Intended for healthcare professionals

Clinical Review Extracts from “Clinical Evidence”

Endometriosis

BMJ 2000; 320 doi: https://doi.org/10.1136/bmj.320.7247.1449 (Published 27 May 2000) Cite this as: BMJ 2000;320:1449
  1. Cynthia M Farquhar, associate professor (c.farquhar{at}auckland.ac.nz)
  1. Department of Obstetrics and Gynaecology, National Women's Hospital, Private Bag 92 189, Auckland 3, New Zealand

    Background

    Definition: Endometriosis is characterised by ectopic endometrial tissue, which can cause dysmenorrhoea, dyspareunia, non-cyclical pelvic pain, and subfertility. Diagnosis is made by laparoscopy. Most endometrial deposits are found in the pelvis (ovaries, peritoneum, uterosacral ligaments, pouch of Douglas, and rectovaginal septum). Extrapelvic deposits, including those in the umbilicus and diaphragm, are rare. Endometriomas are cysts of endometriosis within the ovary.

    Interventions

    Interventions In women with pain attributed to endometriosis

    Beneficial:

    Beneficial: Hormonal treatments (danazol, medroxyprogesterone, gestrinone, gonadotrophin releasing hormone analogues)

    Combined ablation of endometrial deposits and uterine nerve

    Postoperative hormonal treatment

    Cystectomy for ovarian endometrioma (better than drainage)

    Likely to be beneficial:

    Likely to be beneficial: Oral contraceptive pill

    Unknown effectiveness:

    Unknown effectiveness: Dydrogesterone

    Laparoscopic uterine nerve ablation (LUNA)

    Laparoscopic ablation of endometrial deposits

    Preoperative hormonal treatment

    In women with subfertility attributed to endometriosis

    Beneficial:

    Beneficial: Laparoscopic ablation or excision of endometrial deposits

    Cystectomy for ovarian endometrioma (better than drainage)

    Unlikely to be beneficial:

    Unlikely to be beneficial: Hormonal treatment

    Postoperative hormonal treatment

    Incidence/prevalence: In asymptomatic women, the prevalence ranges from 2% to 22%, depending on the diagnostic criteria used and the populations studied.14 In women with dysmenorrhoea, the incidence of endometriosis ranges from 40% to 60%, and in women with subfertility it ranges from 20% to 30%.2 5 6 The severity of symptoms and the probability of diagnosis increase with age.7 Incidence peaks at about age 40.8 Symptoms and laparoscopic appearance do not always correlate.9

    Aetiology: The cause is unknown. Risk factors include early menarche and late menopause. Embryonic cells may give rise to deposits in the umbilicus, while retrograde menstruation may deposit endometrial cells in the diaphragm.10 11 Oral contraceptives reduce the risk of endometriosis, and this protective effect persists for up to a year after their discontinuation.9

    Prognosis: We found one small randomised controlled trial (RCT) in which repeat laparoscopy was performed in the women treated with placebo. Over 12 months, endometrial deposits resolved spontaneously in a quarter, deteriorated in nearly half, and were unchanged in the remainder.12

    Aims: To relieve pain (dysmenorrhoea, dyspareunia, and other pelvic pain) and to improve fertility, with minimal adverse effects.

    Outcomes: American Fertility Society scores for size and number of deposits; recurrence rates; time between stopping treatment and recurrence; rate of adverse effects of treatment. In women with pain: relief of pain, assessed by visual analogue scale and subjective improvement. In women with subfertility: cumulative pregnancy rate, live birth rate. In women undergoing surgery: ease of surgical intervention (rated as easy, average, difficult, or very difficult).13

    Methods

    Clinical Evidence search and appraisal for systematic reviews, January 1999. We sought RCTs by electronic searching of databases, handsearching of 30 key journals, searching the reference lists of other RCTs, and identifying unpublished studies from abstracts, proceedings, and pharmaceutical companies. We used the search strategy and database of the Cochrane Menstrual Disorders and Subfertility Group to identify RCTs on Medline and Embase. We included RCTs that used adequate diagnostic criteria for inclusion of participants (endometriosis diagnosed either by laparoscopy or laparotomy in association with dysmenorrhoea, dyspareunia, other pelvic pain, or infertility) and clinical outcomes. Studies of assisted reproductive technologies were not included.

    Question: What are the effects of hormonal treatments?

    Four small systematic reviews found that all hormonal treatments except dydrogesterone were equally effective, compared with placebo, in reducing pain attributed to endometriosis. One systematic review of small RCTs found no evidence that hormonal treatments improved fertility. RCTs have found that six months' postoperative treatment with gonadotrophin releasing hormone analogues or a combination of danazol plus medroxyprogesterone reduces pain and delays the recurrence of pain significantly better than placebo. They found no evidence of an effect of postoperative gonadotrophin releasing hormone analogues on fertility.

    Benefits

    In women with pain attributed to endometriosis: We found four systematic reviews (search dates 1998, 1996, 1997, 1997) comparing six months' continuous suppression of ovulation (using danazol, gestrinone, medroxyprogesterone acetate, dydrogesterone, oral contraceptives, or gonadotrophin releasing hormone analogues) and placebo.1417 None of the reviews included more than 200 women. They found that except for dydrogesterone, which was given at two different dosages in the luteal phase, with no evidence of effect, all treatments were equally effective at reducing severe and moderate pain at six months. We found no placebo controlled RCTs of oral contraceptives. One RCT compared oral contraceptives and gonadotrophin releasing hormone analogues in 49 women.18 It found no differences in rate of relief for all types of pain except menstrual pain, for which oral contraceptive was better. In women with subfertility attributed to endometriosis: We found one systematic review (search date 1996), which identified four RCTs in a total of 244 women.19 The trials evaluated six months' treatment with danazol, medroxyprogesterone, or gonadotrophin releasing hormone analogues compared with placebo. They found no evidence of an effect on the probability of pregnancy (odds ratio for pregnancy compared with placebo 0.83; 95% confidence interval 0.50 to 1.39). In women who have undergone surgery: We found no systematic review. We found three placebo controlled RCTs of gonadotrophin releasing hormone analogues in a total of 443 women who had undergone surgery for endometriosis.2022 The smallest trial (n=65) evaluated three months' treatment and found no difference in pain relief; the two larger trials (n=109, n=269) evaluated six months' treatment and found that gonadotrophin releasing hormone analogues significantly reduced pain scores (P=0.008) 21 and delayed the recurrence of pain by more than 12 months.21 22 Two of the trials evaluated fertility (n=65, n=269) and found no difference in pregnancy rates or time to conception.20 22 One RCT in 60 women found that postoperative treatment with a combination of danazol (600 mg/day) and medroxyprogesterone (100 mg/day) reduced pain more than placebo six months after surgery.23

    Harms

    Gonadotrophin releasing hormone analogues: Adverse effects occurred in 11% of women taking gonadotrophin releasing hormone analogues,14 which are associated with hypo-oestrogenic symptoms such as hot flushes and vaginal dryness. RCTs have found that adding oestrogen, progesterone, or tibolone significantly relieves hot flushes caused by gonadotrophin releasing hormone analogues (by 50% or more on symptom scores).13 24 25 Danazol: Adverse effects occurred in 15% of women taking danazol.15 Danazol is associated with androgenic symptoms of acne, weight gain, and hirsutism and with decreased breast size, muscle cramps, and hunger. Gestrinone is associated with a higher frequency of hot flushes than are gonadotrophin releasing hormone analogues, and also with greasy skin and hirsutism.15 Medroxyprogesterone: The trials gave no information on adverse effects of medroxyprogesterone.

    Comment

    The trials were mainly small, with no long term follow up. Most trials compared gonadotrophin releasing hormone analogues with danazol. No summary statistics could be calculated because the trials compared different drugs with placebo or with no treatment.

    Question: What are the effects of surgical treatments?

    Option: Laparascopic uterine nerve ablation (LUNA)

    We found insufficient evidence on the effects of laparascopic uterine nerve ablation in women with pain attributed to endometriosis.

    Benefits

    We found one systematic review (search date 1998), which identified two small RCTs in women with endometriosis. These found no difference in pain relief between women treated with laparascopic uterine nerve ablation and those who were not.26

    Harms

    The trials gave no information on adverse effects. Potential harms include denervation of pelvic structures and uterine prolapse.26

    Comment

    The trials may have been too small to rule out a beneficial effect.26

    Option: Laparoscopic ablation of endometrial deposits

    We found insufficient evidence on the effects of laparoscopic ablation of deposits on its own. One RCT found that at six months ablation of deposits combined with laparascopic uterine nerve ablation reduced pain more than diagnostic laparoscopy. One RCT found that laparoscopic surgery increased fertility more than diagnostic laparoscopy.

    Benefits

    In women with pain attributed to endometriosis: We found no systematic review and no RCTs evaluating laparoscopic ablation of deposits alone. We found one RCT comparing the combination of ablation of deposits plus laparascopic uterine nerve ablation with diagnostic laparoscopy in 63 women.27 28 This found that combined ablation reduced pain at six months (median decrease in pain score 2.85 for ablation, 0.05 for diagnostic laparoscopy; P=0.01). In women with subfertility attributed to endometriosis: We found no systematic review. We found one RCT comparing laparoscopic ablation or excision of endometriotic deposits and diagnostic laparoscopy in 341 women with subfertility attributed to mild or moderate endometriosis.29 This found that laparoscopic surgery increased cumulative pregnancy rates (relative risk of pregnancy after 36 weeks 1.7, 1.2 to 2.6; NNT 8). Laser versus diathermy ablation: We found no RCTs.

    Harms

    The trials gave no information on adverse effects.2729 Potential harms include adhesions, reduced fertility, and damage to other pelvic structures.

    Comment

    Further RCTs comparing ablation alone and ablation plus laparascopic uterine nerve ablation are under way (C Sutton and R Dover, personal communication). A systematic review of laser versus diathermy ablation is planned (C Farquhar and N Johnson, personal communication).

    Question: What are the effects of preoperative hormonal treatment?

    One RCT found no evidence that preoperative treatment with gonadotrophin releasing hormone analogues facilitated surgery.

    Benefits

    We found no systematic review. We found one RCT comparing three months' preoperative treatment with a gonadotrophin releasing hormone analogue and no treatment in 75 women with moderate or severe endometriosis.30 There was no difference in ease of surgery between the two groups.

    Harms

    See above under hormonal treatments.

    Comment

    The trial may have been too small to rule out a clinically important effect.

    Question: What are the effects of treatments for ovarian endometrioma?

    Option: Laparoscopic drainage or laparoscopic cystectomy

    One RCT found that pain and fertility improved more with cystectomy than with drainage, and there was no evidence of a difference in complication rates.

    Benefits

    We found no systematic review. We found one RCT comparing laparoscopic cystectomy and laparoscopic drainage in 64 women.31 In women with pain attributed to endometrioma: The trial found that cystectomy reduced recurrence of pain at two years (odds ratio 0.2, 0.05 to 0.77) and increased the pain free interval after operation (median interval 19 months v 9.5 months; P<0.05). In women with subfertility attributed to endometrioma: Cystectomy increased the pregnancy rate (66.7% v 23.5%; odds ratio 8.25, 1.15 to 59; P<0.05).

    Harms

    The trial reported no intraoperative or postoperative complications in either group.

    Comment

    None.

    Key messages

    Four small systematic reviews found that all hormonal treatments except dydrogesterone were equally effective, compared with placebo, in reducing pain attributed to endometriosis

    One systematic review of small RCTs found no evidence that hormonal treatments improved fertility

    Six months' postoperative treatment with gonadotrophin releasing hormone analogues or a combination of danazol and medroxyprogesterone significantly reduces pain and delays the recurrence of pain compared with placebo, but there is no evidence of an effect of postoperative gonadotrophin releasing hormone analogues on fertility

    We found insufficient evidence on the effects of laparoscopic uterine nerve ablation in women with pain attributed to endometriosis and on the effects of laparoscopic ablation of deposits on its own

    One RCT found no evidence that preoperative treatment with gonadotrophin releasing hormone analogues facilitated surgery

    One RCT found that pain and subfertility caused by ovarian endometrioma were improved more by cystectomy than by drainage

    Acknowledgments

    We thank women's health section advisers Mike Dixon, Edinburgh, and Richard Johnson, Stoke on Trent.

    Footnotes

    • Competing interests CF was reimbursed in 1995 by ICI, the manufacturer of Zoladex, for helping to develop educational programmes.


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