ESHRE guideline for the diagnosis and treatment of endometriosis.
Topic: Hormone Therapy

The objective was to develop recommendations for the diagnosis and treatment of endometriosis and its associated symptoms. A working group was convened comprised of practising gynaecologists and experts in evidence-based medicine from Europe, as well as an endometriosis self-help group representative. After reviewing existing evidence-based guidelines and systematic reviews, the expert panel met on three occasions for a day during which the guideline was developed and refined. Recommendations based solely on the clinical experience of the panel were avoided as much as possible. The entire ESHRE Special Interest Group for Endometriosis and Endometrium was given the opportunity to comment on the draft guideline, after which it was available for comment on the ESHRE website for 3 months. The working group then ratified the guideline by unanimous or near-unanimous voting; finally, it was approved by the ESHRE Executive Committee. The guideline will be updated regularly, and will be made available at http://www.endometriosis.org/guidelines.html with hyperlinks to the supporting evidence, and the relevant references and abstracts. For women presenting with symptoms suggestive of endometriosis, a definitive diagnosis of most forms of endometriosis requires visual inspection of the pelvis at laparoscopy as the 'gold standard' investigation. However, pain symptoms suggestive of the disease can be treated without a definitive diagnosis using a therapeutic trial of a hormonal drug to reduce menstrual flow. In women with laparoscopically confirmed disease, suppression of ovarian function for 6 months reduces endometriosis-associated pain; all hormonal drugs studied are equally effective although their side-effects and cost profiles differ. Ablation of endometriotic lesions reduces endometriosis-associated pain and the smallest effect is seen in patients with minimal disease; there is no evidence that also performing laparoscopic uterine nerve ablation (LUNA) is necessary. In minimal-mild endometriosis, suppression of ovarian function to improve fertility is not effective, but ablation of endometriotic lesions plus adhesiolysis is effective compared to diagnostic laparoscopy alone. There is insufficient evidence available to determine whether surgical excision of moderate-severe endometriosis enhances pregnancy rates. IVF is appropriate treatment especially if there are coexisting causes of infertility and/or other treatments have failed, but IVF pregnancy rates are lower in women with endometriosis than in those with tubal infertility. The management of severe/deeply infiltrating endometriosis is complex and referral to a centre with the necessary expertise is strongly recommended. Patient self-help groups can provide invaluable counselling, support and advice.

PICO
Population: Women presenting with symptoms suggestive of endometriosis
Intervention: Therapeutic trial of a hormonal drug to reduce menstrual flow
Comparison: Definitive diagnosis of most forms of endometriosis through visual inspection of the pelvis at laparoscopy
Outcomes: Reduction of endometriosis-associated pain without a definitive diagnosis

Included studies:
title: Effects of 3 month therapy with danazol after laparoscopic surgery for stage III/IV endometriosis: a randomized study.
abstract: The effect of treatment with danazol was evaluated with respect to expectant management after laparoscopic conservative surgery. All patients conservatively operated at laparoscopy for stage III-IV endometriosis from July 1994 to October 1996 were requested to enter the study. Patients who underwent surgery for recurrent endometriosis were excluded from the study, as well as patients who had taken hormonal therapies before laparoscopy. Informed consent was obtained from 77 women who were randomized after surgery to treatment with danazol 600 mg daily for 3 months (n = 36) or to expectant management (n = 41). All patients were regularly followed up every 6 months for evaluation of fertility, recurrence of pain symptoms and disease. During the follow-up, six (55%) of the 11 infertile women allocated to danazol and eight (50%) of the 16 given no treatment became pregnant (not significant). Moderate/severe pelvic pain recurred during follow-up in seven (23%) of the 31 women with pelvic pain allocated to the danazol group and nine (31%) of the 29 allocated to no treatment; the respective cumulative pain recurrence rates at 12 months were 26 and 34% (log rank test, not significant). Three women (8.3%) treated with danazol and six (15%) who received no treatment had disease recurrence as demonstrated by gynaecological examination and/or pelvic ultrasonography (not significant). Our results do not demonstrate a significant advantage of 3 month danazol therapy after laparoscopic surgery for stage III-IV endometriosis with respect to postoperative expectant management.
title: Postoperative administration of monophasic combined oral contraceptives after laparoscopic treatment of ovarian endometriomas: a prospective, randomized trial.
abstract: We sought to evaluate the efficacy of postoperative administration of monophasic, combined, low-dose oral contraceptives on endometrioma recurrence and on persistence-recurrence of associated pain symptoms after laparoscopic treatment of moderate-to-severe endometriosis.
title: Deep infiltrating endometriosis: relation between severity of dysmenorrhoea and extent of disease.
abstract: Little is known about the precise nature of the relationship between dysmenorrhoea (DM) and endometriosis. Our aim was to evaluate the relationship between the severity of DM in women with posterior deep infiltrating endometriosis (DIE) and indicators of the extent of their disease.
title: A gonadotrophin-releasing hormone agonist compared with expectant management after conservative surgery for symptomatic endometriosis.
abstract: To ascertain whether the frequency of pelvic pain recurrence is reduced and time to symptoms recurrence is prolonged in women with symptomatic endometriosis undergoing conservative surgery and post-operative hormonal therapy compared with women treated with surgery only. Pregnancy rates and time to conception in women wanting children were also evaluated.
title: Placebo-controlled comparison of danazol and high-dose medroxyprogesterone acetate in the treatment of endometriosis after conservative surgery.
abstract: To evaluate the clinical value of postoperative hormone therapy in endometriosis, 60 patients with advanced disease were randomized to receive in a double-blind study danazol (200 mg, 3 times daily), medroxyprogesterone acetate (MPA) (100 mg daily) or placebo post-operatively for 6 months. Treatment efficacy was evaluated clinically and at laparoscopy 6 months after medication. In relation to placebo, danazol and high-dose MPA treatments, which did not differ from each other in efficacy, significantly alleviated pelvic pain. In addition, the peritoneal endometriosis lesions found at 6-months laparoscopy were significantly smaller in the MPA and danazol groups than in the placebo group. Breakthrough bleeding, weight gain and acne complicated danazol treatment but only breakthrough bleeding complicated MPA treatment. These data suggest that postoperative treatment of advanced endometriosis with high-dose MPA or danazol is clinically beneficial.
title: Incidence of symptom recurrence after hysterectomy for endometriosis.
abstract: To determine the relative risk of symptom recurrence and/or reoperation after hysterectomy with ovarian preservation for the treatment of endometriosis.
title: The effects and effectiveness of laparoscopic excision of endometriosis: a prospective study with 2-5 year follow-up.
abstract: This study investigates the outcomes for women up to 5 years after laparoscopic excision of endometriosis.
title: Ablation of lesions or no treatment in minimal-mild endometriosis in infertile women: a randomized trial. Gruppo Italiano per lo Studio dell'Endometriosi.
abstract: In order to analyse the efficacy of resection/ablation of minimal/mild endometriotic lesions for improving fertility, we conducted a randomized clinical trial. Eligible patients were women aged </=36 years who were trying to conceive and had a laparoscopically confirmed diagnosis of minimal/mild endometriosis (stage I or II of the revised American Fertility Society classification) and otherwise unexplained infertility for >/=2 years. Eligible women were randomly assigned to resection or ablation of visible endometriosis (54 patients) or diagnostic laparoscopy only (47 patients). After laparoscopy women tried to conceive spontaneously for 1 year (follow-up period). A total of five women withdrew from the study: three for personal reasons, and two were lost to follow-up. Considering 51 women in the resection/ablation and 45 in the no-treatment group who ended the follow-up period, 12 (24%) in the resection/ablation group and 13 (29%) in the no treatment group conceived; the difference was not significant. Two spontaneous abortions were observed in the resection/ablation group and three in the no-treatment one. Thus the 1 year birth rate was 10 out of 51 women (19.6%) in the resection/ablation group and 10 out of 45 women (22.2%) in the no-treatment group. In conclusion, the results of this study do not support the hypothesis that ablation of endometriotic lesions markedly improves fertility rates.
title: Increased pregnancy rates after ultralong postoperative therapy with gonadotropin-releasing hormone analogs in patients with endometriosis.
abstract: To examine whether ultralong GnRH analog (GnRH-a) therapy after surgical treatment of endometriosis and before ART influences the pregnancy rate.
title: A levonorgestrel-releasing intrauterine system for the treatment of dysmenorrhea associated with endometriosis: a pilot study.
abstract: To evaluate the efficacy and safety of an intrauterine system releasing 20 microg of levonorgestrel per 24 hours in the long-term treatment of recurrent dysmenorrhea in women already operated on conservatively for endometriosis.
title: Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis.
abstract: Minimal or mild endometriosis is frequently diagnosed in infertile women. It is often treated by resection or ablation of the lesions, but whether this improves fertility has not been established. We carried out a randomized, controlled trial to determine whether laparoscopic surgery enhanced fecundity in infertile women with minimal or mild endometriosis.
title: Use of nafarelin versus placebo after reductive laparoscopic surgery for endometriosis.
abstract: To evaluate the efficacy of the GnRH agonist (GnRH-a) nafarelin compared with placebo administered for 6 months after reductive laparoscopic surgery for symptomatic endometriosis.
title: Randomized clinical trial of two laparoscopic treatments of endometriomas: cystectomy versus drainage and coagulation.
abstract: To assess the efficacy of two laparoscopic methods for the management of endometriomas with regard to pain relief, pregnancy rate, and disease recurrence.
title: Laparoscopic uterosacral ligament resection for dysmenorrhea associated with endometriosis: results of a randomized, controlled trial.
abstract: To evaluate the efficacy of laparoscopic resection of the uterosacral ligaments in women with endometriosis and predominantly midline dysmenorrhea.
title: Prolonged GnRH agonist and add-back therapy for symptomatic endometriosis: long-term follow-up.
abstract: To assess post-treatment effects in endometriosis patients of a 12-month course of GnRH agonist alone or with one of three "add-back" regimens.
title: Recurrence of endometriosis in women with bilateral adnexectomy (with or without total hysterectomy) who received hormone replacement therapy.
abstract: To estimate the risk of recurrence after administration of hormone replacement therapy (HRT) among women who have had endometriosis and who underwent bilateral salpingo-oophorectomy (BSO).
title: Prospective randomized double-blind trial of 3 versus 6 months of nafarelin therapy for endometriosis associated pelvic pain.
abstract: To determine the effectiveness of a 3-month course of nafarelin and, furthermore, to determine the long-term efficacy in patients treated for 3 and 6 months with nafarelin for symptoms associated with endometriosis.
title: Postsurgical medical treatment of advanced endometriosis: results of a randomized clinical trial.
abstract: Our purpose was to investigate the efficacy of postsurgical treatment with nafarelin in women with advanced endometriosis.
title: Diagnosis of deep endometriosis by clinical examination during menstruation and plasma CA-125 concentration.
abstract: To evaluate a clinical examination during menstruation and plasma CA-125 concentrations to diagnose deep endometriosis.
title: Laparoscopic presacral neurolysis for endometriosis-related pelvic pain.
abstract: Some patients with endometriosis are candidates for sympathectomy of the superior hypogastric plexus. The objective of this paper is to describe our technique of laparoscopic presacral neurolysis for sympathectomy and to report 1 year results of the first 15 cases.
title: Correlation between endometriosis and pelvic pain.
abstract: To evaluate the relationship between prevalence and severity of chronic pelvic pain (CPP) and stage, site, and type of endometriosis.
title: Suggestive evidence that pelvic endometriosis is a progressive disease, whereas deeply infiltrating endometriosis is associated with pelvic pain.
abstract: In a 3-year prospective study of 643 consecutive laparoscopies for infertility, pelvic pain, or infertility and pain, the pelvic area, the depth of infiltration, and the volume of endometriotic lesions were evaluated. The incidence, area, and volume of subtle lesions decreased with age, whereas for typical lesions these parameters and the depth of infiltration increased with age. Deeply infiltrating endometriosis was strongly associated with pelvic pain, women with pain having larger and deeper lesions. Because deep endometriosis has little emphasis in the revised American Fertility Society classification and after analyzing the diagnoses made in each class, considerations for a simplifying revision with inclusion of deep lesions are suggested. In conclusion, suggestive evidence is presented to support the concept that endometriosis is a progressive disorder, and it is demonstrated that deep endometriosis is strongly associated with pelvic pain.
title: Prostaglandins and endometriosis.
abstract: To study the production of prostacyclin (PGI2) and thromboxane A2 (TxA2) in endometriosis in vitro, samples of endometriotic tissue taken during operation from 6 women were superfused for 4.5 hours in 95% O2/5% CO2 at 37 degrees C, and the stable metabolites of PGI2 (=6-keto-PGF1 alpha), and TxA2 (=TxB2) were measured by radioimmunoassays from the superfusates. All samples studied produced 6-keto-PGF1 alpha in the range from 0.2 to 10.5 nanograms/gram of dry tissue/minute with a mean of 3.6 ng/g/min during the whole experiment. TxB2 was also released by each sample at rates between 0.2 and 11.9 ng/g/min (mean 2.6 ng/g/min). The production of these prostanoids tended to be greater in the serosal (n = 2) than in the ovarian (n = 4) endometriosis. The addition of indomethacin of 10(-5) - 10(-3) moles/l to the superfusion medium inhibited concentration-dependently the synthesis of these prostanoids. Apart from these in vitro data implying the production of PGs in endometriosis, 18 patients with pelvic endometriosis sustained no relief for their endometriotic symptoms from the treatments with three anti-prostaglandins (acetylsalicylic acid, indomethacin, tolfenamic acid) in a double-blind, placebo-controlled trial.
title: The impact of preoperative gonadotropin-releasing hormone agonist treatment on laparoscopic excision of ovarian endometriotic cysts.
abstract: To compare surgical performance and recurrence rates in patients submitted to laparoscopy for endometrioma excision following GnRH agonist (GnRH-a) treatment versus no preoperative medical treatment.
title: Effect of prolonged gonadotropin-releasing hormone agonist therapy on the outcome of in vitro fertilization-embryo transfer in patients with endometriosis.
abstract: To evaluate the effect of a 3-month course of GnRH agonist administered immediately before IVF-ET in infertile patients with endometriosis.
title: Laparoscopic endometriosis treatment: is it better?
abstract: To assess the hypothesis that pregnancy rates (PRs) after operative laparoscopy (Laparoscopy Group) for endometriosis treatment would be equal to or greater than diagnostic laparoscopy only (No Treatment Group), diagnostic laparoscopy with medical treatment (Medical Treatment Group), and laparotomy (Laparotomy Group).
title: Low-dose danazol after combined surgical and medical therapy reduces the incidence of pelvic pain in women with moderate and severe endometriosis.
abstract: The most effective therapy for endometriosis is a matter for debate. The aim of the present randomized study was to evaluate the efficacy of low doses of danazol on recurrence of pelvic pain in patients with moderate or severe endometriosis, who had undergone laparoscopic surgery and 6 months of gonadotrophin-releasing hormone analogue (GnRHa) therapy. After surgery, 28 patients with moderate or severe endometriosis underwent therapy for 6 months with GnRHa i. m. every 4 weeks. They were then randomized into two groups: group A (14 subjects) was treated with 100 mg/day danazol for 6 months; group B (14 subjects, control) did not receive any type of therapy. After 12 months of treatment, group A had a significantly (P < 0.01) lower pain score than group B. There was no significant difference between the groups in oestrogen concentrations, bone mineral density or side-effects. The results suggest that low-dose danazol therapy reduces recurrence of pelvic pain in patients with moderate or severe endometriosis, treated surgically, and has few or no metabolic side-effects.
title: Prostaglandin biosynthesis inhibitors and endometriosis.
abstract: Prostaglandins (PGs) may be involved in the development of the symptoms of endometriosis. Therefore 18 patients with pelvic endometriosis were treated in placebo controlled double-blind trial with different prostaglandin biosynthesis inhibitors. These drugs were: acetylsalicylic acid (0.5 g x 3) exerting a weak PG-synthetase inhibition, indomethacin (25 mg x 3) inhibiting PG-synthetase, and as a representative of fenamates, tolfenamic acid (200 mg x 3), which both inhibits PG-synthetase and antagonizes PGs at the target level. The therapeutic effect was evaluated using a specific endometriosis score separately during menstruation and in premenstrum. Prostaglandin biosynthesis inhibitors did not alleviate premenstrual complaints better than placebo. During menstruation tolfenamic acid relieved endometriotic symptoms more effectively than placebo while indomethacin and acetylsalicylic acid did not differ from placebo. A drug which inhibit both the synthesis and action of PGs can thus be used in the alleviation of secondary dysmenorrhea due to endometriosis.
title: Naproxen sodium in dysmenorrhea secondary to endometriosis.
abstract: Twenty patients with moderate to very severe painful menstrual periods secondary to endometriosis were treated in a double-blind, four-period, crossover clinical trial with naproxen sodium and placebo. Complete or substantial pain relief was obtained in 83% of the cases of painful menstruation with naproxen sodium and in 41% with placebo (P = .008). Only 5% of the naproxen sodium-treated women needed supplemental analgesics compared with 36% of the placebo-treated women (P = .002). There was a trend towards diminished interference of dysmenorrhea with normal patient activities during naproxen sodium treatment compared with placebo (P = .069). No significant side effects occurred with either treatment. These results indicated that naproxen sodium is efficacious and safe for the treatment of menstrual distress in patients with endometriosis.
title: Randomized controlled trial of superovulation and insemination for infertility associated with minimal or mild endometriosis.
abstract: To evaluate the efficacy of superovulation and IUI versus no treatment for infertility associated with minimal or mild endometriosis.