical therapy: diagnostic laparoscopy without complete removal of endometriosis may alleviate pain in 50% of patients (295,314,315). Similar results were reported using oral placebos (316). Although some reports claimed pain relief with laser laparoscopy in 60% to 80% of patients with very low morbidity, none was prospective or controlled or allowed a definitive conclusion regarding treatment efficacy (200,317–320). The longstanding effect of surgery on pain is difficult to evaluate


Gynecology_Novak

Gynecology_Novak. low morbidity, none was prospective or controlled or allowed a definitive conclusion regarding treatment efficacy (200,317–320). The longstanding effect of surgery on pain is difficult to evaluate because the follow-up time is too short, usually just a few months. The major shortcoming of surgical treatment in endometriosis related pain is the lack of prospective randomized studies with sufficient follow-up time to draw clear clinical conclusions.


Gynecology_Novak

Gynecology_Novak. In a prospective, controlled, randomized, study, surgical therapy with ablation of endometriotic lesions and LUNA was shown to be superior to expectant management 6 months after treatment of mild and moderate endometriosis (295). In women with mild and moderate disease treated with laser, 74% achieved pain relief. Treatment was least effective in women with minimal disease. There were no reported operative or laser complications (295). One year later, symptom relief was still present in 90% of those who responded initially (268,295). Patients with severe disease were not included because surgery resulted in pain relief in 80% of patients who did not respond to medical therapy (295,319). There is randomized evidence that LUNA is not a necessary part of this treatment because addition of uterosacral ligament resection to conservative laparoscopic surgery for endometriosis stages I to IV did not reduce the medium-or long-term frequency and severity of recurrence of dysmenorrhea


Gynecology_Novak

Gynecology_Novak. of uterosacral ligament resection to conservative laparoscopic surgery for endometriosis stages I to IV did not reduce the medium-or long-term frequency and severity of recurrence of dysmenorrhea (292,293). These data were confirmed in a second randomized trial in women with chronic pelvic pain lasting longer than 6 months without or with minimal endometriosis, adhesions, or pelvic inﬂammatory disease, where LUNA did not result in improvements in pain, dysmenorrhea, dyspareunia, or quality of life compared with laparoscopy without pelvic denervation (321).


Gynecology_Novak

Gynecology_Novak. In a randomized crossover study, laparoscopic excision of endometriosis was found to be more effective than placebo in reducing pain and improving quality of life (294). These results suggest that laparoscopic surgery may be effective for the treatment of pain associated with mild to severe endometriosis. In women with minimal endometriosis, laser treatment may limit progression of disease.


Gynecology_Novak

Gynecology_Novak. In a systematic review assessing the efficacy of laparoscopic surgery in the treatment of pelvic pain associated with endometriosis and including five randomized controlled studies, meta-analysis demonstrated an advantage of laparoscopic surgery when compared to diagnostic laparoscopy only at 6 months (OR 5.72; 95%CI, 3.09–10.60; 171 participants, three trials) and 12 months (OR 7.72; 95%CI, 2.97–20.06; 33 participants, one trial) after surgery (291). Few women diagnosed with severe endometriosis were included in the meta-analysis and any conclusions from this meta-analysis regarding treatment of severe endometriosis should be made with caution. It was not possible to draw conclusions from the meta-analysis which specific laparoscopic surgical intervention is most effective (291).


Gynecology_Novak

Gynecology_Novak. The extent and duration of the therapeutic benefit of surgery for endometriosis-related pain are poorly defined, and the expected benefit is operator dependent (322). In a systematic review based on three randomized controlled studies, the absolute benefit increase of destruction of lesions compared with diagnostic only operation in terms of proportion of women reporting pain relief was between 30% and 40% after short follow-up periods (322). The pain relief ended to decrease with time, and the reoperation rate, based on long-term follow-up studies, was as high as 50% (322). In most case series on excisional surgery for rectovaginal endometriosis, substantial short-term pain relief was experienced by approximately 70% to 80% of the patients who continued the study. At 1-year follow-up, approximately 50% of the women needed analgesics or hormonal treatments (322). Medium-term recurrence of lesions was observed in approximately 20% of the cases, and approximately 25% of the women


Gynecology_Novak

Gynecology_Novak. approximately 50% of the women needed analgesics or hormonal treatments (322). Medium-term recurrence of lesions was observed in approximately 20% of the cases, and approximately 25% of the women underwent repetitive surgery (322). It appears that pain recurrence and reoperation rates after conservative surgery for symptomatic endometriosis are high and probably underestimated (322).


Gynecology_Novak

Gynecology_Novak. In patients with severe endometriosis, it is recommended that surgical treatment be preceded by a 3-month course of medical treatment to reduce vascularization and nodular size (200). A randomized controlled study comparing presurgical medical therapy (3 months of GnRH agonists) with surgery alone in women with moderate to severe endometriosis showed a significant improvement in AFS scores in the medical therapy group (WMD −9.60; 95% CI, −11.42 to −7.78), without significant difference in ease of surgery between the two groups and without documentation of improved outcomes for the patients (323). Hormonal therapy prior to surgery improves r-AFS scores, but there is insufficient evidence of any effect on outcome measures such as pain relief (1,324).


Gynecology_Novak

Gynecology_Novak. Radical procedures such as oophorectomy or total hysterectomy are indicated only in severe situations and can be performed laparoscopically or by laparotomy. Women aged 30 years or younger at the time of hysterectomy for endometriosis-associated pain are more likely than older women to have residual symptoms, to report a sense of loss, and to report more disruption from pain in different aspects of their lives (325). If a hysterectomy is performed, all visible endometriotic tissue should be removed. Although associated with improved pain relief and a reduced chance of future surgery, a bilateral salpingo-oophorectomy in young women should be considered in only the most severe or recurrent cases (326,327). Resection is an effective treatment for rectovaginal endometriosis, in combination with hysterectomy (328).


Gynecology_Novak

Gynecology_Novak. When postoperative hormone therapy with estrogen is used after bilateral oophorectomy, there is a negligible risk for renewed growth of residual endometriosis (329). To reduce this risk, hormone therapy should be withheld until 3 months after surgery. The addition of progestins to this regimen protects the endometrium. The decision to start hormone therapy with a combination of estrogen and progestin should be balanced against the increased risk of breast cancer and heart disease associated with hormone therapy. Some cases of adenocarcinoma were reported, presumably arising from endometriosis lesions remaining in women treated with unopposed estrogen (330).


Gynecology_Novak

Gynecology_Novak. In a systematic review published in 2004 to determine the effectiveness of systemic medical therapies used for hormonal suppression before or after surgery for endometriosis, or before and after surgery for the eradication of endometriosis, improvement of symptoms, pregnancy rates, and overall tolerability, by comparing them with no treatment or placebo, 11 trials were included (324). Five trials compared postsurgical medical therapy with surgery alone (without medical therapy) and assessed the outcomes of pain recurrence, disease recurrence, and pregnancy rates (331–334). There was no statistically significant reduction in pain recurrence at 12 months (relative risk [RR] 0.76; 95% CI, 0.52–1.10), but the difference at 24 months approached statistical significance (RR 0.70; 95% CI, 0.47–1.03). There was no statistically significant difference between the use of these medical therapies after surgery compared to surgery alone with regard to disease recurrence (RR 1.02; 95% CI,


Gynecology_Novak

Gynecology_Novak. 0.47–1.03). There was no statistically significant difference between the use of these medical therapies after surgery compared to surgery alone with regard to disease recurrence (RR 1.02; 95% CI, 0.27–3.84) or pregnancy rates (RR 0.78; 95% CI, 0.50–1.22). Postsurgical medical therapy was compared to surgery plus placebo in three studies (332,335,336). There was no difference between medical therapy and placebo with regard to the measures for pain; multidimensional pain score (WMD −0.40; 95% CI, −2.15–1.35); linear scale score (0.10; 95% CI, −2.24–2.44); or change in pain (−0.40; 95% CI, −1.48–0.68). There was no difference between medical therapy and placebo for pregnancy rates (RR 1.05; 95% CI, 0.44–2.51) or total AFS scores (WMD −2.10; 95% CI, −4.56–0.36). There was no significant difference between presurgery hormonal suppression and postsurgery hormonal suppression for the outcome of pain in one trial (323).


Gynecology_Novak

Gynecology_Novak. These results were confirmed in another randomized controlled trial with 5 years of follow-up, showing that GnRH analogue treatment with triptorelin depot 3.75 intramuscular after operative laparoscopy for stages III and IV endometriosis was comparable to placebo injections with respect to time to relapse of endometrioma, pain recurrence, and time to pregnancy (337). There is circumstantial evidence that regular postoperative use of OCs effectively prevents endometrioma recurrence (338). In a prospective controlled cohort study with a median follow-up of 28 months after laparoscopic excision of ovarian endometriomata, the 36-month cumulative proportion of subjects free from endometrioma recurrence was 94% in women who always used cyclic oral contraception compared with 51% in those who never used it (p <.001; adjusted incidence rate ratio [IRR[0.10; 95% CI, 0.04–0.24) (338).


Gynecology_Novak

Gynecology_Novak. Some randomized controlled studies suggest that postoperative hormonal treatment can be useful in delaying the recurrence of endometriosis and/or pelvic pain. One study supported the long-term postoperative use of OCs to reduce the frequency and the severity of recurrent endometriosisrelated dysmenorrhea (339). The prevention of endometriosis-related pain recurrence by postoperative long-term (24 months) cyclic and continuous administration of OCs was compared to no treatment in women after surgery for ovarian endometrioma. A significant reduction in recurrence rate and VAS scores for dysmenorrhea was evident in the continuous users versus the other groups at 6 months, and in cyclic users versus nonusers at 18 months postoperatively. No significant differences in recurrence rate and VAS scores for dyspareunia and chronic pelvic pain were demonstrated among the groups. The increase of VAS scores for dysmenorrhea, dyspareunia, and chronic pelvic pain during the postoperative follow-up


Gynecology_Novak

Gynecology_Novak. scores for dyspareunia and chronic pelvic pain were demonstrated among the groups. The increase of VAS scores for dysmenorrhea, dyspareunia, and chronic pelvic pain during the postoperative follow-up of 6 to 24 months was significantly higher in nonusers than in the users (339).


Gynecology_Novak

Gynecology_Novak. In a second study, long-term cyclic and continuous postoperative use of OCs was shown to effectively reduce and delay endometrioma recurrence (340). The crude recurrence rate within 24 months was significantly lower in cyclic (14.7%) and continuous users (8.2%) compared with nonusers (29%). The recurrence-free survival was significantly lower in nonusers compared with cyclic and continuous users. The mean recurrent endometrioma diameter at first observation and the mean diameter increase every 6 months of follow-up were significantly lower in cyclic and continuous users compared with nonusers, whereas no significant differences between cyclic users and continuous users in terms of endometrioma recurrence were demonstrated (340).


Gynecology_Novak

Gynecology_Novak. In a third study, women who underwent conservative pelvic surgery for symptomatic endometriosis stages III and IV (r-AFS) were treated postoperatively during 6 months with either placebo, GnRH agonist (triptorelin or leuprorelin, 3.75 mg every 28 days), continuous estroprogestin (ethinylestradiol, 0.03 mg plus gestodene, 0.75 mg) or dietary therapy (vitamins, minerals salts, lactic ferments, fish oil) (341). At 12 months after surgery, patients treated with postoperative hormonal suppression therapy showed a lower VAS score for dysmenorrhea than patients in the other groups. Hormonal suppression therapy and dietary supplementation were equally effective in reducing nonmenstrual pelvic pain. Postoperative medical and dietary therapy allowed a better quality of life when compared to placebo treatment (341).


Gynecology_Novak

Gynecology_Novak. In a systematic review to determine whether postoperative use of an levonorgestrel intrauterine system in women with endometriosis improves pain symptoms associated with menstruation and reduces recurrence compared with surgery only, placebo, or systemic hormones, one small randomized controlled trial was identified showing a statistically significant reduction in the recurrence of painful periods in the levonorgestrel intrauterine system treated group compared with the control group receiving a GnRH agonist (OR 0.14; 95% CI, 0.02–0.75) (342,343). The proportion of women who were satisfied with their treatment was higher in the levonorgestrel intrauterine system treated group than in the control group, but this difference did not reach statistical difference (OR 3.00; 95% CI, 0.79–11.44) (342,343). In another small randomized trial, postsurgical treatment with either levonorgestrel intrauterine system or depot MPA for 3 years indicated symptom control and recurrence were comparable,


Gynecology_Novak

Gynecology_Novak. (342,343). In another small randomized trial, postsurgical treatment with either levonorgestrel intrauterine system or depot MPA for 3 years indicated symptom control and recurrence were comparable, but compliance and change in bone mineral density were better in the levonorgestrel intrauterine system treated group than in the depot MPA group (344).


Gynecology_Novak

Gynecology_Novak. Medical Treatment If the patient desires treatment of pain symptoms that are suggestive of endometriosis in the absence of a definitive diagnosis, empirical treatment is appropriate and includes counseling, analgesia, nutritional therapy, progestins, or combined oral contraceptives. It is unclear whether oral contraceptives should be taken in a conventional, continuous, or tricycle regimen. A GnRH agonist may be taken, but is not recommended, because this class of drug is more expensive and associated with more side effects and concerns about bone density than oral contraceptives (1).


Gynecology_Novak

Gynecology_Novak. Women suffering from dysmenorrhea are treated with analgesics; many women treat themselves with over-the-counter oral analgesics. Primary dysmenorrhea is defined as menstrual pain without organic pathology, based on physical examination alone, and it can be argued that some women with so-called primary dysmenorrhea probably have endometriosis (345). In a systematic review it was concluded that nonsteroidal anti-inﬂammatories (NSAIDs), except niﬂumic acid, were more effective than placebo for relief of primary dysmenorrhea, but there was insufficient evidence to suggest whether any individual NSAID was more effective than another (345). In another review, selective cyclo-oxygenase-2 inhibitors rofecoxib and valdecoxib were as effective as naproxen and more effective than placebo for the treatment of primary dysmenorrhea (346). Concerns were raised about the safety of these medications, and its manufacturers withdrew rofecoxib from the market.


Gynecology_Novak

Gynecology_Novak. According to another systematic review based on two relatively small, randomized controlled trials comparing paracetamol and coproxamol with placebo, coproxamol (paracetamol 650 mg and dextropropoxyphene 65 mg) but not paracetamol (500 mg 4 times daily) was more effective than placebo in reducing primary dysmenorrhea (346). This observation may be explained by the suboptimal dosage of paracetamol used. A small randomized trial demonstrated that paracetamol (acetaminophen) 1,000 mg four times daily was superior to placebo for the treatment of primary dysmenorrhea (347).


Gynecology_Novak

Gynecology_Novak. There is a paucity of information for the use of modern OCs for primary dysmenorrhea. A Cochrane review suggested that first-and second-generation OCs with 50 μg or more estrogen may be more effective than placebo treatment for dysmenorrhea. It concluded that the studies included for analysis were of poor quality and heterogenous so that no recommendation could be made regarding the efficacy of modern, lower dose OCs (evidence level 1a) (348). A randomized controlled trial comparing a low-dose oral contraceptive containing 20 μg ethinyl estradiol and 100 μg levonorgestrel with placebo showed better pain relief in adolescent girls with dysmenorrhea using the OC than placebo (349).


Gynecology_Novak

Gynecology_Novak. There is some evidence in general populations that OCs can effectively treat dysmenorrhea (350). OCs have the advantage of long-term safety; hence they can be used indefinitely in low-risk women. In clinical practice, when they are used for menstrual pain, they may be taken tricyclicly or continuously to reduce the number of periods or avoid them altogether (evidence level 4). There is no direct comparison of these options with the conventional approach. Several Cochrane reviews and one clinical-evidence review suggest that other treatment modalities that might be helpful in primary dysmenorrhea include supplemental thiamine or vitamin E, high frequency transcutaneous nerve stimulation, topical heat and herbal remedy toki-shakuyakusan. They suggest that treatment modalities with unknown benefit are vitamin B12, fish oil, magnesium, acupuncture, other herbal remedies and behavioral interventions, and that spinal manipulation is unlikely to be beneficial (348,350–352).


Gynecology_Novak

Gynecology_Novak. Treatment of Endometriosis-Associated Pain Nonsteroidal Anti-inﬂammatory Drugs


Gynecology_Novak

Gynecology_Novak. Considering that endometriosis is a chronic inﬂammatory disease, anti-inﬂammatory drugs would appear to be effective for treatment of endometriosis-related dysmenorrhea. Although NSAIDs are used extensively and are often the first-line therapy for reduction of endometriosisrelated pain, the analgesic effect of NSAIDs was not studied extensively. Only one small, double-blind, placebo-controlled, four-period, crossover clinical study was published (353). This study claimed complete or substantial pain relief of endometriosis-related dysmenorrhea in 83% of cases treated with naproxen compared with 41% in cases treated with placebo. A different analysis of the data from the same study by the Cochrane Collaborative Network did not confirm a positive effect of naproxen on pain relief (OR 3.27; 95% CI. 0.61–17.69) in women with endometriosis (354). There was inconclusive evidence to indicate whether women taking NSAIDs (naproxen) were less likely to require additional analgesia (OR 0.12; 95%


Gynecology_Novak

Gynecology_Novak. CI. 0.61–17.69) in women with endometriosis (354). There was inconclusive evidence to indicate whether women taking NSAIDs (naproxen) were less likely to require additional analgesia (OR 0.12; 95% CI, 0.01– 1.29) or to experience side effects (OR 0.46; 95% CI, 0.09–2.47) when compared to placebo (354).


Gynecology_Novak

Gynecology_Novak. Endometriosis-related pain is nociceptive, but persistent nociceptive input from endometriotic lesions leads to central sensitization manifested by somatic hyperalgesia and increased referred pain (355). The potential effectiveness of NSAIDs in the reduction of endometriosis-related pain may be explained by a local antinociceptive effect and a reduced central sensitization in addition to the anti-inﬂammatory effect. NSAIDs have significant side effects, including gastric ulceration and possible inhibition of ovulation. Prostaglandins are involved in the follicle rupture mechanism at ovulation, which is why women who wish to become pregnant should not take NSAIDs at the time of ovulation (356).


Gynecology_Novak

Gynecology_Novak. Effect of Hormonal Treatment on Pain Because estrogen is known to stimulate the growth of endometriosis, hormonal therapy is designed to suppress estrogen synthesis, thereby inducing atrophy of ectopic endometrial implants or interrupting the cycle of stimulation and bleeding (1). Implants of endometriosis react to gonadal steroid hormones in a manner similar, but not identical, to normally stimulated ectopic endometrium. Ectopic endometrial tissue displays histologic and biochemical differences from normal ectopic endometrium in characteristics such as glandular activity (proliferation, secretion), enzyme activity (17β-hydroxysteroid dehydrogenase), and steroid (estrogen, progestin, and androgen) hormone receptor levels. Withdrawal of estrogen stimulation causes cellular inactivation and degeneration of endometriotic implants but not their disappearance.


Gynecology_Novak

Gynecology_Novak. There is strong evidence that suppression of ovarian function for 6 months reduces pain associated with endometriosis. Combined oral contraceptives danazol, gestrinone, medroxyprogesterone acetate, and GnRH agonists are all equally effective but their side effects and cost profiles differ (1). Pain relief may be of short duration, presumably because endometriosis and endometriosis-associated pain recur after the cessation of medical treatment. The use of diethylstilbestrol, methyltestosterone, or other androgens is no longer advocated because they lack efficacy, have significant side effects, and pose risks to the fetus if pregnancy occurs during therapy. A new generation of aromatase inhibitors, estrogen receptor modulators, and progesterone antagonists may offer new hormonal treatment options.


Gynecology_Novak

Gynecology_Novak. Hormonal Treatment for Pain from Rectovaginal Endometriosis Surgical treatment may reduce the pain associated with rectovaginal endometriosis, but it is associated with a high risk of morbidity and major complications. The effect of medical treatment in terms of pain relief in women with rectovaginal endometriosis appears to be substantial (357). In a systematic review including 217 cases of medically treated rectovaginal endometriosis, the antalgic effect of the considered medical therapies (vaginal danazol, GnRH agonist, progestin, and estrogen-progestin combinations used transvaginally, transdermally, or orally) for the entire treatment period (from 6 to 12 months) was 60% to 90%, with patients reporting considerable reduction or complete relief from pain symptoms, with the exception of when an aromatase inhibitor was used alone (357).


Gynecology_Novak

Gynecology_Novak. Oral Contraceptives Although oral contraceptives are effective in inducing a decidualized endometrium, the estrogenic component in oral contraceptives may stimulate endometrial growth and increase pelvic pain in the first few weeks of treatment. The long-term significance of this effect is undetermined. Oral contraceptives are less costly than other treatments and may be helpful in the short-term management of endometriosis with potential long-term benefits in some women. The use of cyclic oral contraceptives may provide prophylaxis against the development or recurrence of endometriosis. Estrogens in oral contraceptives may stimulate the proliferation of endometriosis. The reduced menstrual bleeding that often occurs in women taking oral contraceptives may be beneficial to women with prolonged, frequent menstrual bleeding, which is a known risk factor for endometriosis (45).


Gynecology_Novak

Gynecology_Novak. Further research is warranted to assess the effect of low-dose oral contraceptives in preventing endometriosis and treating associated pain, because the evidence for its efficacy is limited. In a systematic review to assess the effects of OC’s in comparison to other treatments for painful symptoms of endometriosis in women of reproductive age, only one study met the inclusion criteria (all truly randomized controlled trials of the use of OCs in the treatment of women of reproductive age with symptoms ascribed to the diagnosis of endometriosis and made visually at surgical procedure were included) (358,359). In this study, a total of 57 women were allocated to two groups to compare an OC to a GnRH analogue (359). Methods of randomization and allocation concealment were unclear and the analogue group became amenorrheic during the treatment period of 6 months, while women in the OC group reported a decrease in dysmenorrhea (358,359). No evidence of a significant difference between the


Gynecology_Novak

Gynecology_Novak. group became amenorrheic during the treatment period of 6 months, while women in the OC group reported a decrease in dysmenorrhea (358,359). No evidence of a significant difference between the two groups was observed in terms of dysmenorrhea at 6 months follow-up after stopping treatment (OR 0.48; 95% CI, 0.08–2.90). Some evidence for a decrease in dyspareunia was found at the end of treatment in women in the GnRH analogue group; although no evidence of a significant difference in dyspareunia was observed at the end of the 6 months follow-up (OR 4.87; 95% CI, 0.96–24.65). According to these data, there is no evidence of a difference in outcomes between the OC studied and GnRH analogue in the treatment of endometriosis-associated painful symptoms (358). The lack of studies with larger sample sizes or studies focusing on other comparable treatments is concerning, and further research is needed to evaluate the role of OCs in managing symptoms associated with management of endometriosis


Gynecology_Novak

Gynecology_Novak. sizes or studies focusing on other comparable treatments is concerning, and further research is needed to evaluate the role of OCs in managing symptoms associated with management of endometriosis (358).


Gynecology_Novak

Gynecology_Novak. In a recent double-blind, randomized, placebo-controlled trial, patients with suspected or surgically proven endometriosis were randomly assigned to receive either monophasic OC (ethinylestradiol plus norethisterone) or placebo during four cycles (360). Total dysmenorrhea scores assessed by verbal rating scale were significantly decreased at the end of treatment in both groups. From the first cycle through the end of treatment, dysmenorrhea in the OC group was significantly milder than in the placebo group. The volume of ovarian endometrioma was significantly decreased in the OC group but not in the placebo group (360).


Gynecology_Novak

Gynecology_Novak. The treatment of endometriosis with continuous low-dose monophasic oral contraceptives (one pill per day for 6 to 12 months) was originally used to induce pseudopregnancy caused by the resultant amenorrhea and decidualization of endometrial tissue (279). The concept was to induce an adynamic endometrium through elimination of the normal cyclic hormonal changes characteristic of the menstrual cycle (361). This induction of a pseudopregnancy state with combination oral contraceptive pills is effective in reducing dysmenorrhea and pelvic pain. The subsequent amenorrhea induced by oral contraceptives could decrease the risk for disease progression by preventing or reducing (retrograde) menstruation. Pathologically, oral contraceptive use is associated with decidualization of endometrial tissue, necrobiosis, and possibly absorption of the endometrial tissue (362). There is no convincing evidence that medical therapy with oral contraceptives offers definitive therapy. Instead, the


Gynecology_Novak

Gynecology_Novak. tissue, necrobiosis, and possibly absorption of the endometrial tissue (362). There is no convincing evidence that medical therapy with oral contraceptives offers definitive therapy. Instead, the endometrial implants survive the induced atrophy and, in most patients, reactivate after termination of treatment.


Gynecology_Novak

Gynecology_Novak. Any low-dose OC containing 30 to 35 μgof ethinyl estradiol used continuously can be used for the management of endometriosis. The objective of the treatment is the induction of amenorrhea, which should be continued for 6 to 12 months. Continuous or extended cyclic use of oral contraceptives is well tolerated when compared to the cyclic use of OCs for contraceptive purposes (363). In a randomized controlled trial of women with recurrent moderate or severe pelvic pain after unsuccessful conservative surgery for symptomatic rectovaginal endometriosis, continuous treatment with oral ethinyl E2, 0.01 mg plus cyproterone acetate, 3 mg per day, or norethindrone acetate, 2.5 mg per day during 12 months resulted in substantially reduced dysmenorrhea, deep dyspareunia, nonmenstrual pelvic pain, and dyschezia scores without major between-group differences in patient satisfaction rates (62% and 73%, respectively) (364).


Gynecology_Novak

Gynecology_Novak. In a patient preference cohort study to evaluate the efficacy and tolerability of a contraceptive vaginal ring (supplying 15 μgof ethinyl E and 120 μg per day of etonogestrel) and transdermal patch (delivering 20 μgof ethinyl E and 150 μg per day norelgestromin) in the treatment of women with recurrent moderate or severe pelvic pain after conservative surgery for symptomatic endometriosis and endometriosis-associated pain, patients who preferred the ring were significantly more likely to be satisfied and to comply with treatment than those who chose the patch (282). Both systems were associated with poor bleeding control when used continuously.


Gynecology_Novak

Gynecology_Novak. Progestins may exert an antiendometriotic effect by causing initial decidualization of endometrial tissue followed by atrophy. They can be considered as the first choice for the treatment of endometriosis because they are as effective as danazol or GnRH analogues and have a lower cost and possibly a lower incidence of side effects than these agents (365). Table 17.1 Medical Treatment of Endometriosis-Associated Pain: Effective Regimens (Usual Duration: 6 Months) PO, oral; SC, subcutaneous; IM, intramuscular; IN, intranasal. There is no evidence that any single agent or any particular dose is preferable to another. The effective doses of several progestins are summarized in Table 17.1. In most studies, the effect of treatment was evaluated after 3 to 6 months of therapy. Progestins appear to be an effective therapy for the painful symptoms associated with endometriosis (366).


Gynecology_Novak

Gynecology_Novak. Medroxyprogesterone Acetate MPA is the most studied agent. It is effective in relieving pain starting at a dose of 30 mg per day, increasing the dose based on the clinical response and bleeding patterns according to data from nonrandomized trials (367,368). A randomized placebo-controlled study reported a significant reduction in stages and scores of endometriosis in both the placebo group and the group treated with MPA 50 mg per day and placebo at laparoscopy within 3 months after cessation of therapy (369). These findings raise questions about the need for medical therapy with MPA in this dose.


Gynecology_Novak

Gynecology_Novak. Evidence suggests a possible role for depot MPA in the treatment of endometriosis. In a randomized controlled study, depot MPA (150 mg every 3 months) was more effective in the relief of dysmenorrhea than treatment with a cyclic 21-day oral contraceptive (ethinyl estradiol 20 μg plus desogestrel 0.15 mg) combined with very low-dose danazol (50 mg per day) (370). In another multicenter, randomized, evaluator-blinded, comparator-controlled trial, depot MPA (150 mg) or leuprolide acetate (11.25 mg), given every 3 months for 6 months were equivalent in reducing endometriosis-associated pain during the study and the 12-month posttreatment follow-up period, with less impact on bone mineral density and fewer hypoestrogenic side effects but more bleeding being observed in the depot MPA treated group (371). Add-back therapy would prevent the negative effects on bone density and hypoestrogenic side effects associated with GnRH-agonist therapy. In a pilot study, pain relief, side effects, and


Gynecology_Novak

Gynecology_Novak. group (371). Add-back therapy would prevent the negative effects on bone density and hypoestrogenic side effects associated with GnRH-agonist therapy. In a pilot study, pain relief, side effects, and treatment satisfaction were comparable during a 12-month treatment with etonogestrel implantate subcutaneous (68 mg) or depot medroxyprogesterone acetate 150 mg intramuscular depot MPA in 41 patients with dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia associated with histologically proven endometriosis (372). Although depot MPA treatment is effective for the treatment of pain associated with endometriosis, it is not indicated in infertile women because it induces profound amenorrhea and anovulation, and a varying length of time is required for ovulation to resume after discontinuation of therapy.


Gynecology_Novak

Gynecology_Novak. Dienogest In two randomized noninferiority trials, treatment during 6 months with dienogest 2 mg per day orally demonstrated equivalent efficacy to depot leuprolide acetate (3.75 mg, depot intramuscular injection, every 4 weeks) or intranasal buserelin acetate (900 μg per day, intranasally) in relieving the pain associated with endometriosis, offering a different safety and tolerability profile (less bone loss, fewer hot ﬂushes, more irregular genital bleeding) (373,374). Dienogest treatment was not compared to the recommended treatment of GnRH agonist combined with add-back (see discussion above) in these two trials.


Gynecology_Novak

Gynecology_Novak. Megestrol Acetate Megestrol acetate was administered in a dose of 40 mg per day with good results (370). Pain was reduced significantly during luteal phase treatment with 60 mg dydrogesterone, and this improvement was still evident at 12-month follow-up (316). Other treatment strategies included dydrogesterone (20 to 30 mg per day, either continuously or on days 5 to 21) and lynestrenol (10 mg per day). Side effects of progestins include nausea, weight gain, ﬂuid retention, and breakthrough bleeding caused by hypoestrogenemia. Breakthrough bleeding, although common, is usually corrected by short-term (7-day) administration of estrogen. Depression and other mood disorders are a significant problem in about 1% of women taking these medications.


Gynecology_Novak

Gynecology_Novak. The levonorgestrel intrauterine system releasing 20 μg per day of levonorgestrel reduces endometriosis-associated pain caused by peritoneal and rectovaginal endometriosis and reduces the risk of recurrence of dysmenorrhea after conservative surgery (375). Levonorgestrel induces endometrial glandular atrophy and decidual transformation of the stroma, reduces endometrial cell proliferation, and increases apoptotic activity (375). A systematic review identified two randomized trials and three prospective observational studies, all involving small numbers and a heterogeneous group of patients (376). The evidence suggests that the levonorgestrel intrauterine system reduces endometriosis associated pain with symptom control maintained over 3 years (377–380). Twelve months of treatment results in a significant reduction in dysmenorrhea, pelvic pain, and dyspareunia; a high degree of patient satisfaction; and a significant reduction in the volume of rectovaginal endometriotic nodules


Gynecology_Novak

Gynecology_Novak. in a significant reduction in dysmenorrhea, pelvic pain, and dyspareunia; a high degree of patient satisfaction; and a significant reduction in the volume of rectovaginal endometriotic nodules (377,378). After the first year of use, a 70% to 90% reduction in menstrual blood loss is observed.


Gynecology_Novak

Gynecology_Novak. Progesterone antagonists and progesterone receptor modulators may suppress endometriosis based on their antiproliferative effects on the endometrium, without the risk for hypoestrogenism or bone loss that occurs with GnRH treatment. These products are not available in the United States, and their clinical effectiveness is unproven. Mifepristone Mifepristone (RU-486) is a potent antiprogestagen with a direct inhibitory effect on human endometrial cells and, in high doses, an antiglucocorticoid action (381). The recommended dose for endometriosis is 25 to 100 mg per day. In uncontrolled studies, mifepristone, 50 to 100 mg per day, reduced pelvic pain and induced 55% regression of the lesions without significant side effects (382,383). In an uncontrolled pilot study, low-dose mifepristone, 5mg per day, resulted in pain improvement, without change in endometriosis lesions, suggesting that this dosage was probably too low (384).


Gynecology_Novak

Gynecology_Novak. Onapristone The progesterone antagonists onapristone (ZK98299) and ZK136799, used in the treatment of rats with surgically induced endometriosis, resulted in a remission in 40% to 60% of treated animals. In animals with persistent endometriosis, growth inhibition was obtained in 48% and 85% of endometriotic lesions after therapy with onapristone and ZK136799, respectively (385).


Gynecology_Novak

Gynecology_Novak. Other Progesterone Antagonists The chemical synthesis and pharmacologic characterization of a highly potent progesterone antagonist, ZK230211, were reported, with little or no other endocrinologic effects. ZK230211 is active on progesterone receptors A and B (386). In primates, this drug blocks ovulation and menstruation at all effective doses, whereas another progesterone antagonist, ZK137316, allowed ovulation but blocked menstruation in a dose-dependent fashion (387). All progesterone antagonist–treated animals maintained normal follicular phase concentration of estradiol and returned to menstrual cyclicity within 15 to 41 days after treatment (387). Both progesterone antagonists block unopposed estrogen action on the endometriosis through their antiproliferative effect.


Gynecology_Novak

Gynecology_Novak. Gestrinone is a 19-nortestosterone derivative with androgenic, antiprogestagenic, antiestrogenic, and antigonadotropic properties. It acts centrally and peripherally to increase free testosterone and reduce sex hormone–binding globulin levels (androgenic effect), reduce serum estradiol values to early follicular phase levels (antiestrogenic effect), reduce mean LH levels, and obliterate the LH and follicle-stimulating hormone (FSH) surge (antigonadotropic effect). Gestrinone causes cellular inactivation and degeneration of endometriotic implants but not their disappearance (388). Amenorrhea occurs in 50% to 100% of women and is dose dependent.


Gynecology_Novak

Gynecology_Novak. Resumption of menses generally occurs 33 days after discontinuing the medication (389,390). An advantage of gestrinone is its long half-life (28 hours) when given orally. The standard dose is 2.5 mg twice a week. Although 1.25 mg twice weekly is effective, a randomized study demonstrated in women with mild to moderate endometriosis that 2.5 mg gestrinone twice weekly for 24 weeks is more effective and has a better effect on bone mass (+7% vs. −7%) when compared with 1.25 mg gestrinone twice weekly for 24 weeks (391). The clinical side effects of gestrinone are dose dependent and similar to but less intense than those caused by danazol (391). They include nausea, muscle cramps, and androgenic effects such as weight gain, acne, seborrhea, and oily hair and skin.


Gynecology_Novak

Gynecology_Novak. In a multicenter, randomized, double-blind study, gestrinone was as effective as GnRH for the treatment of pelvic pain associated with endometriosis, with fewer side effects and the added advantage of twice-weekly administration (392). Pregnancy is contraindicated while taking gestrinone because of the risk for masculinization of the fetus.


Gynecology_Novak

Gynecology_Novak. Recognized pharmacologic properties of danazol include suppression of GnRH or gonadotropin secretion, direct inhibition of steroidogenesis, increased metabolic clearance of estradiol and progesterone, direct antagonistic and agonistic interaction with endometrial androgen and progesterone receptors, and immunologic attenuation of potentially adverse reproductive effects (98,393). The multiple effects of danazol produce a high-androgen, low-estrogen environment (estrogen levels in the early follicular to postmenopausal range) that does not support the growth of endometriosis, and the amenorrhea that is produced prevents new seeding of implants from the uterus into the peritoneal cavity.


Gynecology_Novak

Gynecology_Novak. The immunologic effects of danazol were studied in women with endometriosis and adenomyosis and include a decrease in serum immunoglobulins, a decrease in serum C3, a rise in serum C4 levels, decreased serum levels of autoantibodies against various phospholipid antigens, and decreased serum levels of CA125 during treatment (218,230–234,394,395). Danazol inhibits peripheral blood lymphocyte proliferation in cultures activated by T-cell mitogens but does not affect macrophage-dependent T-lymphocyte activation of B lymphocytes (396). Danazol inhibits IL-1 and TNF production by monocytes in a dose-dependent manner and suppresses macrophage-and monocyte-mediated cytotoxicity of susceptible target cells in women with mild endometriosis (397,398). These immunologic findings may be important in the remission of endometriosis with danazol treatment and may offer an explanation of the effect of danazol in the treatment of a number of autoimmune diseases, including hereditary angioedema,


Gynecology_Novak

Gynecology_Novak. in the remission of endometriosis with danazol treatment and may offer an explanation of the effect of danazol in the treatment of a number of autoimmune diseases, including hereditary angioedema, autoimmune hemolytic anemia, systemic lupus erythematosus, and idiopathic thrombocytopenic purpura (399–403). Doses of 800 mg per day are used frequently in North America, whereas 600 mg per day is prescribed in Europe and Australia. It appears that the absence of menstruation is a better indicator of response than drug dose. A practical strategy for the use of danazol is to start treatment with 400 mg daily (200 mg twice a day) and increase the dose, if necessary, to achieve amenorrhea and relieve symptoms (393).


Gynecology_Novak

Gynecology_Novak. In a systematic review to determine the effectiveness of danazol compared to placebo or no treatment in the treatment of the symptoms and signs, other than infertility, of endometriosis in women of reproductive age, five randomized trials were included in which danazol (alone or as adjunctive therapy to surgery) was compared to placebo or no therapy (404). Treatment with danazol (including adjunctive to surgical therapy) was effective in relieving painful symptoms related to endometriosis when compared to placebo (404). Laparoscopic scores improved with danazol treatment (including as adjunctive therapy) when compared with either placebo or no treatment (404). Side effects were more commonly reported in those patients receiving danazol than for placebo (404).


Gynecology_Novak

Gynecology_Novak. The significant adverse side effects of danazol are related to its androgenic and hypoestrogenic properties. The most common side effects include weight gain, ﬂuid retention, acne, oily skin, hirsutism, hot ﬂashes, atrophic vaginitis, reduced breast size, reduced libido, fatigue, nausea, muscle cramps, and emotional instability. Deepening of the voice is another potential side effect that is nonreversible. Danazol can cause increased cholesterol and low-density lipoprotein levels and decreased high-density lipoproteins levels, but it is unlikely that these short-term effects are clinically important. Danazol is contraindicated in patients with liver disease because it is largely metabolized in the liver and may cause hepatocellular damage. Danazol is contraindicated in patients with hypertension, congestive heart failure, or impaired renal function because it can cause ﬂuid retention. The use of danazol is contraindicated in pregnancy because of its androgenic effects on the fetus.


Gynecology_Novak

Gynecology_Novak. Because of the many side effects of oral danazol, alternative routes of administration were studied. In an uncontrolled pilot study, local danazol treatment using a vaginal danazol ring (1,500 mg) was effective for pain relief in deeply infiltrative endometriosis. This treatment did not cause the classic danazol side effects or detectable serum danazol levels, and it allowed ovulation and conception to occur (405).


Gynecology_Novak

Gynecology_Novak. Gonadotropin-releasing hormone agonists bind to pituitary GnRH receptors and stimulate LH and FSH synthesis and release. The agonists have a much longer biologic half-life (3 to 8 hours) than endogenous GnRH (3.5 minutes), resulting in the continuous exposure of GnRH receptors to GnRH-agonist activity. This exposure causes a loss of pituitary receptors and downregulation of GnRH activity, resulting in low FSH and LH levels. Ovarian steroid production is suppressed, providing a medically induced and reversible state of pseudomenopause. A direct effect of GnRH agonists on ectopic endometrium is possible, because expression of the GnRH receptor gene is documented in ectopic endometrium and because direct inhibition of endometriosis cells was shown in vitro (406). In rat models used to study surgical adhesion formation and endometriosis, GnRH-agonist therapy decreased activity of plasminogen activators and matrix MMPs and increased the activity of their inhibitors, suggesting potential


Gynecology_Novak

Gynecology_Novak. surgical adhesion formation and endometriosis, GnRH-agonist therapy decreased activity of plasminogen activators and matrix MMPs and increased the activity of their inhibitors, suggesting potential GnRH-agonist–regulated mechanisms for reducing adhesion formation (407).


Gynecology_Novak

Gynecology_Novak. Various GnRH agonists were developed and used in treating endometriosis. These agents include leuprolide, buserelin, nafarelin, histrelin, goserelin, deslorelin, and triptorelin. These drugs are inactive orally and must be administered intramuscularly, subcutaneously, or by intranasal absorption. The best therapeutic effect is often associated with an estradiol dose of 20 to 40 pg/mL (75–150 pmol/L). These so-called depot formulations are attractive because of the reduced frequency of administration and because nasal administration can be complicated by variations in absorption rates and problems with patient compliance (390). The results with GnRH agonists are similar to those with oral contraceptive progestin or gestrinone therapy. Treatment for 3 months with a GnRH agonist is effective in improving pain for 6 months (332).


Gynecology_Novak

Gynecology_Novak. Although GnRH agonists do not have an adverse effect on serum lipids and lipoproteins levels, their side effects are caused by hypoestrogenism and include hot ﬂashes, vaginal dryness, reduced libido, and osteoporosis (6% to 8% loss in trabecular bone density after 6 months of therapy). Reversibility of bone loss is equivocal and therefore of concern, because treatment periods of longer than 6 months may be required (408,409). The goal is to suppress endometriosis and maintain serum estrogen levels of 30 to 45 pg/mL. More extreme estradiol suppression will induce bone loss (408). The dose of daily GnRH agonist can be regulated by monitoring estradiol levels, by the addition of low-dose progestin or estrogen–progestin in an add-back regimen, or by draw-back therapy.


Gynecology_Novak

Gynecology_Novak. The goal of add-back therapy is to treat endometriosis and endometriosis-associated pain effectively while preventing vasomotor symptoms and bone loss related to the hypoestrogenic state induced by GnRH analogues. Add-back therapy can be achieved by administering progestins only, including norethisterone, 1.2 mg, and norethindrone acetate, 5 mg, but bone loss is not prevented by medrogestone, 10 mg per day (409–411). Add-back therapy can be achieved by tibolone, 2.5 mg per day, or by an estrogen–progestin combination (i.e., conjugated estrogens, 0.625 mg, combined with medroxyprogesterone acetate, 2.5 mg, or with norethindrone acetate, 5 mg; estradiol, 2 mg, combined with norethisterone acetate, 1 mg) (405,408,410–414). Treatment for up to 2 years with combined estrogen and progestagen add-back appears to be effective and safe in terms of pain relief and bone density protection; progestagen only add-back is not protective (415).


Gynecology_Novak

Gynecology_Novak. GnRH agonists should not be prescribed to girls who have not yet attained their maximal bone density, as some concern remains about the long-term effects of GnRH analogues on bone loss. In one report, bone mineral density reduction occurred during long-term GnRHagonist use and was not fully recovered up to 6 years after treatment (416). Use of add-back therapy (2 mg estradiol and1mg norethisterone acetate) did not affect this process (416). Drawback therapy was suggested as an alternative in a study showing that 6 months of intake of 400 μg per day of nafarelin was as effective as a draw-back regimen consisting of 1 month of intake of 400 μg per day of nafarelin followed by 5 months of 200 μg per day of nafarelin, with similar estradiol levels (30 pg/mL) but less loss of bone mineral density (417).


Gynecology_Novak

Gynecology_Novak. Treatment of rats with induced endometriosis using the nonsteroidal aromatase inhibitor fadrozole hydrochloride or YM511 resulted in a dose-dependent volume reduction of endometriosis transplants (418,419). In one case report, treatment of severe postmenopausal endometriosis with an aromatase inhibitor, anastrozole, 1 mg per day, and elemental calcium, 1.5 g per day for 9 months resulted in hypoestrogenism, pain relief after 2 months, and after 9 months a 10-fold reduction in the 30-mm diameter size of red, polypoid vaginal lesions, along with remodeling to gray tissue (420).


Gynecology_Novak

Gynecology_Novak. There is concern with the use of aromatase inhibitors such as anastrozole or letrozole in the treatment of menopausal women because these drugs are known to stimulate ovulation and continuous administration can result in the development of functional ovarian cysts. This side effect can be prevented by combining aromatase inhibitors with ovarian suppressing drugs such as OCs or progestins in premenopausal women. A systematic review assessing the effects of aromatase inhibitors in women symptomatic of pain with endometriosis included eight studies including 137 women (421). In case series (seven studies, 40 women), aromatase inhibitors combined with progestins or OCs or GnRH analogues reduced mean pain scores and lesion size and improved quality of life (421). A randomized controlled trial including 97 women demonstrated that aromatase inhibitors in combination with GnRH analogues significantly improved pain (p <0.0001), compared with GnRH analogues alone, with significant improvement


Gynecology_Novak

Gynecology_Novak. including 97 women demonstrated that aromatase inhibitors in combination with GnRH analogues significantly improved pain (p <0.0001), compared with GnRH analogues alone, with significant improvement in multidimensional patient scores (p <0.0001), without significant reduction in spine or hipbone densities (422). Aromatase inhibitors appear to have a promising effect on pain associated with endometriosis, but the strength of this inference is limited because of a dearth of evidence and because aromatase inhibitors need to be combined with other hormonal medication (421).


Gynecology_Novak

Gynecology_Novak. The role of selective estrogen receptor modulators (SERMs) in the treatment of endometriosis is unclear. In animal models, raloxifene therapy resulted in regression of endometriosis. The effect was seen in a surgically prepared, rat uterine explant model and in Rhesus macaques diagnosed with spontaneous endometriosis before exposure (423). In a placebo-controlled randomized trial in women with chronic pelvic pain and surgically treated biopsy-proven endometriosis, postoperative treatment with raloxifene during 6 months resulted in a shortened time to return of pain (defined as 2 months of pain equal to or more severe than that at study entry) and to repeat laparoscopy, suggesting that raloxifene is not effective in the treatment of endometriosisassociated pain (424). Biopsy-proven endometriosis was not associated with return of pain, suggesting that other factors were implicated in recurrent pelvic pain after surgery in this study (424).


Gynecology_Novak

Gynecology_Novak. the development of endometriosis. Most of these compounds were tested only in rodent models, and more research is needed in the baboon model for endometriosis and in women to ensure their safety and efficacy, as they may interfere with normal physiological processes like ovulation, menstruation, and implantation (54).


Gynecology_Novak

Gynecology_Novak. Selective Inhibition of Tumor Necrosis Factor-α In rats with experimental endometriosis, recombinant human TNF-α–binding protein can reduce 64% of the size of endometriosis-like peritoneal lesions (425). Several prospective randomized placebo-and drug-controlled studies in baboons showed that TNF-α antagonists effectively prevent and treat induced endometriosis and endometriosis-related adhesions and are effective in the treatment of spontaneous endometriosis in baboons (54). These results were not confirmed in a small placebo-controlled randomized trial in women with deeply infiltrative endometriosis awaiting surgery, possibly because the endometriosis phenotype in these women (deeply infiltrative and fibrotic disease) was different from the endometriosis phenotype in the baboon studies (inﬂammatory peritoneal disease with adhesions) (426). TNF-α antagonists are less effective in fibrotic inﬂammatory bowel disease than in earlier nonfibrotic inﬂammatory bowel disease.


Gynecology_Novak

Gynecology_Novak. Pentoxifylline In a systematic review determining the effectiveness and safety of pentoxifylline, which has anti-inﬂammatory effects in the management of endometriosis in subfertile, premenopausal women, four trials involving 334 participants were included (427). Pentoxifylline had no significant effect on reduction in pain (one randomized trial, MD −1.60; 95% CI, −3.32–0.12), improvement of fertility (three randomized trials, OR 1.54; 95% CI, 0.89–2.66) or recurrence of endometriosis (one randomized trial, OR 0.88; 95% CI, 0.27–2.84) (427). No trials reported the effects of pentoxifylline on the odds of live birth rate per woman, improvement of endometriosis-related symptoms, or adverse events (427). Peroxisome Proliferator Activated Receptor-γ Agonists Peroxisome proliferator activated receptor-γ (PPAR-γ ) agonists prevent and treat endometriosis in both rodent and baboon models for endometriosis and show promise for treatment of human endometriosis (152,153,428,429).


Gynecology_Novak

Gynecology_Novak. Many substances potentially capable of modulating immunologic or inﬂammatory mechanisms involved in the onset or progression of the disease could be the targets for future research in endometriosis (430,431). Preliminary trials with cyclooxygenase-2 (COX-2) inhibitors, leukotriene receptor antagonists, TNF-α inhibitors, antiangiogenic agents and kinase inhibitors show promising results in vitro in rodent and in nonhuman primate models, but their safety is an important issue regarding human use (432).


Gynecology_Novak

Gynecology_Novak. In China, treatment of endometriosis using herbal medicines is routine, and considerable research into the role of herbal medicines in alleviating pain, promoting fertility, and preventing relapse has occurred (433). A systematic review of the effectiveness and safety of herbal medicines in alleviating endometriosis-related pain and infertility, including two Chinese randomized trials involving 158 women, concluded that postsurgical administration of herbal medicines may have comparable benefits to hormonal treatment with gestrinone but with fewer side effects (433). Oral herbal medicines might have a better overall treatment effect than danazol; it could be more effective in relieving dysmenorrhea and shrinking adnexal masses when used in conjunction with an herbal enema (433). More rigorous research is required to accurately assess the potential role of herbal medicines in treating endometriosis (433). Treatment of Endometriosis-Associated Subfertility


Gynecology_Novak

Gynecology_Novak. Treatment of Endometriosis-Associated Subfertility Surgical Treatment The treatment of endometriosis-related infertility is dependent on the age of the woman, the duration of infertility, the stage of endometriosis, the involvement of ovaries, tubes, or both in the endometriosis process, previous therapy, associated pain symptoms, and the priorities of the patient, taking into account her attitude toward the disease, the cost of treatment, her financial means, and the expected results. If surgery is performed and spontaneous pregnancy does not occur within 2 years of surgery, there is little chance of subsequent natural conception (434). Surgery for Minimal to Mild Endometriosis