clinical practice guideline endometriosis

Clinical Practice Guidelines for Pharmaceutical Treatment of

Endometriosis
Ministry of Health Department of Health Care Ordinance no. 144 of 31 March 2010. (Amended 27 August 2010)
Consultants: Cláudia Vieira Mengarda, João Sabino Cunha Filho, Bárbara Corrêa Krug, and Karine Medeiros Amaral Editors: Paulo Dornelles Picon, Maria Inez Pordeus Gadelha, and Alberto Beltrame The authors have declared no conflicts of interest. 1 LITERATURE SEARCH STRATEGY A literature search was conducted using MEDLINE/PubMed (http://www.ncbi.nlm.nih.gov/pubmed). The search was limited to meta-analyses and randomized clinical trials (RCTs) published in Portuguese, Spanish, and English between 1999 and 2010. The following search terms were used: (“1999” [Publication Date]: “3000” [Publication Date]) AND (“Endometriosis/ drug therapy”[MeSH]). A total of 4 meta-analyses and 82 RCTs were retrieved. Since the principal symptoms of endometriosis are pelvic pain and infertility, and patients with infertility alone were considered ‘Special Cases’ in this CPG, 4 meta-analyses and 44 RCTs assessing pain relief after treatment were used in this CPG. A total of 27 studies in which pain symptoms were not assessed and 12 RCTs published in languages other than Portuguese, Spanish, or English were excluded from the analysis. 2 INTRODUCTION Endometriosis is a gynecological disease defined as the development and growth of stroma and 1 endometrial glands outside the uterine cavity, resulting in a chronic inflammatory reaction. The disease is diagnosed almost exclusively in women of reproductive age; postmenopausal women 2 account for only 2-4% of all cases undergoing laparoscopy for suspected endometriosis. Endometriosis prevalence is difficult to determine because there is no correlation between symptoms and severity of the disease and also because an invasive procedure (laparoscopy) is 3,4 required to confirm diagnosis. The prevalence rate is estimated at about 10%. Among infertile 5 women, these values can reach high rates (30-60%). The most commonly affected sites are the ovaries, anterior and posterior cul-de-sac, posterior leaflet of the broad ligament, uterosacral 6 ligaments, uterus, fallopian tubes, sigmoid colon, appendix, and round ligaments. Attempts to explain the pathogenesis of endometriosis involve several theories that point to multiple 4,6 causes, involving genetic factors, immunologic abnormalities, and endometrial dysfunction. According to the implantation theory, retrograde menstruation allows endometrial tissue to have access to pelvic structures through the fallopian tubes to seed the peritoneal cavity, thus 7 establishing blood flow to the endometrial tissue and inducing an inflammatory response. The coelomic metaplasia theory proposes that undifferentiated cells of the pelvic peritoneum have the ability to differentiate into endometrial tissue. The direct transplantation theory is the probable explanation for endometriosis that develops in episiotomy, cesarian section, and other scars after surgery. Dissemination of endometrial cells or tissue through blood and lymph vessels is the probable explanation for sites of endometriosis outside the pelvic cavity. The principal clinical manifestations of endometriosis are infertility and pelvic pain – dysmenorrhea, 8,9 dyspareunia, and cyclic pelvic pain. Symptoms related to atypical sites of endometrial tissue may also be present, such as pleuritic pain, hemoptysis, headache or seizures, painful lesions in surgical 2 scars, edema, and bleeding site. Physical examination is of limited diagnostic value in this disease, due to the absence of pathognomonic findings. Physical findings suggestive of endometriosis include pain on palpation of the cul-de-sac and uterosacral ligaments, palpation of nodules or 1,2 adnexal masses, and a fixed retroverted uterus. The most commonly used staging system is the revised American Society For Reproductive 10,11 Medicine (ASRM) classification of endometriosis, which takes into consideration extent, depth,

and location of endometriotic implants and severity of adhesions. The ASRM endometriosis classification system contains 4 stages: • stage I (minimal endometriosis) – isolated implants without significant adhesions; • stage II (mild endometriosis) – superficial implants less than 5 cm in diameter, without significant adhesions; • stage III (moderate endometriosis) – multiple implants, with evident periovarian and peritubal adhesions; • stage IV (severe endometriosis) – multiple superficial and deep implants, including dense and thick endometriomas and adhesions. Stage IV endometriosis accounts for the most extensive disease. However, disease stage is not 3,4 correlated with prognosis or severity of pain. Pain severity is influenced by the depth of 12,13 endometriotic implants and their location in highly innervated areas. 3 INTERNATIONAL STATISTICAL CLASSIFICATION OF DISEASES AND RELATED HEALTH PROBLEMS (ICD-10) • N80.0 Endometriosis of uterus • N80.1 Endometriosis of ovary • N80.2 Endometriosis of fallopian tube • N80.3 Endometriosis of pelvic peritoneum • N80.4 Endometriosis of rectovaginal septum and vagina • N80.5 Endometriosis of intestine • N80.8 Other endometriosis 4 DIAGNOSIS According to consensus guidelines of the European Society of Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM), the gold standard for diagnosis of endometriosis is visual inspection of the pelvis and implants at 1,11 laparoscopy. Biopsy for histopathological confirmation is not considered to be necessary. Although biopsy has traditionally been recommended for histological correlation in all areas suggestive of endometriosis, a number of authors have reported extremely high correlations 14 between laparoscopic and histologic findings (97-99%), no longer requiring histologic confirmation and thus preventing further or unnecessary investigation of these patients. An apparent discrepancy between studies examining the need for biopsy results from different designs and number of cases evaluated. The diagnosis of endometriosis may be ruled out in patients with normal-appearing 15 peritoneum. 5 INCLUSION CRITERIA Patients may be included in this CPG for treatment with danazol or GnRH analogues if they meet the following eligibility criteria: • pelvic pain as a clinical symptom to be treated; • unresponsiveness to previous 6-month treatment with oral contraceptives or progestagens or recurrence of endometriosis-related pain symptoms; • evidence of endometriosis at laparoscopy/laparotomy, as established and reported in writing by a physician according to the revised ASRM classification, or anatomicopathologic confirmation of peritoneal biopsy. 6 EXCLUSION CRITERIA Patients should be excluded from this CPG if they meet any of the following criteria: • pregnancy (possible androgenic effects in female fetuses); • breastfeeding; • genital bleeding of unknown origin (only for danazol treatment); • severe hepatic dysfunction (only for danazol treatment); • hypersensitivity to the drug. 7 SPECIAL CASES

• Danazol administration in patients with porphyria (the drug may exacerbate the disease) or in patients with a history of thromboembolic event • Use of oral contraceptives by smokers aged > 35 years (higher risk of thromboembolism) • Indication of retreatment or treatment for a longer period of time 8 TREATMENT The choice of treatment will depend on the severity of symptoms, the extent and location of disease, whether there is a desire for pregnancy, and the age of the patient. Patients may undergo 5 drug therapy or surgical treatment, or even a combination of both. Effectiveness of treatment has 5 been associated with pain relief and improved fertility rates. All hormonal treatments are effective in relieving pain attributed to endometriosis when compared with placebo and are equally effective 9 when compared to each other. Drug therapy focuses mainly on hormonal manipulation in order to induce pseudopregnancy, pseudomenopause, or chronic anovulation, thus setting an environment unsuitable for growth and 4 maintenance of endometriotic implants. 4 Hormonal suppression of ovulation in women with infertility is deemed unnecessary. Clinical treatment is not indicated for patients with endometriosis-related infertility because the commonly 16,17 used drugs are not effective in this setting. Surgical intervention with electrocautery destruction of implants has proven effective in the treatment of infertile women with stage I and II endometriosis. A multicenter study evaluating 341 infertile women with minimal to moderate endometriosis showed significantly higher pregnancy rates in the group assigned to undergo 18 laparoscopy with resection or ablation of endometriosis. Therefore, after electrocautery of endometriotic implants, this group may be treated for infertility. Several surgical and clinical approaches have been tested for the treatment of endometriosis. Treatment decisions should take into account clinical manifestations – whether pain or infertility –, patient age and history of reproduction, and the extent of disease. Cases in which laparoscopy is indicated should undergo surgical resection or ablation of the largest number of endometriotic 19 implants. 8.1 CLINICAL TREATMENT Oral contraceptives (OC) The use of OCs should be considered for empirical treatment in women with symptoms and physical examination findings suggestive of endometriosis, provided that other diseases associated 1 with pelvic pain have been ruled out. This treatment produces a delay in disease progression as 20 well as protection in cases in which there is no desire for pregnancy. A study comparing administration of OC (ethinyl estradiol 0.035 mg + norethisterone 1 mg) with placebo showed a significant decrease in dysmenorrhea and nonmenstrual pain scores assessed by the verbal rating scale and the visual analog scale in both groups; however, both dysmenorrhea and nonmenstrual 21 pain were significantly milder in the OC group (-2) than in the placebo group (-0.6). The volume of endometrioma was significantly decreased in the OC group, but not in the placebo group. No serious adverse events were observed in the OC group, although this group showed a higher incidence of nausea and irregular bleeding. An important potential bias in that study concerns the fact that only 10 women in the OC group and 7 in the placebo group had a laparoscopic diagnosis of endometriosis. Ultrasound scanning has limited value as a diagnostic tool for peritoneal 1 endometriosis, and there may have been more patients with deep peritoneal endometriosis and persistence of pain in the placebo group. Cyclic OCs have been compared with GnRH agonists. GnRH agonists were more effective in relieving dysmenorrhea, but OCs and GnRH agonists were equally effective in reducing 22 dyspareunia and nonspecific pelvic pain. A randomized clinical trial comparing OCs with goserelin showed that OCs were more effective in the management of dysmenorrhea and that goserelin was 23 superior to OCs in reducing dyspareunia. An open multicenter clinical trial showed that both treatments are effective in improving dysmenorrhea and nonmenstrual pelvic pain, with no 24 differences in response between treatments. Danazol

Danazol induces pseudomenopause, inhibits GnRH release and LH peaks, increases androgen levels (free testosterone), and decreases estrogen levels (by inhibiting the production of ovarian 26 steroids with decreased production of estrogen), thus leading to atrophy of endometriotic implants. A meta-analysis conducted in 2007 showed a significant reduction in pelvic pain, back pain, pain associated with defecation, and total pain scores compared with placebo 3 and 6 months after 26 treatment; such improvement was maintained for up to 6 months after treatment discontinuation. In that meta-analysis, danazol was not effective in reducing dyspareunia compared with placebo, and no improvement was observed in fertility rates. A randomized clinical trial evaluating medroxyprogesterone (100 mg/day) and danazol (600 mg) showed that both drugs were equally effective in reducing pain scores over placebo, and effects 4 were maintained for up to 6 months after treatment discontinuation. A study comparing danazol (800 mg/day) with several GnRH analogues showed statistically significant advantage of danazol in 27 terms of time to recurrence after treatment. An open clinical trial comparing danazol (200 mg, 3 times daily) with triptorelin (3.75 mg, every 6 weeks) showed a decrease in pain scores in both treatments, with no significant differences between groups. More patients failed to complete the whole course of danazol because of its adverse effects, which included weight gain, acne, hoarseness, and edema. The most common complaints in the triptorelin group were vasomotor symptoms, mood swings, insomnia, and 28 nightmares. Danazol has been associated with androgenic effects (some irreversible ones), lipid 5 29 disorders, liver damage, decreased breast volume, cramps, increased appetite, acne, and 26 edema. Progestagens Progestagens inhibit the growth of endometriotic tissue directly through decidualization and atrophy of the endometrium. This agent can also inhibit pituitary gonadotropin secretion and ovarian hormone production. Medroxyprogesterone acetate (MPA) has proved superior to placebo and equally effective to danazol in providing pain relief and resolution of implants, with adverse effects 30 that resolve spontaneously after discontinuing the drug. A study comparing MPA (150 mg, intramuscularly, every 90 days) with a low-dose cyclic OC combined with danazol showed that at 1year assessment MPA was more effective in reducing dysmenorrhea, in addition to inducing 30 amenorrhea. 31 A multicenter, randomized, evaluator-blinded clinical trial, involving 274 women with symptomatic endometriosis and comparing MPA (104 mg, subcutaneously) with leuprorelin acetate (11.25 mg, intramuscularly), showed that MPA was equivalent to leuprorelin in reducing dysmenorrhea, dyspareunia, pelvic pain, and pelvic tenderness. Regarding bone mineral density (BMD), at month 6, the leuprorelin group showed a significant decrease in total hip and lumbar spine BMD, whereas the MPA group showed a reduction only in spine BMD. At 12 months’ follow-up, the leuprorelin group maintained a significant reduction in total hip (-1,3%) and spine (-1.7%) BMD, whereas the MPA group (104 mg) showed no significant reduction at these sites (0 and 0.2%, respectively). Similar results were found in another clinical trial involving 300 women with symptomatic 32 endometriosis, in which MPA (104 mg) and leuprorelin (11.25 mg) produced equivalent reductions in at least 4 pain categories (p < 0.02) and improvements in composite score at months 6 and 18. At month 6, reductions in total hip and lumbar spine BMD were significantly lower with MPA (104 mg) compared to leuprorelin. BMD returned to pretreatment levels 12 months posttreatment in the MPA but not the leuprorelin group. Total productivity also improved significantly in both groups at months 6 and 18. A randomized clinical trial comparing continuous treatment for 6 months with a progestagen only preparation containing desogestrel (75 mg) versus OC (ethinyl estradiol 20 mg + desogestrel 150 33 mg), in patients with endometriosis who showed recurrent dysmenorrhea and/or pelvic pain after conservative surgery, showed improvement of both dysmenorrhea and pelvic pain following both treatments. The use of desogestrel progestagen only pill was associated with a breakthrough bleeding in 20% of patients, while a significant body weight increase was observed in 15% of patients after OC. Another open randomized clinical trial, involving women with recurrent pelvic pain after unsuccessful conservative surgery for symptomatic rectovaginal endometriosis who received either OC (ethinyl estradiol 0.01 mg + cyproterone acetate 3 mg) or norethindrone acetate (2.5 mg/day) for 12 months, showed similar reduction between groups in dysmenorrhea, deep

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dyspareunia, and nonmenstrual pelvic pain scores. According to an intention-to-treat analysis, 62% of patients in the OC group were satisfied or very satisfied with the treatment received after 12 34 months, against 73% in the norethindrone acetate group. GnRH analogues These drugs exert a negative feedback effect on the pituitary, causing hypogonadotrophic hypogonadism that leads to amenorrhea and anovulation, which account for their therapeutic effect. 35,36 This inhibitory effect is reversible. These analogues cannot be administered orally because they are readily destroyed by the digestive process, but they may be given parenterally – 35 subcutaneously, intramuscularly, by nasal spray, or in vaginal pessaries. Efficacy of GnRH analogues is equivalent to that of danazol for promoting regression of implants and reducing pain, 36 with fewer adverse effects. A study assessing changes in endometriosis-associated pain and quality of life during the stimulatory phase of GnRH analogue therapy showed that, after 2 weeks, visual analog scale pain scores were higher in the treatment group. After 4 weeks, women treated with leuprorelin had a significant improvement in pain. Regarding quality of life, measured with the 37 SF-36 instrument, there was no significant difference between groups. • Leuprorelin In comparison with placebo, dysmenorrhea, pelvic pain, and pelvic tenderness responded 38,39 significantly to leuprorelin treatment. A placebo-controlled clinical trial comparing nafarelin and leuprorelin showed that the drugs were more effective than placebo in relieving pain, with no 40,41 differences between active treatment groups. Treatment with leuprorelin (3.75 mg) compared with a 3-month expectant management in 89 women with symptomatic endometriosis stage III-IV showed no statistically significant differences between GnRH and control groups regarding pregnancy rates (33 vs. 40%), moderate/severe pain recurrence rates (23 vs. 24%), and cumulative 42 pain recurrence rates at 18 months (23 vs. 29%). In an open clinical trial comparing leuprorelin acetate (3.75 mg, every 28 days) with danazol (200 mg, 3 times daily, for 24 weeks), endometriosis symptoms significantly improved in both treatment groups. Hypoestrogenic side effects (hot flushes) were more common in patients receiving leuprorelin, but anabolic/androgenic effects (weight gain and acne) were more common in those 43 receiving danazol. • Goserelin A study comparing goserelin (3.6 mg, subcutaneously, every 28 days) with danazol (200 mg, 3 times daily) showed that both treatments were equally effective in reducing AFS scores (adhesions, 44-46 implants), pelvic symptoms, and physical examination findings. Improvements could still be 45 observed 6 months after drug withdrawal. • Triptorelin In a randomized clinical trial comparing triptorelin (3.75 mg, intramuscularly, every 28 days) with placebo, pain scores and extent of endometriosis were significantly reduced in the actively treated 47 group (50% reduction in the triptorelin group vs. 17% increase in the placebo group). An open randomized clinical trial, with a small sample, showed no significant differences between groups regarding pelvic pain persistence or recurrence assessed by the verbal rating scale, endometrioma 48 relapse, or pregnancy rates. Curves of pain recurrence and pregnancy during a 5-year follow-up did not show significant differences between treatment and intervention groups. There are only a few clinical trials comparing different GnRH analogues in the treatment of endometriosis. Results have shown no differences between GnRH analogues in terms of symptom improvement in patients with endometriosis. A randomized clinical trial comparing nafarelin and 41 leuprorelin found no significant improvement in quality of life scores at 3 and 6 months. A randomized, double-blind study comparing treatment for 3 months with triptorelin (T) and leuprorelin (L) showed no significant differences in LH, FSH, estradiol, liver function, and lipid profile 49 biochemical parameters. Likewise, no differences were observed in the onset of hypoestrogenic symptoms and vaginal bleeding. In that same study, during the crossover phase, the drugs were evaluated for an additional 3-month period. Eight weeks after the last dose of the analogue, more patients in the L/T group (80%) than in the T/L group (51.9%) had abnormally low estradiol and LH

levels. Time to the return of menstruation was significantly longer in the L/T group than in the T/L group; however, because of a change in the sequence of drugs, it was not possible to conclude whether the prolonged action observed was due to the last drug used or to the sequence adopted. 50 In an open randomized clinical trial comparing goserelin and nafarelin, both drugs significantly reduced pain scores from baseline, with no significant differences between groups. There were no significant differences between groups in pain scores or adverse events (hot flushes, headache, sweating, vaginal dryness, vaginal bleeding). In summary, GnRH analogues are similar in terms of efficacy and effectiveness. Although nafarelin shows similar efficacy to that of the remaining GnRH analogues, this drug does not provide further effectiveness and its dosage requirements hinder adherence to treatment. Therefore, nafarelin therapy was not included in this CPG. Add-back therapy Add-back therapy (a combination of hormonal or nonhormonal treatment with GnRH analogues) is indicated to reduce adverse effects of GnRH analogues – hypoestrogenic effects, vasomotor symptoms, and bone loss. The most commonly used hormone replacement therapies (HRT) include progestagens, estrogens, or a combination of progestagens and estrogens. A study comparing goserelin with or without HRT (17-beta estradiol 2 mg + norethisterone acetate 1 mg) showed that the addition of HRT resulted in fewer hot flushes and alterations in libido and less vaginal dryness. Add-back therapy does not reduce treatment efficacy (pain relief and reduction of 51 endometriotic implants) and provides substantial improvement in hypoestrogenic symptoms and 52 quality of life. A meta-analysis comparing tibolone and medroxyprogesterone acetate (100 mg/day) with norethisterone, in a combination of estradiol (2 mg) and norethisterone (1 mg/day), showed no differences between various regimens in relation to pain relief. There was significant 53-57 improvement in adverse effects – hot flushes, vaginal dryness, and decreased bone loss. Another study observed an earlier return of dysmenorrhea, pelvic pain, and pelvic nodules to baseline levels in the group receiving add-back therapy with a higher dose of estrogen (norethindrone acetate 5 mg/day + conjugated estrogens 1.25 mg/day) than in the remaining groups (placebo, norethindrone acetate 5 mg/day, and norethindrone acetate 5 mg/day + 58 conjugated estrogens 0.625 mg/day). Similarly, a randomized clinical trial, with a small sample, comparing the use of GnRH analogues with placebo or combined with ethinyl estradiol (20 mg) and desogestrel (0.15 mg) showed significant improvements in dysmenorrhea and pelvic pain in both groups. The GnRH + placebo group had significantly higher serum calcium levels and significantly 59 higher loss of BMD. 60 In a clinical trial, 133 women with a surgical diagnosis of endometriosis and recurrent pelvic pain, dysmenorrhea, or dyspareunia were randomized into 3 treatment groups: group A) leuprorelin acetate (11.25 mg, every 3 months) + transdermal estrogen and norethindrone (5 mg, orally); group B) leuprorelin acetate (11.25 mg, every 3 months); and group C) OC E/P (ethinyl estradiol 0.03 mg + gestodene 0.75 mg). Patients treated either with GnRH analogue alone or GnRH analogue plus add-back therapy showed a higher reduction of pelvic pain, dysmenorrhea, and dyspareunia than patients treated with OC. Patients treated with add-back therapy showed better quality of life scores, as assessed by the SF-36, lower bone loss, and fewer episodes of hot flushes than patients treated with GnRH analogue alone, but with scores similar to those of patients treated with OC. 61 In a meta-analysis including 15 studies and 910 women with a laparoscopic diagnosis of endometriosis, add-back therapy with progestagen alone did not improve BMD after a 6-month follow-up period (95%CI -0.21 to 0.52). When add-back therapy with estrogen alone or estrogen + progesterone was adopted, there was a significant increase in BMD after 6 months (95%CI -0.77 to -0.21) and after 12 months (95%CI -1.02 to -0.10). This result was also demonstrated in a 62 randomized double-blind clinical trial comparing leuprorelin acetate (3.75 mg, monthly), which, after the third injection, was used in combination with promegestone (0.5 mg + placebo (PP)), with leuprorelin acetate (3.75 mg, monthly), which, after the third injection, was used in combination with estradiol (2 mg + promegestone (EP)). At month 12, BMD changes were higher in the group with progestagens and were prevented in the group with estrogens. A study with a small sample also observed that the number of endometriotic implants was significantly reduced in both groups, with 63 no significant differences between groups. BMD decreased by 5.02% in the group that received goserelin + placebo and increased by 0.18% in the group that received add-back HRT. The

Kupperman Index score decreased by 75, 129, and 113% in the placebo group, after 4, 12, and 24 months, respectively, with a significant difference between groups at the end of treatment. Monthly goserelin acetate without HRT was compared with estradiol (2 mg/day combined with norethisterone acetate 1 mg/day, both orally, for 2 years), and no differences were observed between groups in relation to BMD at the end of treatment. After a 6-year follow-up period, mean BMD was 87.2% in the group with HRT and 86.8% in the group without HRT. However, sample size 64 was small and the study was underpowered to detect differences. Only a study with a small sample of 13 patients, in which estradiol (1 mg/day, orally, in 6 patients ) was combined with leuprorelin acetate, showed a trend toward increasing pain with estrogen addback therapy. Hot flushes were less severe in the estradiol group. However, differences observed 65 between groups did not reach statistical significance. 66-69 70,71 Other treatments, such as levonorgestrel-releasing intrauterine device, pentoxifylline, 72,73 74 75 76,77 78 dienogest, anastrozole, lynestrenol, Chinese herbal medicine, infliximab, etonogestrel 79 80 implant, and raloxifene, have been tested for endometriosis, but evidence is deemed insufficient to justify their recommendation. 8.2 SURGICAL TREATMENT Surgical treatment is indicated in the following cases: presence of severe or disabling symptoms; unresponsiveness to empirical treatment wit oral contraceptives or progestagens; endometrioma; distortion of pelvic anatomy; adhesions; intestinal or urinary tract obstruction; and endometriosis1,25 associated infertility. Surgical interventions may be classified as conservative or definitive surgery. Conservative surgery This procedure involves the destruction of endometriotic implants and removal of adhesions with consequent restoration of pelvic anatomy. There is a significant degree of pain relief at 6 months after laparoscopic surgery in patients with minimal, mild, or moderate endometriosis in comparison 81 to expectant management (OR 4.97; 95%CI 1.85 to 13.39). Definitive surgery This procedure involves hysterectomy with or without oophorectomy (according to the age of the patient). It is indicated in the presence of severe disease, persistence of disabling symptoms after drug therapy or conservative surgery, other pelvic diseases with indication for hysterectomy, and cases in which there is no desire for pregnancy. Hysterectomy with bilateral salpingo-oophorectomy and resection of all endometriotic implants resulted in cure in 90% of cases (non-controlled 2 studies). A randomized clinical trial showed greater efficacy of laparoscopic surgery (ablation of implants, adhesiolysis, and uterosacral nerve ablation) compared with diagnostic laparoscopy, with significant 82 continued pain relief at 1 year after treatment in up to 90% of patients. Regarding infertility associated with minimal or mild endometriosis, a study of 341 patients showed that laparoscopic surgery (resection or surgical ablation of implants) increased the cumulative probability of 18 83 pregnancy. A study with a smaller sample failed to reproduce these results. 8.3 ADD-BACK THERAPY Hormonal suppression prior to surgery may reduce the need for surgical dissection, but it cannot 20 prolong disease-free interval, increase fertility rates, or reduce recurrence rates. The addition of low-dose danazol (100 mg/day) after combined surgical and GnRH analogue 84 therapy was effective in improving painful symptoms and managing pain for 12 and 24 months. However, short-term (3 months) danazol therapy showed no benefits in a study of patients with 85 stage III-IV endometriosis. A prospective, non-controlled study evaluating the efficacy of postoperative administration of oral contraceptives found no differences in the recurrence rate of 86 endometriosis symptoms or endometrioma formation. Two studies analyzing postoperative administration of GnRH analogues showed better pain management and delayed recurrence of endometriosis in a follow-up period longer than 12 months compared to placebo, but with no 17,87 improvement in fertility rates. Other clinical trials, with small sample size, testing short-term (3 16,42,48 months) GnRH analogue therapy showed no benefit for pain relief or fertility rates.

Evidence supporting the benefits of add-back therapy is not clear, and drug therapy is therefore restricted to patients with recurrent symptoms after surgery. 88 A meta-analysis included 11 studies that evaluated the effectiveness of medical treatment before and after surgery in women with endometriosis. A randomized clinical trial comparing surgical treatment alone with pre-surgical use of medical therapy showed significant improvement in AFS scores in the group receiving drug therapy. Regarding post-surgical hormonal suppression, 8 randomized clinical trials were included and showed no benefit for the outcomes of pain or pregnancy rates but a significant improvement in disease recurrence. A randomized clinical trial showed no significant difference between pre- and postoperative hormonal suppression between groups for the outcomes of pelvic pain, pelvic nodules, or dyspareunia. When comparing hormonal suppression before and after surgery with surgery alone, a randomized clinical trial showed no difference between groups regarding AFS scores or pregnancy rates. In that meta-analysis, there is insufficient evidence to conclude that hormonal suppression in combination with surgery is associated with a significant benefit in the treatment of endometriosis. 8.4 DRUGS • Oral contraceptives: formulations available in the Brazilian Public Health System • Danazol: capsules of 50, 100, and 200 mg • GnRH analogues – Goserelin: injection with a single dose of 3.6 or 10.8 mg – Leuprorelin: vials of 3.75 or 11.25 mg – Triptorelin: vials of 3.75 or 11.25 mg 8.5 ADMINISTRATION • Oral contraceptives: administration according to formulations available in the Brazilian Public Health System • Danazol: 200 mg, orally, 2 times daily; the dose may be increased up to 400 mg, 2 times daily • GnRH analogues – Goserelin: 3.6 mg, subcutaneously, monthly or 10.8 mg every 3 months – Leuprorelin: 3.75 mg, intramuscularly, monthly or 11.25 mg every 3 months – Triptorelin: 3.75 mg, intramuscularly, monthly or 11.25 mg every 3 months 8.6 EXPECTED BENEFITS OF CLINICAL TREATMENT • Pain relief (usually within 3 weeks) • Regression of endometriotic nodules (usually within 6 weeks) 8.7 TREATMENT DURATION – CRITERIA FOR DISCONTINUATION 26,40,41,45,51,89,90 The majority of studies have treated patients for a 6-month period. The recommended duration of treatment is 3-6 months. Patients who have used GnRH analogues for a 6-month period, but still have pain symptoms or recurrence of endometriosis-related pain, should be referred to a specialized service. 9 MONITORING • Danazol: platelet count every 4-6 months (thrombocytosis/thrombocytopenia were observed). Patients on concomitant use of danazol and carbamazepine may show a significant increase in carbamazepine levels resulting in toxicity. • GnRH analogues: patients referred to a specialized service receiving GnRH analogues for more than 6 months should be assessed for risk of osteoporosis. • Medroxyprogesterone: due to central inhibition of FSH release, BMD should be assessed every 2 years to rule out osteoporosis. 10 POST-TREATMENT FOLLOW-UP Patients should be reassessed every 6 months for withdrawal of danazol and GnRH analogues. Requests for retreatment or treatment for longer periods of time are covered in the section ‘Special Cases’. Patients who have used escalated doses (oral contraceptives, progestagens, GnRH analogues), but still have pain symptoms or recurrence of endometriosis-related pain should be

referred to a specialized service for reevaluation. Retreatment in these cases does not require new diagnostic tests, only a confirmation of symptoms present and absence of treatment response reported in writing by a physician. 11 REGULATION/CONTROL/MANAGER ASSESSMENT Patients with endometriosis should be referred to specialized gynecology services for proper diagnosis and subsequent inclusion in the appropriate CPG. Aspects such as criteria for inclusion and exclusion of patients in this CPG, treatment duration and monitoring, regular evaluation of the doses prescribed and dispensed, adequacy of drug therapy, and post-treatment follow-up should be observed. Treatment with danazol or GnRH analogues will only be prescribed if patients are diagnosed according to the criteria listed under ‘Diagnosis’ and ‘Inclusion Criteria’ and if patients are unresponsive to previous treatment with OC or progestagens, as established and reported in writing by a physician. 12 INFORMED CONSENT AND LIABILITY FORM It is a legal requirement that patients or their legal guardians be informed of the potential risks, benefits, and adverse effects associated with the pharmacological treatment recommended in this guideline. Informed consent should be obtained with the appropriate form when prescribing drugs included in the Specialized Program for Pharmaceutical Assistance. 13 REFERENCES
1. European Society for Human Reproduction and Embryology (ESHRE). The ESHRE Guideline for the Diagnosis and Treatment of Endometriosis [Internet]. Grimbergen: ESHRE; [updated 2007 Jun 30; cited 2009 Oct 9]. Available from: http://guidelines.endometriosis.org. 2. Olive DL, Schwartz LB. Endometriosis. N Engl J Med. 1993;328(24):1759-69. 3. Gruppo Italiano per lo Studio dell’Endometriosi. Relationship between stage, site and morphological characteristics of pelvic endometriosis and pain. Hum Reprod. 2001;16(12):2668-71. 4. Olive DL, Pritts EA. Treatment of endometriosis. N Engl J Med. 2001;345(4):266-75. 5. Moghissi KS. Medical treatment of endometriosis. Clin Obstet Gynecol. 1999;42(3):620-32. 6. Schenken RS. Pathogenesis, clinical features, and diagnosis of endometriosis [Internet]. Waltham (MA):UpTo Date; 2009 [cited 2010 May17]. Available from:http://www.uptodate.com/patients content/topic.do?topicKey=~ZtfKKr4dLaTYds/&selectedTitle=1~150. 7. Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447):1789-99. 8. Fauconnier A, Chapron C. Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications. Hum Reprod Update. 2005;11(6):595-606. Epub 2005 Sep 19. 9. Farquhar C. Endometriosis. Clin Evid. 2002;(7):1654-62. 10. Revised American Fertility Society classification of endometriosis: 1985. Fertil Steril. 1985;43(3):351-2. 11. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67(5):817-21. 12. Berkley KJ, Rapkin AJ, Papka RE. The pains of endometriosis. Science. 2005;308(5728):1587-9. 13. Chapron C, Fauconnier A, Dubuisson JB, Barakat H, Vieira M, Bréart G. Deep infiltrating endometriosis: relation between severity of dysmenorrhoea and extent of disease. Hum Reprod. 2003;18(4):760-6. 14. Martin DC, Hubert GD, Vander Zwaag R, el Zeky FA. Laparoscopic appearances of peritoneal endometriosis. Fertil Steril. 1989;51(1):63-7. 15. Walter AJ, Hentz JG, Magtibay PM, Cornella JL, Magrina JF. Endometriosis: correlation between histologic and visual findings at laparoscopy. Am J Obstet Gynecol. 2001;184(7):1407-13. 16. Parazzini F, Fedele L, Busacca M, Falsetti L, Pellegrini S, Venturini PL, et al. Postsurgical medical treatment of advanced endometriosis: results of a randomized clinical trial. Am J Obstet Gynecol. 1994;171(5):1205-7. 17. Vercellini P, Crosignani PG, Fadini R, Radici E, Belloni C, Sismondi P. A gonadotrophin-releasing hormone agonist compared with expectant management after conservative surgery for symptomatic endometriosis. Br J Obstet Gynaecol. 1999;106(7):672-7. 18. Marcoux S, Maheux R, Bérubé S. Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis. N Engl J Med. 1997;337(4):217-22. 19. Gambone JC, Mittman BS, Munro MG, Scialli AR, Winkel CA; Chronic Pelvic Pain/Endometriosis Working Group. Consensus statement for the management of chronic pelvic pain and endometriosis: proceedings of an expert-panel consensus process. Fertil Steril. 2002;78(5):961-72.

20. Schenken RS. Overview of the treatment of endometriosis [Internet]. Waltham (MA): UpToDate; 2009 [cited 2010 May 17]. Available from: http://www.uptodate.com/patients/content/topic.do?topicKey=~ie7xLcpH_ GU9HJi&selectedTitle=1~150. 21. Harada T, Momoeda M, Taketani Y, Hoshiai H, Terakawa N. Low-dose oral contraceptive pill for dysmenorrhea associated with endometriosis: a placebo-controlled, double-blind, randomized trial. Fertil Steril. 2008;90(5):1583-8. Epub 2007 Dec 27. 22. Sesti F, Pietropolli A, Capozzolo T, Broccoli P, Pierangeli S, Bollea MR, et al. Hormonal suppression treatment or dietary therapy versus placebo in the control of painful symptoms after conservative surgery for endometriosis stage III-IV. A randomized comparative trial. Fertil Steril. 2007;88(6):1541-7. Epub 2007 Apr 16. 23. Vercellini P, Trespidi L, Colombo A, Vendola N, Marchini M, Crosignani PG. A gonadotropin-releasing hormone agonist versus a low-dose oral contraceptive for pelvic pain associated with endometriosis. Fertil Steril. 1993;60(1):75-9. 24. Parazzini F, Di Cintio E, Chatenoud L, Moroni S, Ardovino I, Struzziero E, et al. Estroprogestin vs. gonadotrophin agonists plus estroprogestin in the treatment of endometriosis-related pelvic pain: a randomized trial. Gruppo Italiano per lo Studio dell’Endometriosi. Eur J Obstet Gynecol Reprod Biol. 2000;88(1):11-4. 25. Reddy S, Rock JA. Treatment of endometriosis. Clin Obstet Gynecol. 1998;41(2):387-92. 26. Selak V, Farquhar C, Prentice A, Singla A. Danazol for pelvic pain associated with endometriosis. Cochrane Database Syst Rev. 2007;(4):CD000068. 27. Miller JD, Shaw RW, Casper RF, Rock JA, Thomas EJ, Dmowski WP, et al. Historical prospective cohort study of the recurrence of pain after discontinuation of treatment with danazol or a gonadotropin-releasing hormone agonist. Fertil Steril. 1998;70(2):293-6. 28. Wong AY, Tang L. An open and randomized study comparing the efficacy of standard danazol and modified triptorelin regimens for postoperative disease management of moderate to severe endometriosis. Fertil Steril. 2004;81(6):1522-7. 29. Prentice A, Deary AJ, Bland E. Progestagens and anti-progestagens for pain associated with endometriosis. Cochrane Database Syst Rev. 2000;(2):CD002122. 30. Vercellini P, De Giorgi O, Oldani S, Cortesi I, Panazza S, Crosignani PG. Depot medroxyprogesterone acetate versus an oral contraceptive combined with very-low-dose danazol for long-term treatment of pelvic pain associated with endometriosis. Am J Obstet Gynecol. 1996;175(2):396-401. 31. Schlaff WD, Carson SA, Luciano A, Ross D, Bergqvist A. Subcutaneous injection of depot medroxyprogesterone acetate compared with leuprolide acetate in the treatment of endometriosis-associated pain. Fertil Steril. 2006;85(2):314-25. 32. Crosignani PG, Luciano A, Ray A, Bergqvist A. Subcutaneous depot medroxyprogesterone acetate versus leuprolide acetate in the treatment of endometriosis-associated pain. Hum Reprod. 2006;21(1):248-56. Epub 2005 Sep 21. 33. Razzi S, Luisi S, Ferretti C, Calonaci F, Gabbanini M, Mazzini M, et al. Use of a progestogen only preparation containing desogestrel in the treatment of recurrent pelvic pain after conservative surgery for endometriosis. Eur J Obstet Gynecol Reprod Biol. 2007;135(2):188-90. Epub 2006 Sep 11. 34. Vercellini P, Pietropaolo G, De Giorgi O, Pasin R, Chiodini A, Crosignani PG. Treatment of symptomatic rectovaginal endometriosis with an estrogen-progestogen combination versus low-dose norethindrone acetate. Fertil Steril. 2005;84(5):1375-87. 35. Moghissi KS. A clinician’s guide to the use of gonadotropin-releasing hormone analogues in women. Medscape Womens Health. 2000;5(1):5. 36. Prentice A, Deary AJ, Goldbeck-Wood S, Farquhar C, Smith SK. Gonadotrophin-releasing hormone analogues for pain associated with endometriosis. Cochrane Database Syst Rev. 2000;(2):CD000346. 37. Miller JD. Quantification of endometriosis-associated pain and quality of life during the stimulatory phase of gonadotropin-releasing hormone agonist therapy: a double-blind, randomized, placebo-controlled trial. Am J Obstet Gynecol. 2000;182(6):1483-8. 38. Dlugi AM, Miller JD, Knittle J. Lupron depot (leuprolide acetate for depot suspension) in the treatment of endometriosis: a randomized, placebo-controlled, double-blind study. Lupron Study Group. Fertil Steril. 1990;54(3):419-27. 39. Ling FW. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Pelvic Pain Study Group. Obstet Gynecol. 1999;93(1):51-8. 40. Agarwal SK, Hamrang C, Henzl MR, Judd HL. Nafarelin vs. leuprolide acetate depot for endometriosis. Changes in bone mineral density and vasomotor symptoms. Nafarelin Study Group. J Reprod Med. 1997;42(7):413-23. 41. Zhao SZ, Kellerman LA, Francisco CA, Wong JM. Impact of nafarelin and leuprolide for endometriosis on quality of life and subjective clinical measures. J Reprod Med. 1999;44(12):1000-6. 42. Busacca M, Somigliana E, Bianchi S, De Marinis S, Calia C, Candiani M, et al. Post-operative GnRH analogue treatment after conservative surgery for symptomatic endometriosis stage III-IV: a randomized controlled trial. Hum Reprod. 2001;16(11):2399-402.

43. Rotondi M, Labriola D, Rotondi M, Ammaturo FP, Amato G, Carella C, et al. Depot leuprorelin acetate versus danazol in the treatment of infertile women with symptomatic endometriosis. Eur J Gynaecol Oncol. 2002;23(6):523-6. 44. Goserelin depot versus danazol in the treatment of endometriosis the Australian/New Zealand experience. Aust N Z J Obstet Gynaecol. 1996;36(1):55-60. 45. Shaw RW. An open randomized comparative study of the effect of goserelin depot and danazol in the treatment of endometriosis. Zoladex Endometriosis Study Team. Fertil Steril. 1992;58(2):265-72. 46. Rock JA, Truglia JA, Caplan RJ. Zoladex (goserelin acetate implant) in the treatment of endometriosis: a randomized comparison with danazol. The Zoladex Endometriosis Study Group. Obstet Gynecol. 1993;82(2):198-205. 47. Bergqvist A, Bergh T, Hogström L, Mattsson S, Nordenskjöld F, Rasmussen C. Effects of triptorelin versus placebo on the symptoms of endometriosis. Fertil Steril. 1998;69(4):702-8. 48. Loverro G, Carriero C, Rossi AC, Putignano G, Nicolardi V, Selvaggi L. A randomized study comparing triptorelin or expectant management following conservative laparoscopic surgery for symptomatic stage III-IV endometriosis. Eur J Obstet Gynecol Reprod Biol. 2008;136(2):194-8. Epub 2006 Dec 18. 49. Cheung TK, Lo KW, Lam CW, Lau W, Lam PK. A crossover study of triptorelin and leuprorelin acetate. Fertil Steril. 2000;74(2):299-305. 50. Bergqvist A; SCANDET Group. A comparative study of the acceptability and effect of goserelin and nafarelin on endometriosis. Gynecol Endocrinol. 2000;14(6):425-32. 51. Kiilholma P, Tuimala R, Kivinen S, Korhonen M, Hagman E. Comparison of the gonadotropin-releasing hormone agonist goserelin acetate alone versus goserelin combined with estrogen-progestogen add-back therapy in the treatment of endometriosis. Fertil Steril. 1995;64(5):903-8. 52. Bergqvist A, Theorell T. Changes in quality of life after hormonal treatment of endometriosis. Acta Obstet Gynecol Scand. 2001;80(7):628-37. 53. Hornstein MD, Surrey ES, Weisberg GW, Casino LA. Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month study. Lupron Add-Back Study Group. Obstet Gynecol. 1998;91(1):16-24. 54. Mäkäräinen L, Rönnberg L, Kauppila A. Medroxyprogesterone acetate supplementation diminishes the hypoestrogenic side effects of gonadotropin-releasing hormone agonist without changing its efficacy in endometriosis. Fertil Steril. 1996;65(1):29-34. 55. Moghissi KS, Schlaff WD, Olive DL, Skinner MA, Yin H. Goserelin acetate (Zoladex) with or without hormone replacement therapy for the treatment of endometriosis. Fertil Steril. 1998;69(6):1056-62. 56. Taskin O, Yalcinoglu AI, Kucuk S, Uryan I, Buhur A, Burak F. Effectiveness of tibolone on hypoestrogenic symptoms induced by goserelin treatment in patients with endometriosis. Fertil Steril. 1997;67(1):40-5. 57. Cheung TH, Lo KW, Yim SF, Lam C, Lau E, Haines C. Dose effects of progesterone in add-back therapy during GnRHa treatment. J Reprod Med. 2005;50(1):35-40. 58. Surrey ES, Hornstein MD. Prolonged GnRH agonist and add-back therapy for symptomatic endometriosis: long-term follow-up. Obstet Gynecol. 2002;99(5 Pt 1):709-19. 59. Gnoth CH, Gödtke K, Freundl G, Godehardt E, Kienle E. Effects of add-back therapy on bone mineral density and pyridinium crosslinks in patients with endometriosis treated with gonadotropin-releasing hormone agonists. Gynecol Obstet Invest. 1999;47(1):37-41. 60. Zupi E, Marconi D, Sbracia M, Zullo F, De Vivo B, Exacustos C, et al. Add-back therapy in the treatment of endometriosis-associated pain. Fertil Steril. 2004;82(5):1303-8. 61. Sagsveen M, Farmer JE, Prentice A, Breeze A. Gonadotrophin-releasing hormone analogues for endometriosis: bone mineral density. Cochrane Database Syst Rev. 2003;(4):CD001297. 62. Fernandez H, Lucas C, Hedon B, Meyer JL, Mayenga JM, Roux C. One year comparison between two add-back therapies in patients treated with a GnRH agonist for symptomatic endometriosis: a randomized double-blind trial. Hum Reprod. 2004;19(6):1465-71. Epub 2004 Apr 22. 63. Franke HR, van de Weijer PH, Pennings TM, van der Mooren MJ. Gonadotropin-releasing hormone agonist plus “add-back” hormone replacement therapy for treatment of endometriosis: a prospective, randomized, placebo-controlled, double-blind trial. Fertil Steril. 2000;74(3):534-9. 64. Pierce SJ, Gazvani MR, Farquharson RG. Long-term use of gonadotropin-releasing hormone analogs and hormone replacement therapy in the management of endometriosis: a randomized trial with a 6-year follow-up. Fertil Steril. 2000;74(5):964-8. 65. Hurst BS, Gardner SC, Tucker KE, Awoniyi CA, Schlaff WD. Delayed oral estradiol combined with leuprolide increases endometriosis-related pain. JSLS. 2000;4(2):97-101. 66. Abou-Setta AM, Al-Inany HG, Farquhar CM. Levonorgestrel-releasing intrauterine device (LNG-IUD) for symptomatic endometriosis following surgery. Cochrane Database Syst Rev. 2006;(4):CD005072. 67. Petta CA, Ferriani RA, Abrao MS, Hassan D, Rosa E Silva JC, Podgaec S, et al. Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis. Hum Reprod. 2005;20(7):1993-8. Epub 2005 Mar 24.

68. Vercellini P, Frontino G, De Giorgi O, Aimi G, Zaina B, Crosignani PG. Comparison of a levonorgestrelreleasing intrauterine device versus expectant management after conservative surgery for symptomatic endometriosis: a pilot study. Fertil Steril. 2003;80(2):305-9. 69. Fedele L, Bianchi S, Zanconato G, Portuese A, Raffaelli R. Use of a levonorgestrel-releasing intrauterine device in the treatment of rectovaginal endometriosis. Fertil Steril. 2001;75(3):485-8. 70. Kamencic H, Thiel JA. Pentoxifylline after conservative surgery for endometriosis: a randomized, controlled trial. J Minim Invasive Gynecol. 2008;15(1):62-6. 71. Lv D, Song H, Li Y, Clarke J, Shi G. Pentoxifylline versus medical therapies for subfertile women with endometriosis. Cochrane Database Syst Rev. 2009;(3):CD007677. 72. Harada T, Momoeda M, Taketani Y, Aso T, Fukunaga M, Hagino H, et al. Dienogest is as effective as intranasal buserelin acetate for the relief of pain symptoms associated with endometriosis – a randomized, double-blind, multicenter, controlled trial. Fertil Steril. 2009;91(3):675-81. 73. Cosson M, Querleu D, Donnez J, Madelenat P, Konincks P, Audebert A, et al. Dienogest is as effective as triptorelin in the treatment of endometriosis after laparoscopic surgery: results of a prospective, multicenter, randomized study. Fertil Steril. 2002;77(4):684-92. 74. Soysal S, Soysal ME, Ozer S, Gul N, Gezgin T. The effects of post-surgical administration of goserelin plus anastrozole compared to goserelin alone in patients with severe endometriosis: a prospective randomized trial. Hum Reprod. 2004;19(1):160-7. 75. Regidor PA, Regidor M, Schmidt M, Ruwe B, Lübben G, Förtig P, et al. Prospective randomized study comparing the GnRH-agonist leuprorelin acetate and the gestagen lynestrenol in the treatment of severe endometriosis. Gynecol Endocrinol. 2001;15(3):202-9. 76. Flower A, Liu JP, Chen S, Lewith G, Little P. Chinese herbal medicine for endometriosis. Cochrane Database Syst Rev. 2009;(3):CD006568. 77. Yang DX, Ma WG, Qu F, Ma BZ. Comparative study on the efficacy of Yiweining and Gestrinone for postoperational treatment of stage III endometriosis. Chin J Integr Med. 2006;12(3):218-20. 78. Koninckx PR, Craessaerts M, Timmerman D, Cornillie F, Kennedy S. Anti-TNF-alpha treatment for deep endometriosis-associated pain: a randomized placebo-controlled trial. Hum Reprod. 2008;23(9):2017-23. Epub 2008 Jun 12. 79. Walch K, Unfried G, Huber J, Kurz C, van Trotsenburg M, Pernicka E, et al. Implanon versus medroxyprogesterone acetate: effects on pain scores in patients with symptomatic endometriosis – a pilot study. Contraception. 2009;79(1):29-34. Epub 2008 Sep 25. 80. Stratton P, Sinaii N, Segars J, Koziol D, Wesley R, Zimmer C, et al. Return of chronic pelvic pain from endometriosis after raloxifene treatment: a randomized controlled trial. Obstet Gynecol. 2008;111(1):88-96. 81. Jacobson TZ, Barlow DH, Garry R, Koninckx P. Laparoscopic surgery for pelvic pain associated with endometriosis. Cochrane Database Syst Rev. 2001;(4):CD001300. 82. Sutton CJ, Pooley AS, Ewen SP, Haines P. Follow-up report on a randomized controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal to moderate endometriosis. Fertil Steril. 1997;68(6):1070-4. 83. Parazzini F. Ablation of lesions or no treatment in minimal-mild endometriosis in infertile women: a randomized trial. Gruppo Italiano per lo Studio dell‘Endometriosi. Hum Reprod. 1999;14(5):1332-4. 84. Morgante G, Ditto A, La Marca A, De Leo V. Low-dose danazol after combined surgical and medical therapy reduces the incidence of pelvic pain in women with moderate and severe endometriosis. Hum Reprod. 1999;14(9):2371-4. 85. Bianchi S, Busacca M, Agnoli B, Candiani M, Calia C, Vignali M. Effects of 3 month therapy with danazol after laparoscopic surgery for stage III/IV endometriosis: a randomized study. Hum Reprod. 1999;14(5):1335-7. 86. Muzii L, Marana R, Caruana P, Catalano GF, Margutti F, Panici PB. Postoperative administration of monophasic combined oral contraceptives after laparoscopic treatment of ovarian endometriomas: a prospective, randomized trial. Am J Obstet Gynecol. 2000;183(3):588-92. 87. Hornstein MD, Hemmings R, Yuzpe AA, Heinrichs WL. Use of nafarelin versus placebo after reductive laparoscopic surgery for endometriosis. Fertil Steril. 1997;68(5):860-4. 88. Yap C, Furness S, Farquhar C. Pre and post operative medical therapy for endometriosis surgery. Cochrane Database Syst Rev. 2004;(3):CD003678. 89. Henzl MR, Kwei L. Efficacy and safety of nafarelin in the treatment of endometriosis. Am J Obstet Gynecol. 1990;162(2):570-4. 90. Shaw RW. Nafarelin in the treatment of pelvic pain caused by endometriosis. Am J Obstet Gynecol. 1990;162(2):574-6

Informed Consent and Liability Form Danazol, Goserelin, Leuprorelin, and Triptorelin
I, ____________________________________________________ (name of patient), declare that I have been clearly informed of the benefits, risks, contraindications, and major adverse effects associated with the use of danazol, goserelin, leuprorelin, and triptorelin, indicated for the treatment of endometriosis. The medical terms have been explained and all my questions were answered by the physician, Dr. _______________________________________________________ (name of the prescribing physician). Therefore, I declare that I have been clearly informed that the drug that I will receive may result in the following improvements: • pain relief; • reduction of endometrial nodules. I have also been clearly informed of the following contraindications, potential adverse effects, and risks of using this drug: • contraindicated in pregnancy or in women planning to become pregnant; • contraindicated in women who are breastfeeding; • adverse effects of danazol – common: menstrual disorders, weight gain, hot flushes; less common: swelling, dark urine, fatigue, drowsiness, acne, oily hair and skin, hair loss, voice change, enlarged clitoris; rare: adenoma, cataracts, eosinophilia, hepatic dysfunction, pancreatitis, increased intracranial pressure manifested as headache, nausea and vomiting, leukocytosis, skin rash, Stevens-Johnson syndrome, thrombocytopenia, and photosensitivity; • adverse effects of goserelin – common: hot flushes, menstrual disorders; less common: blurred vision, decreased libido, fatigue, headache, nausea, vomiting, difficulty sleeping, weight gain, vaginitis; rare: angina or myocardial infarction, and thrombophlebitis; • adverse effects of leuprorelin – common: hot flushes, diarrhea, menstrual disorders; less common: cardiac arrhythmias, palpitation; rare: dry mouth, thirst, appetite changes, anxiety, nausea, vomiting, personality disorders, memory disorders, decreased libido, weight gain, difficulty sleeping, delirium, body aches, hair loss, and eye problems; • adverse effects of triptorelin – common: hot flushes, bone pain, injection site pain, hypertension, headache; less common: leg pain, fatigue, vomiting, and insomnia; rare: dizziness, diarrhea, urinary retention, urinary tract infection, anemia, and pruritus; • contraindicated in cases of hypersensitivity (allergy) to the drug; • the risk of adverse effects increases with overdose. I am aware that this drug can be used only by myself, and I commit myself to returning the drug if I do not want or cannot use it, or if treatment is discontinued. I am also aware that I will continue to receive medical care even if I quit using the drug. I authorize the Ministry of Health and the Departments of Health Care to make use of information concerning my treatment, provided that my privacy is protected. My treatment consists of the following drug(s): ! danazol ! goserelin ! leuprorelin ! triptorelin Place: Date: Patient's name: National Health Card: Name of legal guardian: Identification document of legal guardian: _____________________________________ Signature of patient or legal guardian License number:

Physician in charge:

State:

___________________________ Signature and stamp of physician Date: ___________________ Note: This Form is required when requesting drugs included in the Specialized Program for Pharmaceutical Assistance and should be completed in duplicate: one copy should be filed in the pharmacy, the other delivered to the user or their legal guardian.

Flow Chart of Medical Treatment Endometriosis
[arquivo anexo]

Dispensing Flow Chart: Danazol, Goserelin, Leuprorelin, and Triptorelin Endometriosis
[arquivo anexo]

Drug Therapy Registration Form Endometriosis 1 Patient Data
Name: _________________________________________________________________________ National Health Card: ___________________________ ID: _______________________________ Name of caregiver: _______________________________________________________________ National Health Card: ________________________________ ID: __________________________ Sex: ! Male ! Female DOB: ___ / ___ / ____ Age: ____ Weight: _______ Height: _____________ Address: _______________________________________________________________________ Telephones: _____________________________________________________________________ Primary physician: _________________________________________ License number: ________ Telephones: _____________________________________________________________________

2 Drug Therapy Evaluation
2.1 What treatments have been previously employed to treat endometriosis? When? _______________________________________________________________________________ _______________________________________________________________________________ _______________________________________________________________________________ 2.2 Patient has other diagnosed diseases: ! no ! yes " Please describe: __________________________________________________________ 2.3 Patient uses other drugs*: ! no ! yes " Please describe: Trade name Generic name Total dose/day and route Prescription ! no ! yes ! no ! yes ! no ! yes ! no ! yes * Concomitant use of danazol and carbamazepine may result in carbamazepine toxicity. 2.4 Patient has had allergic reactions to drugs: ! no ! yes " What types of reactions? To what drugs? _______________________________________ Start date

3 Treatment Monitoring
Laboratory Tests for Danazol Therapy Baseline Scheduled date Date Platelets 6th month 12th month

3.1 Patient presented abnormal platelet count: no " Dispense drug yes " Dispense drug and refer patient to the primary physician 3.2 Patient presented symptoms suggestive of adverse events (fill in the Adverse Event Record): no " Dispense drug yes " Go to question 3.3 3.3 Patient needs to be assessed by the primary physician regarding the adverse event: no " Dispense drug

yes " Dispense drug and refer patient to the primary physician

Adverse Event Record
Date of interview Adverse event *Intensity #Management strategy

Main adverse reactions previously reported: Danazol: menstrual disorders, weight gain, hot flushes, swelling, dark urine, fatigue, drowsiness, acne, oily hair and skin, alopecia, voice change, enlarged clitoris, headache, nausea and vomiting, skin rash, photosensitivity Goserelin: hot flushes, menstrual disorders, blurred vision, decreased libido, fatigue, headache, nausea, vomiting, insomnia, weight gain, vaginitis, chest pain, leg pain Leuprorelin: hot flushes, menstrual disorders, cardiac arrhythmias, palpitation, dry mouth, thirst, appetite changes, anxiety, nausea, vomiting, personality disorders, memory disorders, decreased libido, weight gain, insomnia, delirium, myalgia, alopecia, and eye problems Triptorelin: hot flushes, bone pain, injection site pain, hypertension, headache, leg pain, fatigue, vomiting, insomnia, dizziness, diarrhea, urinary retention, urinary tract infection, anemia, pruritus * Intensity: (Mi) mild; (Mo) moderate; (S) severe # Management strategy: (P) pharmacological (indication of over-the-counter drugs); (NP) nonpharmacological (dietary practices, water intake, exercise, others); (RP) referral to the primary physician; (OT) other (please describe)

Dispensing Record
1st month Date Trade name Batch/Expiration date Prescribed dose Amount dispensed Next dispensation date (medical opinion required: yes/no) Pharmacist in charge/license number Notes 7th month Date Trade name Batch/Expiration date Prescribed dose Amount dispensed Next dispensation date (medical opinion required: yes/no) Pharmacist in charge/license number 8th month 9th month 10th month 11th month 12th month 2nd month 3rd month 4th month 5th month 6th month

Notes * GnRH analogues may be dispensed every 3 months (for 3-month drug formulations).

Patient Orientation Guide Danazol, Goserelin, Leuprorelin, and Triptorelin This guide presents information on the drug that you are receiving free from the Brazilian Public Health System. By following these guidelines, you have more chances of benefiting from treatment. This drug is used in the treatment of endometriosis. 1 Disease
• The inner layer of tissue lining the uterus that bleeds during menstruation is known as the endometrium. Endometriosis is a disease in which this tissue grows outside the uterus, resulting in inflammation. The most common symptom is pain in the lower abdomen.

2 Drug
• This drug does not provide permanent cure, but it improves pain and provides women with a chance to get pregnant.

3 Drug storage
Danazol: • Keep the drug away from heat, that is, avoid places where variations in temperature are frequent (e.g. kitchen and bathroom). Keep capsules in the original package. Goserelin, leuprorelin, triptorelin: • Store the drug in places at a temperature below 25° C.

4 Drug administration
Danazol: • Swallow the capsules whole (without chewing or opening them), with a glass of water. Try to take the capsules always on the time established at the beginning of treatment. • Take the exact number of capsules prescribed by the doctor. Goserelin, leuprorelin, triptorelin: • The drug should be administered by subcutaneous or intramuscular injections. • If you are having the injections at home, basic rules for drug injection should be followed. In this case, consult the doctor or a nursing professional for further guidance. Do not prepare or inject the drug until you are well trained. • Consult the pharmacist on how to properly dispose syringes and needles after use.

5 Unpleasant reactions
Danazol: • Despite the benefits of this drug, a few unpleasant reactions may occur, such as nausea, vomiting, diarrhea, headache, nervousness, confusion, weakness, seizures, weight gain, swelling, altered taste, increased blood pressure, onset of “pimples”, hair growth, and deepening of the voice. Goserelin, leuprorelin, triptorelin: • Despite the benefits of this drug, a few unpleasant reactions may occur, such as pain or swelling at the injection site, hot flushes, bone pain, skin allergies, headache, nausea, vomiting, and hair loss. • If any of these or other signs/symptoms occur, report them to the doctor or pharmacist. • Further information on adverse reactions can be found in the Informed Consent and Liability Form, a document signed by you or your legal guardian and by the doctor.

6 Use of other drugs

• Do not use other drugs without the doctor's consent or without obtaining guidance from a health professional.

7 Other important information
• Goserelin, leuprorelin, and triptorelin may be used once a month or every 3 months. Therefore, check the drug formulation that you received to avoid using the drug at intervals different than those recommended. In case of doubt, consult a health professional (doctor, nurse, or pharmacist of the Brazilian Public Health System).

8 Laboratory tests
• The performance of laboratory tests ensures an accurate evaluation of the effect of the drug on your body. In some cases, dose adjustments or even discontinuation of treatment may be necessary.

9 To continue receiving the drug
• Return to the pharmacy every month, with the following documents: $ Current prescription $ National Health Card or ID ! Tests for danazol: platelet count every 4-6 months

10 In case of doubt
• If you have any questions that have not been addressed in this guide, consult the doctor or pharmacist of the Brazilian Public Health System before taking any action.

11 Additional information
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If, for any reason, you do not use the drug(s) received, return it to the pharmacy of the Brazilian Public Health System.