Clinical Topic A-Z Clinical Speciality

Endometriosis

Endometriosis
D004715Endometriosis
Women's health
2009-06-29Last revised in June 2009

Endometriosis - Summary

Endometriosis is the presence of tissue resembling endometrial glands and stroma outside the uterine cavity, which induces a chronic inflammatory reaction. It is often associated with dysmenorrhoea, pelvic pain, and subfertility.

Most deposits occur in the pelvis, and this ectopic tissue responds to the hormonal changes of the menstrual cycle. If the ovaries are affected, ovarian cysts (endometriomas) may develop.

Subfertility may be due to distortion of pelvic anatomy by adhesions and cysts or disturbance of reproductive processes.

Endometriosis is most commonly diagnosed in women between 30 and 40 years of age, and is uncommon in those younger than 20 years of age.

The following signs and symptoms may indicate the presence of endometriosis:

Secondary dysmenorrhoea — usually before or during menstruation.

Deep dyspareunia.

Chronic pelvic pain.

Ovulation-related pain.

Cyclical or peri-menstrual bowel or bladder symptoms.

Subfertility.

Pain on defecation or micturition (especially during menses).

Examination is likely to be normal, as most endometriosis is mild or moderate in severity. However, endometriosis may be more extensive if, on a speculum and bimanual pelvic examination, there is localized pelvic tenderness, a fixed retroverted uterus, tenderness of the uterosacral ligaments, enlargement of the ovaries (due to cystic lesions), or palpable nodules on the uterosacral ligaments or in the pouch of Douglas.

Diagnosis is confirmed by laparoscopy (this requires referral to a gynaecologist).

Other conditions that may present with similar symptoms include:

Adenomyosis or uterine fibroids.

Adhesions.

Recurrent urinary tract infections.

Irritable bowel syndrome.

Pelvic inflammatory disease.

Primary dysmenorrhoea.

Musculoskeletal disorders, such as referred pain.

Malignancy (of the cervix, uterus, ovary, rectum, or bladder).

A palpable abdominal or pelvic mass on examination that is not obviously uterine fibroids, or not of gastrointestinal or urological origin requires an urgent ultrasound scan. If an urgent ultrasound is not available, or the scan is suggestive of cancer, the woman should be referred urgently to a gynaecologist.

Management of endometriosis is usually specialist-led and may be medical or surgical.

Medical management is used to treat the pain associated with endometriosis. Options include:

Combined oral contraceptive pill.

Progestogens, such as medroxyprogesterone or norethisterone.

Progestogen-only pill, intrauterine system, or implant.

Androgens and gonadotrophin-releasing hormone (GnRH) analogues (started in secondary care).

Surgical treatment (excision or ablation) may improve symptoms and subfertility.

Urgent admission should be considered if there are suspected complications in a woman with known endometriosis (such as rupture of an endometriotic cyst, or symptoms of bowel obstruction).

Have I got the right topic?

192months3060monthsFemale

This CKS topic is based on a guideline from the Royal College of Obstetricians and Gynaecologists, The investigation and management of endometriosis [RCOG, 2006].

This CKS topic covers the management of endometriosis located within the pelvic cavity.

This CKS topic does not cover the management of dysmenorrhoea or adenomyosis.

There are separate CKS topics on Dysmenorrhoea, and Menorrhagia.

The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary health care.

How up-to-date is this topic?

How up-to-date is this topic?

Changes

Last revised in June 2009

July 2013 — minor update. Update to the text to reflect recent advice from the MHRA regarding diclofenac [MHRA, 2013].

February 2013 — minor update. The 2013 QIPP options for local implementation have been added to this topic [NICE, 2013].

October 2012 — minor update. The 2012 QIPP options for local implementation have been added to this topic [NPC, 2012].

May 2011 — minor update. The 2010/2011 QIPP options for local implementation have been added to this topic [NPC, 2011]. Issued in June 2011.

October 2010 — minor update. From mid-October 2010, Nexplanon® will replace Implanon®. Nexplanon® is bioequivalent to Implanon®. The main differences are that Nexplanon® is radio-opaque, and the insertion technique is different [FSRH, 2010]. Issued in October 2010.

September 2010 — minor update. A prescription for Rigevidon®, another new ethinylestradiol plus levonorgestrel combined oral contraceptive pill, has been added. Issued in September 2010.

June 2010 — minor update. A prescription for Levest®, a new ethinylestradiol plus levonorgestrel combined oral contraceptive pill, has been added. Issued in June 2010.

February to June 2009 — converted from CKS guidance to CKS topic structure. The evidence-base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence.

There are no major changes to the recommendations.

Previous changes

February 2009 — minor update. Dydrogesterone tablets no longer available in the UK. Prescriptions removed. The upper age limits on the combined oral contraceptive pill prescriptions have been reduced to 50 years. Issued in March 2009.

January–March 2006 — reviewed. Validated in June 2006 and issued in July 2006.

October 2005 — minor technical update. Issued in November 2005.

August 2002 — reviewed. Validated in December 2002 and issued in February 2003.

July 1999 — written. Validated in October 1999 and issued in January 2000.

Update

New evidence

Evidence-based guidelines

Guidelines published since the last revision of this topic:

Dunselman, G.A., Vermeulen, N., Becker, C., et al. (2014) ESHRE guideline: management of women with endometriosis. Human Reproduction epub ahead of print. [Abstract] [Free Full-text]

SOGC (2010) Endometriosis: diagnosis and management. Society of Obstetricians and Gynaecologists of Canada. www.sogc.org [Free Full-text (pdf)]

HTAs (Health Technology Assessments)

No new HTAs since 1 January 2009.

Economic appraisals

No new economic appraisals relevant to England since 1 January 2009.

Systematic reviews and meta-analyses

Systematic reviews published since the last revision of this topic:

Bonocher, C.M., Montenegro, M.L., Rosa E Silva, J.C., et al. (2014) Endometriosis and physical exercises: a systematic review. Reproductive Biology and Endocrinology 12(1), 4. [Abstract]

Brown, J., Pan, A., and Hart, R.J. (2010) Gonadotrophin-releasing hormone analogues for pain associated with endometriosis (Cochrane Review). The Cochrane Library. Issue 12. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Ferrero, S., Gillott, D.J., Venturini, P.L. and Remorgida, V. (2011) Use of aromatase inhibitors to treat endometriosis-related pain symptoms: a systematic review. Reproductive Biology and Endocrinology 9, 89. [Abstract] [Free Full-text]

Flower, A., Liu, J.P., Chen, S., et al. (2009) Chinese herbal medicine for endometriosis (Cochrane Review). The Cochrane Library. Issue 3. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Hansen, S.O. and Knudsen, U.B. (2013) Endometriosis, dysmenorrhoea and diet. European Journal of Obstetrics, Gynecology, and Reproductive Biology 169(2), 162-171. [Abstract]

Lan, S., Ling, L., Jianhong, Z., et al. (2013) Analysis of the levonorgestrel-releasing intrauterine system in women with endometriosis. Journal of International Medical Research 41(3), 548-558. [Abstract]

Lv, D., Song, H., and Shi, G. (2010) Anti-TNF-α treatment for pelvic pain associated with endometriosis (Cochrane Review). The Cochrane Library. Issue 3. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Lv, D., Song, H., Li, Y., et al. (2009) Pentoxifylline versus medical therapies for subfertile women with endometriosis (Cochrane Review). The Cochrane Library. Issue 3. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Nnoaham, K.E., Webster, P., Kumbang, J., et al. (2012) Is early age at menarche a risk factor for endometriosis? A systematic review and meta-analysis of case-control studies. Fertility and Sterility 98(3), 702-712.e6. [Abstract]

Parazzini, F., Cipriani, S., Bravi, F., et al. (2013) A meta-analysis on alcohol consumption and risk of endometriosis. American Journal of Obstetrics and Gynecology 209(2), 106.e1-106.e10. [Abstract]

Richardson, W.S., Stefanidis, D., Chang, L., et al. (2009) The role of diagnostic laparoscopy for chronic abdominal conditions: an evidence-based review. Surgical Endoscopy 23(9), 2073-2077. [Abstract]

Soares, S.R., Martinez-Varea, A., Hidalgo-Mora, J.J., and Pellicer, A. (2012) Pharmacologic therapies in endometriosis: a systematic review. Fertility and Sterility 98(3), 529-555. [Abstract]

Vercellini, P., Eskenazi, B., Consonni, D., et al. (2011) Oral contraceptives and risk of endometriosis: a systematic review and meta-analysis. Human Reproduction Update 17(2), 159-170. [Abstract] [Free Full-text]

Zhu, X., Hamilton, K.D., and McNicol, E.D. (2011) Acupuncture for pain in endometriosis (Cochrane Review). The Cochrane Library. Issue 9. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Primary evidence

Randomized controlled trials published since the last revision of this topic:

Serracchioli, R., Mabrouk, M., Frascà, C., et al. (2009) Long-term oral contraceptive pills and postoperative pain management after laparoscopic excision of ovarian endometrioma: a randomized controlled trial. Fertility and Sterility 94(2), 464-471. [Abstract]

Strowitzki, T., Marr, J., Gerlinger, C., et al. (2010) Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial. Human Reproduction 25(3), 633-641. [Abstract] [Free Full-text]

New policies

No new national policies or guidelines since 1 January 2009.

New safety alerts

No new safety alerts since 1 January 2009.

Changes in product availability

No changes in product availability since 1 January 2009.

Goals and outcome measures

Goals

To suspect a diagnosis of endometriosis appropriately

To confirm the diagnosis by referral to secondary care or other specialist service

To offer appropriate treatment in primary care settings

To provide appropriate contraceptive advice

To manage menopausal symptoms appropriately

QIPP — Options for local implementation

QIPP — Options for local implementation

Non-steroidal anti-inflammatory drugs (NSAIDs)

Review the appropriateness of NSAID prescribing widely and on a routine basis, especially in people who are at higher risk of both gastrointestinal (GI) and cardiovascular (CV) morbidity and mortality (e.g. older patients).

If initiating an NSAID is obligatory, use ibuprofen (1200 mg per day or less) or naproxen (1000 mg per day or less).

Review patients currently prescribed NSAIDs. If continued use is necessary, consider changing to ibuprofen (1200 mg per day or less) or naproxen (1000 mg per day or less).

Review and, where appropriate, revise prescribing of etoricoxib to ensure it is in line with MHRA advice and the NICE clinical guideline on osteoarthritis [CSM, 2005; NICE, 2008].

Co-prescribe a proton pump inhibitor (PPI) with NSAIDs for people with osteoarthritis, rheumatoid arthritis, or low back pain (for people over 45 years) in accordance with NICE guidance [NICE, 2008; NICE, 2009a; NICE, 2009b].

Take account of drug interactions when co-prescribing NSAIDs with other medicines (see Summaries of Product Characteristics). For example, co-prescribing NSAIDs with ACE inhibitors or angiotensin receptor blockers (ARBs) may pose particular risks to renal function; this combination should be especially carefully considered and regularly monitored if continued.

[NICE, 2013]

Background information

Definition

What is it?

Endometriosis is the presence of tissue resembling endometrial glands and stroma outside the uterine cavity, which induces a chronic inflammatory reaction [RCOG, 2006]. It is often associated with dysmenorrhoea, pelvic pain, and subfertility.

Most deposits occur in the pelvis (such as on the peritoneum, uterosacral ligaments, pouch of Douglas, rectovaginal septum, and ovaries). Extrapelvic deposits, such as on the pleura, are rare [Drife and Magowan, 2004b]. Occasionally, endometriosis develops in surgical scars after Caesarean section.

This ectopic tissue responds to the hormonal changes of the menstrual cycle, with subsequent bleeding, inflammation, and pain. If the ovaries are affected, endometriotic ovarian cysts (endometriomas) may develop.

Subfertility may be due to distortion of pelvic anatomy by adhesions and cysts or disturbance of reproductive processes such as folliculogenesis [Grace and Taylor, 2004].

There is poor correlation between symptoms and the extent of the disease [Drife and Magowan, 2004a].

Causes

What causes it?

A long established 'anatomical' theory of why endometriosis occurs is that retrograde menstruation leads to endometrial tissue being passed through patent fallopian tubes into the peritoneal cavity, where it seeds and subsequently grows [Drife and Magowan, 2004b; Bulun, 2009]. However, current consensus is that endometriosis has a multifactorial aetiology, involving genetic, immunological, and endocrinological factors.

Prevalence

How common is it?

Prevalence is estimated to vary from 2–22% of women [Johnson and Farquhar, 2007].

Endometriosis is most commonly diagnosed between 30 and 40 years of age, and is uncommon in those younger than 20 years of age [Jewell, 2003].

Endometriosis is present in 20–30% of women undergoing investigations for subfertility [Johnson and Farquhar, 2007] and in 1–5% of women undergoing sterilization [Grace and Taylor, 2004].

In women with dysmenorrhoea, the incidence of endometriosis is 40–60% [Johnson and Farquhar, 2007].

In women with chronic pelvic pain presenting in primary care, 4.1% were diagnosed with endometriosis [Zondervan et al, 1999].

Diagnosis

Diagnosis of endometriosis

When to suspect

When should I suspect endometriosis?

Suspect endometriosis in women who present with:

Secondary dysmenorrhoea (which may be severe) — usually before or during menstruation.

Deep dyspareunia.

Chronic pelvic pain.

Ovulation-related pain.

Cyclical or peri-menstrual bowel or bladder symptoms, with or without abnormal bleeding or pain.

Subfertility.

Pain on defecation (especially during menses).

Painful Caesarean-section scar.

Painful micturition (especially during menses). This is very rare.

In adolescents, consider endometriosis if pain is unresponsive to the combined oral contraceptive pill and to nonsteroidal anti-inflammatory drugs.

Examination is likely to be normal, as most endometriosis is mild or moderate in severity. However, more extensive endometriosis should be suspected if, on a speculum and bimanual pelvic examination:

There is localized pelvic tenderness, a fixed retroverted uterus, tenderness of the uterosacral ligaments, or enlargement of the ovaries (due to cystic lesions).

There are palpable nodules on the uterosacral ligaments (like a string of beads) or in the pouch of Douglas. Nodules are more likely to be felt during menstruation but pelvic examination at this time is not acceptable to many women.

Lesions are visible in the vagina or on the cervix.

Consider referring all women with suspected endometriosis, as laparoscopy is usually required to confirm the diagnosis.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert advice in guidelines published by the Royal College of Obstetricians and Gynaecologists [RCOG, 2006] and the European Society of Human Reproduction and Embryology [Kennedy et al, 2005], and two non-systematic reviews [Brosens, 1997; Farquhar, 2007].

A non-systematic review found that [Laufer et al, 2003]:

Endometriosis in adolescents may present with acyclic, cyclic, or continuous pelvic pain.

Several studies have shown that between 50% and 70% of adolescents undergoing laparoscopy for pelvic pain unresponsive to nonsteroidal anti-inflammatory drugs and the combined oral contraceptive pill have endometriosis.

Differential diagnosis

What else might it be?

Consider other conditions that may present with similar symptoms:

Uterine causes, such as adenomyosis or uterine fibroids.

Adhesions.

Interstitial cystitis or recurrent urinary tract infections.

Irritable bowel syndrome or other bowel pathology.

Pelvic inflammatory disease.

Primary dysmenorrhoea.

Musculoskeletal disorders, such as referred pain from degenerative disc disease of the spine.

Malignancy (of the cervix, uterus, ovary, rectum, or bladder).

Congenital anomalies of the reproductive tract.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert advice in two textbooks [Edmonds, 1999; Drife and Magowan, 2004b] and a non-systematic review [Practice Committee of the American Society for Reproductive Medicine, 2008].

Management

Management

Scenario: Management : covers the management of women with endometriosis.

Scenario: Management

Scenario: Management of endometriosis

192months3060monthsFemale

Managing suspected endometriosis

How should I manage a woman with suspected endometriosis?

Consider referring all women with suspected endometriosis to a gynaecologist (especially women with severe symptoms or subfertility) to confirm the diagnosis by laparoscopy, and for medical or surgical management.

The choice regarding referral and treatment depends on:

The wishes of the woman.

The severity and duration of symptoms.

Requirements for fertility.

Previous treatment.

Abnormalities identified on pelvic ultrasound or clinical examination.

Prescribe analgesia for women who are awaiting referral or who do not wish to be referred, if symptoms are troublesome and the women does not require contraception or does not wish to take hormonal treatment.

A nonsteroidal anti-inflammatory drug (NSAID, such as ibuprofen, naproxen, mefenamic acid, or diclofenac) is recommended first-line. Ibuprofen may be preferred because of its more favourable risk–benefit ratio.

Note: diclofenac is now contraindicated for people with ischaemic heart disease, cerebrovascular disease, peripheral arterial disease, mild, moderate, or severe heart failure.

Offer paracetamol if an NSAID is poorly tolerated or contraindicated, or in addition to an NSAID if the response is insufficient. Regular use may be more effective than as-required use.

Codeine (15 mg or 30 mg) may be added to paracetamol and/or an NSAID if the response is insufficient.

If symptoms are troublesome and are not sufficiently controlled with analgesics or contraception is required, consider prescribing hormonal treatment.

Consider an ultrasound scan to rule out a pelvic mass (such as an endometrioma) before prescribing hormonal treatment.

Consider the combined oral contraceptive (COC) pill, first-line.

Monophasic COCs containing 30–35 micrograms of ethinylestradiol, and either norethisterone or levonorgestrel, are usually the first choice.

It is not known whether the COC should be taken conventionally, continuously without a break, or in a tricycling regimen to control endometriosis.

CKS suggests a three month trial of conventional treatment, then switching to tricycling after three months if necessary. Some women may find continuous use helpful.

Consider a progestogen if the COC is contraindicated:

A 3-month course of medroxyprogesterone (not contraceptive).

A 4–6-month course of norethisterone (not contraceptive).

A progestogen-only contraceptive is a further alternative.

Not all women will achieve amenorrhoea with this method.

If symptom relief is not obtained after a 3–6 month trial, consider switching to an alternative hormonal method or refer.

Suitable progestogen-only contraceptives include the levonorgestrel-releasing intra-uterine system (Mirena®), Cerazette® (a progestogen-only pill), depot medroxyprogesterone acetate (Depo-Provera®), or the etonogestrel subdermal contraceptive implant (Nexplanon® [formely Implanon®]).

See the CKS topics on Contraception - combined hormonal methods, Contraception - progestogen-only methods, and Contraception - IUS/IUD for detailed information on prescribing hormonal contraceptives. Whilst licensed for contraceptive use, the COC, Cerazette®, Depo-Provera®, Mirena®, and Implanon® are not specifically licensed for the treatment of endometriosis.

Review after 10–12 weeks (earlier if symptoms are troublesome). Refer if there is no improvement.

Basis for recommendation

Basis for recommendation

Referral for diagnosis

Establishing a diagnosis of endometriosis on the basis of symptoms alone is difficult because symptoms are variable and overlap with other conditions (for example pelvic inflammatory disease and irritable bowel syndrome).

There are no investigations in primary care that are helpful in making a diagnosis of endometriosis. However, CKS expert reviewers commented that:

A normal ultrasound scan of the pelvis does not exclude endometriosis but can be reassuring, particularly as it can exclude ovarian endometrioma with good certainty.

A successful trial of hormonal suppression therapy (for example COC or oral progestogens), in the presence of normal pelvic ultrasound, is suggestive that at least mild endometriosis may be present.

Laparoscopy is the gold standard diagnostic test.

The Royal College of Obstetrician and Gynaecologists [RCOG, 2006] and the European Society of Human Reproduction and Embryology Special Interest group for Endometriosis and Endometrium guideline development group [Kennedy et al, 2005] recommend visual inspection of the pelvis by laparoscopy as the gold standard diagnostic test [RCOG, 2006] except, rarely, when the disease is visible (such as in the posterior vaginal fornix).

Other tests are less useful:

Transvaginal ultrasound has no value in diagnosing peritoneal deposits but is useful to confirm or exclude an ovarian endometrioma [RCOG, 2006].

There is insufficient evidence to recommend magnetic resonance imaging as a useful diagnostic test for endometriosis [Kennedy et al, 2005; RCOG, 2006].

Although serum CA-125 may be elevated in endometriosis, it has no value as a diagnostic tool [Kennedy et al, 2005].

Nonsteroidal anti-inflammatory drugs

Although there is good evidence that NSAIDs are effective in the treatment of primary dysmenorrhoea, there is less evidence regarding their use in women with secondary dysmenorrhoea or confirmed endometriosis. A Cochrane systematic review (that included only one small randomized controlled trial) showed:

Naproxen may be no more effective than placebo in the management of endometriosis-associated pain.

Insufficient evidence to indicate whether one NSAID is more effective than any other for the treatment of endometriosis.

Despite the lack of evidence to support their use, NSAIDs are widely prescribed for the treatment of endometriosis-associated pain and seem to be effective for many women.

Ibuprofen, diclofenac, naproxen, and mefenamic acid are recommended in the treatment of endometriosis-associated pain because:

Ibuprofen is considered to have a lower risk of gastrointestinal adverse effects than other NSAIDs [García Rodríguez and Hernández-Díaz, 2001; BNF 57, 2009].

Naproxen and diclofenac are associated with an intermediate risk of gastrointestinal adverse effects; mefenamic acid, having a short half-life, is likely to be associated with a low-to-intermediate risk [García Rodríguez and Hernández-Díaz, 2001; BNF 57, 2009].

The MHRA now recommend that like coxibs, diclofenac is contraindicated for people with ischaemic heart disease, peripheral arterial disease, cerebrovascular disease, and, congestive heart failure (New York Heart Association [NYHA] classification II–IV) [MHRA, 2013].

Paracetamol

CKS found no trials on the use of paracetamol to treat endometriosis-associated pain.

There is only very limited evidence from one small (n = 35) randomized controlled trial for its use in the relief of primary dysmenorrhoea. This trial showed paracetamol (at a sub-therapeutic dose) to be no better than placebo.

Codeine

CKS found no direct evidence on the use of codeine in the treatment of endometriosis-associated pain. However, the addition of codeine seems reasonable in women who are unable to take an NSAID or who do not get adequate pain relief from paracetamol plus an NSAID.

Hormonal treatments

Hormone treatments aim to induce atrophy of ectopic endometrium, either by altering the effect of oestrogen on endometriotic tissue or by reducing circulating oestrogen levels. They reduce endometriosis-associated pain by reducing menstrual blood flow or by inducing amenorrhoea. CKS expert reviewers agreed that although this may alter the laparoscopic appearance of the disease, in practice this was not a concern.

The combined oral contraceptive pill

The limited evidence available suggests that there is no difference between the effectiveness of the low-dose COC taken cyclically and goserelin in relieving endometriosis-associated pain.

There is a lack of evidence to guide which COC or treatment regimen to use [Kennedy et al, 2005; RCOG, 2006] therefore, CKS recommends the preparations that are usually used first-line for contraception. See the CKS topic on Contraception - combined hormonal methods for more information. Different treatment regimens may be considered:

Conventional use of COCs. There is evidence from a small randomized trial supporting the effectiveness of low-dose oral contraception, used cyclically.

Tricycling COCs (using COCs continuously for 3 months followed by 1 week without pills) has not been studied in women with endometriosis, but as it reduces the frequency of menstrual bleeding it may improve quality of life [Nasir and Bope, 2004]. This practice is an off-label use. The regimen is regarded as having a good safety profile, and is well tolerated and acceptable to women (although this does not specifically relate to women with endometriosis) [FFPRHC, 2005].

Continuous use (also off-label) could be considered if tricycling does not provide sufficient symptom relief.

Evidence for continuous use of COCs comes from a prospective, non-randomized, self-controlled trial of women (n = 50) who had experienced recurrence of dysmenorrhoea within a year of having surgery for endometriosis despite taking the COC cyclically [Vercellini et al, 2003]. Women were offered ethinyl estradiol 0.02 mg and desogestrel 0.15 mg daily for 2 years but could choose at each 6 monthly review whether they wanted to continue daily treatment, revert to the standard 21-day cycle, or discontinue treatment. Forty one women completed the study: 80% were either satisfied (54%) or very satisfied (27%) with the treatment. The following adverse effects were reported: amenorrhoea (38%), spotting (36%), and breakthrough bleeding (13%).

The Faculty of Sexual and Reproductive Healthcare (FSRH), formerly the Faculty of Family Planning and Reproductive Healthcare (FFPRHC), does not report on the safety of this regimen, but other authors [Miller and Hughes, 2003] have commented that it is unlikely that the loss of the pill-free week will greatly alter the safety profile.

Oral progestogens that are not contraceptives

Progestogens induce endometrial atrophy and reduce oestrogen levels by inhibiting ovulation.

CKS expert reviewers commented that treatment with oral progestogens (medroxyprogesterone or norethisterone) could be started by primary healthcare professionals provided that the symptoms were suggestive of endometriosis. Some expert reviewers suggested an ultrasound scan, to rule out pathology such as an endometrioma, before prescribing.

Evidence is limited due to lack of data, but continuous high-dose progestogen (medroxyprogesterone acetate) appears to be effective for the treatment of endometriosis-associated pain.

Luteal phase dydrogesterone does not appear to be effective and is no longer available.

There is limited evidence for the use of norethisterone.

Progestogen-only contraceptives

CKS expert reviewers commented that not all women achieve amenorrhoea with these methods.

Some expert reviewers stressed that a pelvic examination should be normal before prescribing progestogen-only contraception. They also suggested an ultrasound scan to rule out pathology such as an endometrioma.

Most CKS expert reviewers recommended that the levonorgestrel-releasing intrauterine system (LNG-IUS) could be initiated by a GP, particularly if the woman needed contraception or had experienced good symptom relief from this method in the past.

There is limited evidence from two small randomized controlled trials and three small prospective observational studies that the LNG-IUS reduces endometriosis-associated pain, with symptom control maintained over 3 years.

There is limited evidence from a Cochrane systematic review that found one small open-label study for its use following surgery for endometriosis.

Most CKS expert reviewers recommended that depot medroxyprogesterone (Depot-Provera®) could also be initiated by a GP, particularly if the woman needed contraception or had experienced good symptom relief from this method in the past, but that not all women would achieve amenorrhoea.

There is limited evidence from one small randomized trial that depot medroxyprogesterone is effective in the treatment of pelvic pain associated with endometriosis.

Some CKS expert reviewers also recommended that Cerazette® (a progestogen-only pill) or the etonogestrel subdermal implant (Implanon®) were alternatives if the woman needed contraception or had experienced good symptom relief from this method in the past.

Note that from mid-October 2010, Nexplanon® will replace Impanon®. Nexplanon® is bioequivalent to Implanon®. The main differences are that Nexplanon is radio-opaque, and the insertion technique is different [FSRH, 2010].

CKS found no evidence assessing the effectiveness of Cerazette® for endometriosis.

Very limited evidence from a small randomized controlled trial, an open-label study, and five case studies suggests that the etonogestrel subdermal implant might be useful in relieving endometriosis-associated pelvic pain.

Referral if no response to treatment

Referral if symptoms do not resolve after 3 months' treatment with oral progestogens is based on expert opinion.

Hormonal treatment

What hormonal treatments are available for confirmed endometriosis?

Treatment for endometriosis may be initiated by a specialist. Follow the specialist management plan if available.

The following hormonal treatments are used to treat the pain associated with endometriosis and may be initiated in primary or secondary care. They are not used to treat subfertility:

Combined oral contraceptive pill.

Progestogens:

Medroxyprogesterone or norethisterone (not contraceptive). See prescribing information on Progestogens.

Cerazette®.

Depot medroxyprogesterone acetate (Depo-Provera®).

The levonorgestrel-releasing intrauterine system (Mirena®).

The etonogestrel subdermal contraceptive implant (Nexplanon® [formerly Implanon®]).

See the CKS topics on Contraception - combined hormonal methods, Contraception - IUS/IUD, and Contraception - progestogen-only methods for detailed information on prescribing hormonal contraceptives.

The following hormonal treatments are used to treat the pain associated with endometriosis and may be initiated in secondary care. They are not used to treat subfertility:

Androgens — danazol and gestrinone are not commonly used now.

See prescribing information on Androgens.

Gonadotrophin-releasing hormone (GnRH) analogues. See prescribing information on Gonadotrophin-releasing hormone (GnRH) analogues.

Basis for recommendation

Basis for recommendation

Hormone treatments aim to induce atrophy of ectopic endometrium, either by altering the effect of oestrogen on endometriotic tissue or by reducing circulating oestrogen levels.

Androgens

Androgens (danazol and gestrinone) inhibit secretion of pituitary gonadotrophins. They have androgenic, anti-oestrogenic, and anti-progestogenic activity, and usually cause amenorrhoea and induce a reversible postmenopausal state. Their use is limited by androgenic adverse effects.

Evidence is limited due to lack of data, but gestrinone appears to be effective for the treatment of pain associated with endometriosis.

There is limited evidence from a Cochrane systematic review (of two randomized, double-blind, placebo-controlled trials) that danazol is effective at treating the symptoms of endometriosis when compared with placebo, but its use is limited by the occurrence of androgenic adverse effects.

GnRH analogues

The GnRH analogues (buserelin, goserelin, nafarelin, leuprorelin, and triptorelin) initially stimulate pituitary secretion and then rapidly inhibit secretion due to pituitary down-regulation. This is followed by anovulation, markedly reduced oestrogen levels, and amenorrhoea, inducing a reversible postmenopausal state and regression of endometriotic deposits.

There is limited evidence, due to poor quality data, that GnRH analogues are as effective as other medical treatments in relieving the pain associated with endometriosis.

There is evidence from one prospective, double-blind, randomized controlled trial (n = 179) [Hornstein et al, 1995] that 3 months of treatment with nafarelin may be as effective as 6 months of treatment, for pain relief [RCOG, 2006].

Add-back therapy

GnRH analogues reduce bone mineral density, typically by 4–6% during 6 months of treatment [DTB, 1999]; this bone loss may not be entirely reversible [RCOG, 2006]. They can also cause postmenopausal symptoms. These adverse effects may be reduced by the use of additional add-back therapy.

Tibolone, or combined progestogen plus oestrogen can be used as add-back therapy for women taking GnRH analogues.

There is good evidence that both combined progestogen plus oestrogen add-back therapy or danazol add-back therapy are protective of bone mineral density in women treated with GnRH analogues. Progestogen alone is not effective. However, danazol has significant adverse effects that limit its use.

We have recommended tibolone because most CKS expert reviewers agree that tibolone (2.5 mg daily) is the preferred treatment. There is evidence from a small trial that tibolone is more effective than placebo.

Surgical treatment

What surgical treatments are available for confirmed endometriosis?

Surgical treatment aims to remove (excise) or destroy (ablate) areas of endometriosis in order to improve symptoms, and increase the chance of pregnancy.

Ideally, endometriosis should be removed or destroyed at the time of diagnosis.

However this may not be possible as symptoms do not always relate to severity: unexpectedly severe disease may be discovered at laparoscopy.

Surgery for severe endometriosis should only be performed in a specialized tertiary endometriosis centre.

Surgical treatment may be conservative (minimally invasive when continued fertility is required) or radical (when continuing fertility is no longer required).

Conservative surgery is generally carried out laparoscopically and includes techniques such as diathermy, laser ablation or excision of deposits, ovarian cystectomy, denervation procedures, and helium plasma coagulation.

Radical surgery (such as total abdominal hysterectomy or salpingo-oophorectomy) is reserved for women who have completed their families and in whom other treatments have failed.

Relapse is common after surgical procedures for endometriosis; it may be as high as 50% at 1-year follow up.

Basis for recommendation

Basis for recommendation

Treatment at the time of diagnosis

The recommendation for laparoscopic surgery at the time of diagnosis is based on guidelines from the Royal College of Obstetricians and Gynaecologists and the European Society of Human Reproduction and Embryology [Kennedy et al, 2005; RCOG, 2006]. There is widespread consensus for treating endometriosis at the time of surgical diagnosis, depending on the experience and competency of the surgeon and the severity of disease present [Varma, Personal Communication, 2009].

Surgery for the treatment of pain associated with mild-to-moderate endometriosis

The recommendation that laparoscopic ablation of endometrial deposits may relieve pain in some women is based on guidelines from the Royal College of Obstetricians and Gynaecologists and the European Society of Human Reproduction and Embryology [Kennedy et al, 2005; RCOG, 2006].

Ablation of endometriotic lesions reduces the pain associated with endometriosis compared with diagnostic laparoscopy. There is limited evidence from a Cochrane systematic review (of one small randomized controlled trial [RCT]) that laser ablation, adhesiolysis, and uterine nerve ablation performed together are beneficial in the treatment of pain due to mild or moderate endometriosis compared with diagnostic laparoscopy alone. There is limited evidence from one RCT that women who have a laparoscopy with excisional surgery are likely to have less pain and an improved quality of life at 1 year compared with women who have had a diagnostic laparoscopy alone.

The Royal College of Obstetricians and Gynaecologists guidelines state that there is no evidence that it is necessary to add laparoscopic uterine nerve ablation (LUNA, which aims to interrupt the nerve pathways that conduct pain sensation from the pelvic area to the brain) to laser ablation. Used in isolation, LUNA has no effect on endometriosis-associated dysmenorrhoea [RCOG, 2006].

Laparoscopic helium plasma coagulation is a more recent minimally-invasive procedure used to vaporize endometriotic deposits. Current evidence on the safety and efficacy of this procedure is not adequate to recommend its use without special arrangements for consent [NICE, 2006].

Surgery for the treatment of subfertility

There is evidence that laparoscopic surgery for the treatment of minimal and mild endometriosis may improve the chance of pregnancy, but the evidence is conflicting and limited to two RCTs.

The role of surgery in improving pregnancy rates in women with moderate-to-severe endometriosis is uncertain. A review from the Practice Committee of the American Society for Reproductive Medicine concluded that women who have moderate or severe endometriosis, without other identifiable infertility factors, may improve their chance of conceiving with conservative surgical treatment such as laparoscopy and possibly laparotomy [Practice Committee of the American Society for Reproductive Medicine, 2006].

There is evidence from a Cochrane systematic review [Hart et al, 2008] of six non-randomized trials of women with endometrioma that excision of the endometrioma is preferable to drainage and ablation in regard to recurrence of symptoms, recurrence of an endometrioma, and spontaneous pregnancy rates.

Treatment of severe endometriosis

The Royal College of Obstetricians and Gynaecologists guidelines recommend radical surgery for severe and deeply-infiltrating endometriosis [RCOG, 2006]. There is high morbidity associated with these procedures, and therefore surgery for severe endometriosis should only be conducted by gynaecologists accredited in advanced laparoscopy, and should be performed in specialized tertiary endometriosis centres, where the volume of work and level of expertise ensures the best care for the woman. Multidisciplinary input in the treatment pathway for women with severe endometriosis may involve gynaecologists, radiologists, colorectal surgeons, urologists, anaesthetic pain specialists, and psychologists [Varma, Personal Communication, 2009].

Relapse rate

A systematic review included three RCTs and found that the absolute benefit on pain relief at short-term follow up (6 months or 1 year) was 30–40% in women with mild to severe endometriosis. Data from case series also analysed in this review suggested that 50% of women still needed analgesics or hormonal treatment at 1 year. One study in the review reported long-term follow up (12–14 years) and found that the repeat surgery rate was 52% in the excision group and 48% in the observational laparoscopic group [Vercellini et al, 2009].

Use of hormonal treatment before or after surgery

There is insufficient evidence to suggest that hormonal suppression in association with surgery for endometriosis will significantly benefit eradication of endometriosis, improvement of symptoms, pregnancy rates, and overall tolerability. The Royal College of Obstetricians and Gynaecologists does not recommend its use [RCOG, 2006].

Managing relapse

How should I manage relapse?

If the woman has been successfully treated for endometriosis, but the symptoms have returned:

Exclude other conditions with similar symptoms.

Explain that relapse is common.

Management options include:

Treatment with a nonsteroidal anti-inflammatory drug, simple analgesia, and/or medical treatment (such as combined oral contraception for symptomatic relief; particularly if this has worked well in the past and contraception is required). Refer the woman if such strategies prove ineffective.

Referral, if subfertility is a problem.

Further hormonal treatment under specialist supervision (referral required) or on specialist advice.

Surgery .

Basis for recommendation

Basis for recommendation

Relapse rate

Relapse is common once hormonal treatment is discontinued. In trials of treatment with a gonadotrophin-releasing hormone (GnRH) analogue or danazol, approximately 10–20% of women required further treatment within 12 months. Uncontrolled cohort studies report relapse in about half of women at 5 years [Farquhar and Sutton, 1998].

Relapse is also common after surgical procedures, and up to 50% of women may require analgesics or hormonal treatment 1 year later [Vercellini et al, 2009].

Further medical treatment

There is a lack of trial evidence regarding the safety and effectiveness of repeat courses of hormonal treatment for endometriosis. Specialist advice is therefore recommended. Several CKS expert reviewers advised that it would be reasonable to prescribe medical treatment such as combined oral contraception if this had been effective in the past, if subfertility was not an issue, and in the absence of findings that the disease had significantly worsened (such as ovarian endometriomas or deeply infiltrating nodules).

Surgery

Repeat surgery may also be considered.

Contraception

What advice should I give about contraception?

If the woman is currently taking hormonal treatment for endometriosis that does not provide contraception, advise her to use a non-hormonal method of contraception to prevent pregnancy.

Non-contraceptive hormonal treatments include oral medroxyprogesterone, norethisterone, danazol, gestrinone, and gonadotrophin-releasing hormone analogues.

Contraceptive methods that can be used in women with endometriosis, provided there are no contraindications, include:

Combined oral contraceptive.

The levonorgestrel-releasing intrauterine system (Mirena®).

Depot medroxyprogesterone acetate (Depot-Provera®).

Progestogen-only pill (such as Cerazette®).

Etonogestrel-only implant (Nexplanon® [formerly Implanon®]).

Barrier methods — male or female condom, diaphragm (with spermicide), and cervical cap.

A copper intrauterine device may worsen dysmenorrhoea but the advantages of this method generally outweigh the risks in women with endometriosis.

Sterilization should only be undertaken by an experienced surgeon, as severe endometriosis may make access to the fallopian tubes difficult and may increase the risk of complications.

Basis for recommendation

Basis for recommendation

These recommendations are based on the UK medical eligibility criteria for contraceptive use [FFPRHC, 2006].

HRT

How do I manage a woman who is considering hormone replacement therapy?

For women who are considering hormone replacement therapy (HRT) for menopausal symptoms and who are not currently prescribed hormonal treatment for endometriosis, discuss treatment options with a specialist. It is important to discuss the risks of HRT and balance the potential benefits against the risks.

If HRT is prescribed, monitor for symptoms that may indicate reactivation of the disease. If these occur, either stop the HRT or seek specialist advice.

HRT is recommended for young women who have had a bilateral oophorectomy.

Seek specialist advice about whether to prescribe combined HRT, unopposed HRT, combined-continuous HRT, or tibolone.

Unless there are contraindications, this should be continued until 50 years of age, when a decision should be made to either stop or continue the HRT.

Monitor for symptoms that may indicate reactivation of the disease. If these occur, seek specialist advice.

Basis for recommendation

Basis for recommendation

Seek specialist advice

CKS recommends seeking specialist advice as it is not clear what type of hormone replacement therapy (HRT) is best for women who have endometriosis, whether or not they have had a total hysterectomy or oophorectomy. The decision should be made on an individual basis taking the following into account:

The woman's family history.

Unopposed oestrogen may reactivate any residual disease and combined HRT may protect against this [RCOG, 2006].

Adenocarcinomas arising from pelvic endometriosis have been reported in women treated with unopposed oestrogen [Van Gorp and Neven, 2002]. Limited evidence suggests that combined HRT is associated with a lower risk of malignant change than treatment with unopposed oestrogens [Oxholm et al, 2007]. 

The risk of breast cancer appears to be increased by all HRT regimens (unopposed oestrogen, combined HRT, and tibolone) but seems to be greatest with combined HRT [Rees and Purdie, 2006].

Tibolone may slightly increase the risk of endometrial cancer [Rees and Purdie, 2006].

CKS expert reviewers stressed the importance of explaining the risks and benefits to the woman.

Women who have had bilateral oophorectomy

The Royal College of Obstetricians and Gynaecologists recommend HRT in young women who have had a bilateral oophorectomy, because of the overall health benefits and the small risk of recurrence of endometriosis whilst taking HRT [RCOG, 2006].

A Cochrane systematic review concluded that although there is a risk that HRT might cause recurrence of endometriosis in women who have had a bilateral oophorectomy for severe endometriosis, the available evidence (from two small randomized controlled trials) is not strong enough to deprive severely symptomatic women of treatment.

There is no good evidence on whether to recommend an unopposed HRT regimen, a combined-continuous regimen, or tibolone [Rees and Purdie, 2006].

Prescribing combined HRT after hysterectomy may protect against the unopposed action of the oestrogen on any residual disease [RCOG, 2006]. However the small risk of avoiding reactivation of the endometriosis or malignant transformation should be balanced against the increased risk of breast cancer reported with combined HRT regimens and with tibolone [RCOG, 2006].

Referral

When should I refer?

If there is a palpable abdominal or pelvic mass on examination that is not obviously uterine fibroids, or not of gastrointestinal or urological origin:

Refer urgently for a scan.

If the scan is suggestive of cancer or an urgent ultrasound is not available, refer urgently to a gynaecologist.

If endometriosis is suspected (especially if symptoms are severe or there is difficulty conceiving), consider referral to a gynaecologist to confirm the diagnosis by laparoscopy, and for medical or surgical management.

If the woman has been successfully treated for endometriosis, but the symptoms have returned, seek advice or refer to gynaecologist for consideration of further hormonal treatment or surgery.

If there are suspected complications in a woman with known endometriosis (such as rupture of an endometriotic cyst, or symptoms of bowel obstruction), consider urgent admission.

Seek specialist advice regarding prescribing hormone replacement therapy (HRT) or tibolone:

As add-back treatment for women receiving gonadotrophin-releasing hormone analogues.

For women who have menopausal symptoms and are not currently prescribed hormonal treatment for endometriosis.

For young women who have had a bilateral oophorectomy.

Basis for recommendation

Basis for recommendation

Referral if there is a palpable abdominal or pelvic mass

These recommendations are based on referral guidelines for suspected cancer from the National Institute for Health and Clinical Excellence [NICE, 2005].

Referral for suspected endometriosis

Referral is recommended because establishing a diagnosis on the basis of symptoms alone is difficult and laparoscopy is the gold standard diagnostic test [RCOG, 2006].

Referral for subfertility

CKS found no evidence that hormonal treatment improves the chance of pregnancy in women with endometriosis-associated subfertility. Use of the combined oral contraceptive pill, progestogens, androgens, and gonadotrophin-releasing hormone analogues in women with subfertility may cause adverse effects and delay the use of treatment such as surgery, or assisted reproductive techniques.

Laparoscopic surgery in women with endometriosis-associated subfertility and minimal or mild disease may improve the chance of pregnancy. However, the evidence is conflicting and limited to two small randomized controlled trials.

Specialized subfertility treatments, such as in vitro fertilization (IVF), may need to be considered in some women. For further information, see the CKS topic on Infertility.

When to consider urgent admission

The advice on when to admit urgently is based on expert opinion in standard textbooks [Edmonds, 1999; Jewell, 2003].

Seeking advice before prescribing HRT

There is a lack of evidence about the risks of HRT in perimenopausal women who have endometriosis: HRT may increase the risk of reactivation of the endometriosis, unopposed HRT may increase the risk malignant change in endometriotic deposits, and combined HRT increases the risk of breast cancer. There is also a lack of evidence about the best type of HRT to prescribe (tibolone, continuous-combined HRT, unopposed HRT, or combined HRT). Therefore, CKS recommends seeking specialist advice before initiating HRT. See HRT for more information.

HRT can also be used as add-back therapy to manage the adverse effects of gonadotrophin-releasing hormone analogues. This is generally prescribed on the advice of a specialist.

Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC) (http://medicines.org.uk/emc), or the British National Formulary (BNF) (www.bnf.org).

Progestogens

Progestogens

Progestogens should generally be prescribed under specialist supervision.

Medroxyprogesterone acetate

Medroxyprogesterone acetate (10 mg three times a day) should be started on the first day of the menstrual cycle.

Continue treatment for 90 consecutive days. Some clinicians prescribe it for longer than 90 days (off-label duration) if adverse effects are minimal and symptoms are well controlled.

Advise a non-hormonal method of contraception, where appropriate, as doses of up to 30 mg a day may not suppress ovulation.

Avoid during pregnancy, and in women with impaired liver function or active liver disease.

Breakthrough bleeding, which is self-limiting, may occur but additional hormonal treatment is not recommended to manage this. High doses may cause weight gain and fluid retention.

[ABPI Medicines Compendium, 2009c]

Norethisterone

Norethisterone 5 mg twice a day should be started on the fifth day of the cycle (this is the licensed regimen). If breakthrough bleeding occurs, increase the dosage after a few weeks to 20 mg and, if necessary, 25 mg daily. After bleeding has ceased, the dosage can usually be reduced to 10 mg daily again.

Continue treatment for 4–6 months, or longer if necessary.

Avoid during pregnancy, and in women with impaired liver function or active liver disease.

Adverse effects include breakthrough bleeding (particularly when treatment is continuous over a long period), nausea, vomiting, acne, oedema, changes in appetite or weight, fluid retention, melasma, allergic skin rashes, and urticaria.

[ABPI Medicines Compendium, 2008]

Contraceptives

See the CKS topics on Contraception - IUS/IUD and Contraception - progestogen-only methods for information on prescribing:

Cerazette® (a progestogen-only pill).

Depot medroxyprogesterone acetate (Depo-Provera®).

The etonogestrel implant (Nexplanon® [formerly Implanon®]).

The levonorgestrel-releasing intrauterine system (Mirena®).

Androgens

Androgens

Androgens should only be prescribed under the supervision of a specialist. They are rarely used.

Danazol

Danazol may be used either in conjunction with surgery or as a sole hormonal treatment. It is only licensed for use when other treatments have failed.

Start danazol during menstruation (to ensure the woman is not pregnant; a pregnancy test is advisable if there is any doubt).

If endometriosis is severe, prescribe 400 mg twice a day.

Otherwise, prescribe 100 mg twice a day and increase to a maximum of 800 mg daily if normal cyclical bleeding still persists after 2 months.

Continue treatment for 3–6 months, and up to 9 months if necessary. Danazol is only licensed to be taken continuously for up to 6 months.

Repeat courses may be necessary, but care should be taken as there are no safety data available in relation to repeated courses of treatment.

Advise a non-hormonal method of contraception, where appropriate, when danazol is administered at lower doses (100–400 mg daily) as ovulation may not be suppressed.

Avoid danazol during pregnancy and breastfeeding, and if the woman has marked hepatic, renal, or cardiac impairment, porphyria, thromboembolic disease, androgen-dependent tumours, or undiagnosed vaginal bleeding.

Adverse effects are mainly due to its androgenic effects and include weight gain, bloating, hirsutism, acne, deepened voice, oily skin, muscle cramps, headaches, hot flushes, decreased libido, irritability, and depression.

Danazol may increase the effects of warfarin, and increase the risk of bleeding. If concurrent use cannot be avoided, the dose of warfarin should be reduced appropriately.

Danazol does not reduce bone mineral density, as its anabolic effects counteract the effect of lowered oestrogen levels.

[Stevenson, 1995; Bergqvist, 1999; Kennedy and Moore, 2003; ABPI Medicines Compendium, 2009a]

Gestrinone

Gestrinone has similar actions to danazol but has a longer half-life, allowing twice-weekly (instead of daily) dosing. It is less androgenic than danazol, and therefore may be better tolerated.

Start gestrinone (2.5 mg) on the first day of the menstrual cycle (to ensure the woman is not pregnant). The second dose should be taken 3 days later. Thereafter, gestrinone capsules should be taken on the same two days of the week (preferably at the same time) every week.

Continue treatment for 6 months. Gestrinone is licensed to be taken continuously for up to 6 months.

Advise a non-hormonal method of contraception, where appropriate.

Avoid during pregnancy and breastfeeding, and if the woman has severe hepatic, renal, or cardiac impairment.

Adverse effects include acne, oily skin, fluid retention, weight gain, hirsutism, voice change, hair loss, and other androgen-type effects.

[ABPI Medicines Compendium, 2009b]

Gonadotrophin-releasing hormone (GnRH) analogues

Gonadotrophin-releasing hormone (GnRH) analogues

Gonadotrophin-releasing hormone (GnRH) analogues should only be prescribed under the supervision of a gynaecologist. The effects should be monitored by both the GP and the gynaecologist.

The GnRH analogues are available in a number of different preparations:

Buserelin — intranasally, used daily.

Goserelin — subcutaneous injection (implant), administered every 28 days.

Leuprorelin — subcutaneous or intramuscular injection, administered monthly (or prolonged-release preparation given every 3 months).

Nafarelin — intranasally, used daily.

Triptorelin — subcutaneous or intramuscular injection, administered every 28 days.

Oral contraceptives should be discontinued before starting treatment. Start the GnRH analogue on the first or second day of menstruation (to ensure the woman is not pregnant; a pregnancy test is advisable if there is any doubt) [BNF 57, 2009].

Continue treatment for 6 months. GnRH analogue treatment is licensed for 6 months, and only a single course of treatment is recommended by the manufacturers. However, repeated or longer courses may be recommended by specialists for some women, even though there are limited data regarding the safety and efficacy of this approach [Olive, 2004]. Options include:

Treatment for 3 months, as this may be as effective as treatment for 6 months in terms of pain relief. A double-blind, prospective, multicentre trial of women with pelvic pain and endometriosis (n = 179) found that a 3-month course of nafarelin was as effective as a 6-month course for pain relief [Hornstein et al, 1995].

Repeated shorter courses of treatment. This approach offers the theoretical possibility of a sustained beneficial effect combined with less impact on bone mineral density and fewer hypo-oestrogenic adverse effects [Rice, 2002].

Repeated courses of treatment in combination with add-back therapy.

Warn women about the flare effect that can occur in the first few days of treatment: this is an exacerbation of symptoms caused by an initial rise in estradiol levels [BNF 57, 2009].

Advise a non-hormonal method of contraception, where appropriate. If treatment is interrupted even for only a few days, ovulation may occur and there is a risk of pregnancy [BNF 57, 2009].

Avoid during pregnancy and lactation, and in women with undiagnosed vaginal bleeding or hormone-dependent cancer [BNF 57, 2009].

Adverse effects include hot flushes, insomnia, reduced libido, vaginal dryness, irritability, depression, palpitations, joint stiffness, insomnia, and headaches [Kennedy and Moore, 2003]. GnRH analogues affect bone mineral density, which typically falls by 4–6% during treatment [DTB, 1999].

The addition of add-back treatment usually reduces these adverse effects.

Add-back therapy

Add-back therapy

Add-back therapy can reduce the bone loss and hot flushes that accompany GnRH analogue treatment [RCOG, 2006]. It should generally be initiated under specialist supervision; if it is prescribed in primary care, the specialist should be kept informed.

There are a variety of regimens for add-back therapy, and a lack of evidence to guide treatment choice. Feedback from CKS expert reviewers suggests that:

Tibolone (2.5 mg daily) is generally preferred by experts because it has oestrogenic, progestogenic, and androgenic activity, and is licensed for use as add-back therapy. CKS suggests seeking specialist advice before prescribing.

Hormone replacement therapy (usually continuous-combined) can also be used as add-back therapy for women taking a gonadotrophin-releasing hormone analogue (off-label use).

If induction of amenorrhoea does not relieve symptoms, it may be necessary to consider an alternative diagnosis [Drife and Magowan, 2004a].

Evidence

Evidence

Supporting evidence

Analgesics

Evidence on analgesics

Paracetamol

Evidence on paracetamol

There is no evidence on the use of paracetamol for the pain associated with endometriosis.

CKS found no direct evidence to support the use of paracetamol in relieving the pain associated with endometriosis.

Evidence for the use of paracetamol to treat primary dysmenorrhoea is very limited.

A systematic review investigated the efficacy of minor analgesics for relieving pain in primary dysmenorrhoea. One small randomized controlled trial (n = 35) found paracetamol (500 mg four times a day — a sub-therapeutic dose) was no better than placebo at relieving pain (relative risk 1.00, 95% CI 0.28 to 3.63) [Zhang and Li Wan Po, 1998].

A Cochrane systematic review of nonsteroidal anti-inflammatory drugs (NSAIDs) for the treatment of primary dysmenorrhoea found two trials (n = 165) comparing paracetamol with an NSAID. No difference in pain relief was found, but the authors of the review pointed out that the available evidence had little power to detect such differences [Marjoribanks et al, 2003].

NSAIDs

Evidence on nonsteroidal anti-inflammatory drugs

There is inconclusive evidence from one small randomized placebo-controlled trial that naproxen is effective for the management of the pain associated with endometriosis. There is no evidence to indicate whether any one nonsteroidal anti-inflammatory drug (NSAID) is better than another in treating the pain associated with endometriosis.

A Cochrane systematic review (search date: to May 2005) looked at whether NSAIDs are effective in managing the pain caused by endometriosis, compared with placebo, no treatment, or other pain-management drugs [Allen et al, 2009].

The review found only two trials addressing the use of NSAIDs for endometriosis, but only one small trial (n = 24) was included in the review due to methodological limitations of the other study.

Naproxen sodium (275 mg four times per day) showed no statistically significant improvement in the pain associated with endometriosis compared with placebo (odds ratio 3.27, 95% CI 0.61 to 17.69).

There is inconclusive evidence to show whether any one NSAID is more effective than another.

However, there is good evidence to support the use of NSAIDs in the treatment of primary dysmenorrhoea (see the CKS topic on Dysmenorrhoea).

Effect of ovulation suppression on subfertility

Evidence on the effect of ovulation suppression on subfertility

There is no evidence to support the use of ovulation suppression with hormonal treatments to treat endometriosis-associated subfertility.

A Cochrane systematic review [Hughes et al, 2007] (search date: to 2007) looked at the effect of ovulation suppression (with gonadotrophin-releasing hormone [GnRH] analogues, danazol, medroxyprogesterone acetate, gestrinone, and combined oral contraceptives) on endometriosis-associated subfertility when compared with no treatment or placebo. Twenty three trials were found (n = 3043 women).

Ovulation suppression was compared with placebo or no treatment (eleven studies, n = 386, odds ratio for pregnancy 0.79, 95% CI 0.54 to 1.14). This suggests no statistically significant benefit from treatment.

There was no statistically significant difference between danazol and other ovulation suppression drugs in subfertile women.

When GnRH analogues were compared with danazol there was no evidence of benefit in subfertile women.

When GnRH analogues were compared with combined oral contraception, in a single study, there was no evidence of benefit of one treatment over the other.

The authors concluded that there was no evidence to support treating women with endometriosis-associated subfertility with ovulation suppression.

Combined oral contraceptives

Evidence on combined oral contraceptives

There is limited evidence from one small randomized controlled trial (RCT) to show that the low-dose combined oral contraceptive (COC) is more effective than placebo at treating the pain associated with endometriosis. Limited evidence available from one small RCT suggests that the low-dose COC is as effective as goserelin in relieving the pain associated with endometriosis.

A double-blind, randomized, placebo-controlled trial studied the effectiveness of a low-dose COC for dysmenorrhoea associated with endometriosis [Harada et al, 2008].

Women were randomized to receive either a monophasic COC (ethinylestradiol 0.035 mg plus norethisterone 1 mg) for 21 days plus 7 days of placebo, or identical placebo, for four cycles.

Pain scores for dysmenorrhoea were significantly reduced by the end of treatment in both groups, but the reduction in the pain score was significantly greater (p < 0.0001) in the group that took the low-dose COC than in the placebo group.

It was concluded that low-dose COCs are an effective treatment for dysmenorrhoea associated with endometriosis.

A Cochrane systematic review [Davis et al, 2007] (search date: September 2006) looked at the efficacy of COCs for reducing the pain of endometriosis and found only one RCT (n = 57) that satisfied the inclusion criteria [Vercellini et al, 1993]. The included women had laparoscopically-diagnosed endometriosis and moderate or severe pain, and were randomized to receive either goserelin 3.6 mg subcutaneously monthly, or a low-dose COC.

After 6 months of treatment, the low-dose COC (ethinylestradiol 0.02 mg plus desogestrel 0.15 mg taken cyclically) was as effective as a gonadotrophin-releasing hormone (GnRH) analogue (goserelin 3.6 mg subcutaneously once a month) for the relief of dyspareunia (odds ratio [OR] 4.87, 95% CI 0.96 to 24.65) and non-menstrual pain (OR 0.93, 95% CI 0.25 to 3.53).

In addition, the COC reduced dysmenorrhoea, and the GnRH analogue induced amenorrhoea. At the end of a 6 month follow-up period there was no significant difference between the two groups in the reduction of recurrence of dysmenorrhoea (OR 0.48, 95% CI 0.08 to 2.9).

It should be noted that the dosage of oestrogen in the preparations included in this review was lower than that usually prescribed for endometriosis (20 micrograms compared with 30–35 micrograms).

The authors concluded that there was no significant difference between the effectiveness of low-dose COCs and a GnRH analogue in the relief of dyspareunia and non-menstrual pain. However this study may have been underpowered to detect a difference.

Progestogens and androgens

Evidence on progestogens and androgens

Evidence is limited due to lack of data, but continuous high-dose oral progestogen (medroxyprogesterone acetate) and gestrinone appear to be effective for the treatment of the pain associated with endometriosis. Luteal-phase dydrogesterone does not appear to be effective. There is limited evidence for the use of norethisterone for pelvic pain. There is limited evidence from a Cochrane systematic review of two randomized, double-blind, placebo-controlled trials that danazol is effective at treating the symptoms of endometriosis when compared with placebo, but its use is limited by androgenic adverse effects.

A Cochrane systematic review (search date: to January 2000) compared the efficacy of progestogens and androgens at relieving the pain associated with endometriosis with other hormonal treatments [Prentice et al, 2000].

Seven studies were included in the review. Three evaluated progestogens (comparing progestogens with placebo, danazol, and an oral contraceptive plus danazol), and four studies compared gestrinone with other medical treatment.

There was a general lack of data, and none of the studies included enough women for any firm conclusions to be reached.

The authors cautiously concluded that treatment with androgens or continuous progestogens is likely to be effective.

However, there appears to be some doubt with respect to the efficacy of luteal-phase dydrogesterone.

An open label parallel group randomized controlled trial compared a twelve month course of ethinyl E2, 0.01 mg plus cyproterone acetate 3 mg daily with norethisterone acetate 2.5 mg daily for the treatment of pelvic pain in women with persistent, infiltrating rectovaginal plaques (n = 90) who had had conservative surgery for rectovaginal endometriosis. The primary outcome measure was satisfaction with treatment [Vercellini et al, 2005].

An intention to treat analysis found that 62% of the women in the ethinyl E2 plus cyproterone acetate group were satisfied or very satisfied after 12 months of treatment compared with 73% of women in the norethisterone acetate group (p = 0.37, odds ratio [OR] 0.9, 95% CI 0.25 to 1.46).

The authors concluded that low dose norethisterone could be used temporarily for treatment of rectovaginal endometriosis.

There is limited evidence from two retrospective studies that norethisterone may relieve symptoms of endometriosis.

A retrospective analysis of 52 women with laparoscopically diagnosed endometriosis who received norethisterone (up to a maximum daily dose of 20 mg) to induce amenorrhoea found that 49/52 (94%) experienced pain relief [Muneyyirci-Delale and Karacan, 1998]. Breakthrough bleeding was reported by 30 women (58%) and was severe in 7 women. Some of the women in this trial also received oestrogen if their symptoms were not controlled by norethisterone.

A retrospective study of 82 women with surgically diagnosed endometriosis had a mean follow up time of 5.7 years [Muneyyrici-Delale and Jalou, 2001]. Forty women received norethisterone acetate in various formulations (dependent on what the woman could afford) and the control group (n = 42) received either oral contraceptives, other progestogens or even a short course of norethisterone. The study reported that dysmenorrhoea and non-cyclic pelvic pain were relieved in 39/40 women taking norethisterone, but only in 3/42 (dysmenorrhoea) or 5/42 (pelvic pain) in the control group.

A Cochrane systematic review (search date: April 2007) [Selak et al, 2007] looked at the effectiveness of danazol compared with placebo or no treatment.

Five trials were originally included in the review but three were excluded because their outcomes related only to subfertility. Two randomized controlled trials (RCTs) that examined the effect of danazol on the pelvic pain associated with endometriosis (n = 119) were analysed. There is a possibility of participant overlap between these studies as they were carried out by the same researcher.

In both studies women took either danazol 200 mg three times a day, or oral medroxyprogesterone 100 mg daily plus placebo twice daily, or placebo three times a day.

Without surgery (n = 59), danazol significantly reduced total pain scores compared with placebo after 6 months of treatment (weighted mean difference [WMD] –5.7, 95% CI –7.5 to –3.8). The improvement in pain was still present 6 months after danazol was stopped. However, no significant difference was found between the two groups in terms of the levels of dysuria and dyspareunia.

With surgery (n = 60), danazol significantly reduced total pain scores compared with placebo after 6 months of treatment (WMD –3.4, 95% CI –4.8 to –1.8). The improvement in pain was still present 6 months after the danazol treatment ended. The extent of the surgery was not described other than that it was conservative.

There was a significant increase in adverse effects in women treated with danazol compared with placebo at 6 months.

Adverse effects with danazol alone, compared with placebo (one study, n = 59).

Acne (OR 10.8, 95% CI 2.7 to 42.8).

Muscle cramps (OR 9.7, 95% CI 1.7 to 55.3).

Oedema (OR 7.11, 95% CI 1.5 to 31.6).

Vaginal spotting (OR 14.0, 95% CI 3.3 to 59.7).

Adverse effects with danazol as an adjunct to surgery, compared with placebo (one study, n = 60).

Acne (OR 8.9, 95% CI 2.16 to 36.7).

Weight gain (OR 3.0, 95% CI 1.3 to 4.6).

Vaginal spotting (OR 8.9, 95% CI 2.6 to 36.7).

Depot medroxyprogesterone acetate

Evidence on depot medroxyprogesterone acetate

There are no randomized placebo-controlled trials to support the use of depot medroxyprogesterone acetate for the treatment of the pain associated with endometriosis. There is indirect evidence from one small randomized trial that compared depot medroxyprogesterone acetate with the combined oral contraceptive (COC) pill plus danazol that suggests depot medroxyprogesterone acetate is effective for the treatment of the pelvic pain associated with endometriosis.

In a small randomized controlled trial (RCT) [Vercellini et al, 1996], women with endometriosis and moderate or severe pelvic pain (n = 80) were randomized to receive 12 months' treatment with either intramuscular depot medroxyprogesterone acetate (150 mg every 3 months) or a low-dose COC (ethinyl estradiol 0.02 mg, desogestrel 0.15 mg) combined with danazol for 21 days of a 28 day cycle.

More women (29/40 [72.5%]) in the depot medroxyprogesterone acetate group were satisfied after 1 year of treatment than in the COC plus danazol group (23/39 [57.5%]) (p = 0.24, odds ratio 1.95, 95% CI 0.76 to 4.97).

Both groups had a significant decrease in symptom scores.

At the 1-year assessment, dysmenorrhea was significantly greater in women who had taken the low-dose COC plus danazol.

The authors concluded that depot medroxyprogesterone acetate seems to be an effective treatment for endometriosis, with a good safety profile.

One RCT (n = 274) compared subcutaneous depot medroxyprogesterone acetate with leuprolide (a gonadotrophin-releasing hormone analogue), for 6 months, with 12 months post-treatment follow up. This preparation of medroxyprogesterone was formulated especially for subcutaneous use and its composition and ratio of ingredients differs from the intramuscular formulation [Schlaff et al, 2006].

Medroxyprogesterone acetate was as effective as leuprolide at treating the symptoms of endometriosis (dysmenorrhoea, dyspareunia, pelvic pain, and pelvic tenderness). The mean change from baseline in composite scores for the medroxyprogesterone acetate group was –6.2 at 6 months and –5.3 at 18 months, whereas the corresponding values for the leuprolide group were –7.7 and –5.1. This was statistically significant (p < 0.001).

In addition, women treated with medroxyprogesterone acetate had significantly less bone mineral density loss and fewer hypo-oestrogenic adverse effects, but more bleeding or spotting days.

Levonorgestrel-releasing intrauterine system

Evidence on the levonorgestrel-releasing intrauterine system

There is limited evidence from one small, open-label study for use of the levonorgestrel-releasing intrauterine system (LNG-IUS) following surgery for endometriosis, and limited evidence from two small, randomized controlled trials (RCTs) and three small, prospective, observational studies that it may be useful for the pain associated with endometriosis.

A Cochrane systematic review (search date: January 2006) [Abou-Setta et al, 2006] studied the post-operative use of the LNG-IUS to see if it relieved the pain due to endometriosis or reduced the recurrence rate compared with treatment with surgery alone, placebo, or oral hormones.

One small, open-label, parallel-group, prospective RCT was found [Vercellini et al, 2003]. This included women (n = 40), 41 years of age and older, who had experienced disabling pain for at least 6 months and who were undergoing operative laparoscopy. The trial compared the LNG-IUS with a control group receiving a gonadotrophin-releasing hormone (GnRH) agonist. In the LNG-IUS group there was a:

Statistically significant reduction in the recurrence of painful periods (odds ratio [OR] 0.14, 95% CI 0.02 to 0.75).

Statistically non-significant number of participants who were more satisfied with their treatment (75%, 15/20) than in the control group (50%, 10/20) (OR 3.00, 95% CI 0.79 to 11.44).

No extractable data were available for the recurrence rates, dyspareunia and painful passage of bowel movements, or quality of life.

A systematic review (search date: to February 2005) found limited evidence to suggest that the LNG-IUS may be beneficial in women with endometriosis [Varma et al, 2006].

The studies included women with: early- and late-stage endometriosis; rectovaginal endometriosis; a history of endometriosis; chronic pelvic pain with or without dysmenorrhoea; and women who had just had surgical treatment.

The review included two RCTs and three prospective observational studies; however, all studies had small sample sizes (n = 11–39) and there was considerable heterogeneity between them, which limits the strength and validity of the findings.

The results suggested that the LNG-IUS reduces the pain associated with endometriosis, with symptom control lasting 3 years.

More research is needed in order to consider the LNG-IUS as a treatment in women with endometriosis.

Contraceptive implant

Evidence on the contraceptive implant

Very limited evidence from a small randomized controlled trial, an open-label study, and five case studies suggests that the etonogestrel subdermal implant might be useful in relieving the pelvic pain associated with endometriosis.

Note that from mid-October 2010, Nexplanon® will replace Impanon®. Nexplanon® is bioequivalent to Implanon®. The main differences are that Nexplanon® is radio-opaque, and the insertion technique is different [FSRH, 2010].

An open-label, prospective, randomized, controlled, pilot trial studied women with dysmenorrhoea, non-menstrual pelvic pain, and dyspareunia who had histologically-proven endometriosis. The effect on pelvic pain of the etonogestrel subdermal implant (Implanon®) (n = 21) was compared with depot medroxyprogesterone acetate (n = 21) [Walch et al, 2009]. After 6 months the average decrease in pain was 68% in the Implanon® group and 53% in the depot medroxyprogesterone acetate group: this difference was not significant. Adverse effects and the degree of satisfaction were similar in both groups.

A open-label clinical trial in Thailand recruited 50 women with laparoscopically-proven endometriosis or whose symptoms had recurred after surgery [Ponpuckdee and Taneepanichskul, 2005]. They all received an etonogestrel subdermal implant and were assessed at 4 and 12 weeks for both the effect on pelvic pain and adverse effects. There was a significant reduction in pain scores on a visual analogue scale at both 4 weeks (p < 0.001) and 12 weeks (p = 0.001). Amenorrhoea was reported by 28% of participants, regular menstruation by 42%, breakthrough bleeding by 4%, and spotting by 26%. At the final evaluation, 80% of women were either satisfied or very satisfied; 20% were uncertain of the benefit. All were willing to continue treatment with the implant.

A report on five case studies of women with severe endometriosis treated with the etonogestrel subdermal implant (Implanon®) found that all five women experienced relief of pelvic pain. One woman withdrew from treatment because of unacceptable adverse effects, but the remaining four women were happy to continue with the implant [Yisa et al, 2005].

Gonadotrophin-releasing hormone analogues

Evidence on gonadotrophin-releasing hormone analogues

Endometriosis-associated symptoms

Evidence on the effect on endometriosis-associated symptoms

Gonadotrophin-releasing hormone (GnRH) analogues appear to be as effective as other medical treatments in relieving the pain of endometriosis, but the evidence is limited by the quality of the data.

A Cochrane systematic review (search date: to January 1999) concluded that there was little or no difference in the effectiveness of GnRH analogues compared with other medical treatments for endometriosis [Prentice et al, 1999].

Seven studies were included in the review. GnRH analogues were compared with placebo, no treatment, danazol, gestrinone, oral contraceptives, and to GnRH analogues plus add-back therapy. Some of the data were incomplete or did not allow for meta-analysis and it was difficult to judge the quality of the trials.

The differences that were reported related to adverse effects, not to the primary endpoints of pain relief and disease resolution.

This review has now been withdrawn; it was published in 1999 and an updated review has not yet been submitted.

Add-back therapy and bone density

Evidence on the effect of add-back therapy on bone mineral density

There is good evidence that danazol add-back therapy, or combined progestogen plus oestrogen add-back therapy, are protective of bone mineral density (BMD) in women receiving gonadotrophin-releasing hormone (GnRH) analogues. Progestogen alone is not effective. Danazol has significant adverse effects that limit its use. Evidence from a small trial suggests that tibolone is more effective than placebo.

A Cochrane systematic review (search date: to March 2003) [Sagsveen et al, 2003] examined the effect of treatment with GnRH analogues on the bone mineral density of women with endometriosis, compared with placebo, no treatment, or other treatments for endometriosis, including GnRHs with add-back therapy. Thirty prospective randomized controlled trials (n = 2391) were found but only 15 trials (n = 910) were included in the meta-analysis.

Treatment with GnRH analogues resulted in a decrease in BMD (in the lumbar spine) compared with an increase following treatment with danazol (standard mean difference [SMD] –1.17, 95% CI –1.73 to –0.62).

BMD was significantly higher in women treated with GnRH analogues with oestrogen add-back therapy (either oestrogen and progestogen, or oestrogen alone) compared with women treated with GnRH analogues alone (SMD –0.49, 95% CI –0.77 to –0.21).

Progestogen-only add-back therapy was not effective: there was no difference in BMD between GnRH analogues alone and GnRH analogues with progestogen-only add-back therapy (SMD 0.06, 95% CI –0.45 to +0.32).

There was no difference in BMD between GnRH analogues and calcium-regulating agents (such as calcitonin); but only two such trials were included in the meta-analysis and it is not possible to draw firm conclusions (SMD 0.22, 95% CI –0.43 to +0.88).

The authors concluded that both danazol, and progestogen plus oestrogen add-back therapy, are protective of BMD while on treatment, and up to 6 months and 12 months later (respectively). However 24 months after stopping treatment there was no difference in BMD between women who had received add-back therapy and women who had not.

A small, double-blind, randomized, prospective study examined the effect of add-back therapy with tibolone on women with endometriosis (n = 29) or fibroids (n = 2) treated with the GnRH triptorelin [Lindsay et al, 1996].

Women received either tibolone 2.5 mg as add-back therapy or placebo.

BMD decreased by 1.1% in the tibolone group and by 5.1% in the placebo group. The difference in bone loss of 3.9% between the groups was significant (p = 0.001, 95% CI 1.7 to 6.2).

The daily frequency of hot flushes was significantly lower in the tibolone group (p = 0.017).

Surgery

Evidence on surgery

Surgical procedures and subfertility

Evidence on the effects of surgical procedures on subfertility

The use of laparoscopic surgery in the treatment of minimal and mild endometriosis may improve the chance of pregnancy, but the evidence is conflicting and limited to two randomized controlled trials (RCTs).

A Cochrane systematic review reported that the use of laparoscopic surgery in the treatment of minimal and mild endometriosis may improve fertility rates, although the studies included in the review had conflicting results and some methodological problems [Jacobson et al, 2002].

The meta-analysis included two RCTS that compared the effectiveness of laparoscopic surgery in the treatment of endometriosis associated with subfertility with diagnostic laparoscopy alone.

The larger study (n = 341) reported an increased chance of pregnancy (odds ratio [OR] 2.03, 95% CI 1.28 to 3.24) and ongoing pregnancy rate after 20 weeks (OR 1.95, 95% CI 1.18 to 3.22).

However, the smaller study (n = 101) reported no benefit in either pregnancy rate (OR 0.76, 95% CI 0.31 to 1.88) or live births (OR 0.85, 95% CI 0.32 to 2.28).

Surgical treatments for pelvic pain

Evidence on surgical treatments for pelvic pain

There is limited evidence from a Cochrane systematic review of one small randomized controlled trial (RCT) that laser ablation, adhesiolysis, and uterine nerve ablation performed together are beneficial in the treatment of pain due to mild or moderate endometriosis compared with diagnostic laparoscopy alone. There is limited evidence from one RCT that women who have a laparoscopy with excisional surgery are likely to have less pain and an improved quality of life at 1 year compared with women who have had a diagnostic laparoscopy alone.

A Cochrane systematic review [Jacobson et al, 2001] examined the effects of laparoscopic surgery on the treatment of pelvic pain in women with endometriosis, and found only one RCT.

Women (n = 74) with mild-to-moderate endometriosis and pain were randomized to receive either laser treatment, adhesiolysis and uterine nerve transection, or diagnostic laparoscopy alone. Eleven were subsequently excluded from the trial.

Pain scores were measured at 3 and 6 months of follow up.

There was a significant degree of pain relief at 6 months in the group who received laser laparoscopic surgery compared to the group that received diagnostic laparoscopy alone (odds ratio 4.97, 95% CI 1.85 to 13.39).

The results should be interpreted cautiously as only one trial was analysed.

In a subsequent RCT (n = 39) [Abbott et al, 2004], women with histologically-proven endometriosis were randomized to have either a diagnostic laparoscopy, or surgical excision of endometriotic lesions followed by a laparoscopy 6 months later, at which time any endometriosis present was treated. The women who received the initial excisional surgery reported greater improvement in symptoms and quality of life than the women in the placebo group (16/20 [80%] compared with 6/19 [32%]). Both groups reported a significant reduction in pain symptoms (except pain on defecation) at 12 months.

Pre- and post-operative hormonal treatment

Evidence on pre- and post-operative hormonal treatment

There is insufficient evidence to suggest that hormonal suppression in association with surgery for endometriosis will significantly benefit eradication of endometriosis, improvement of symptoms, pregnancy rates, and overall tolerability.

A Cochrane systematic review (search date: September 2003) [Yap et al, 2004] looked at the effectiveness of hormonal suppression, before or after surgery for endometriosis, on the eradication of endometriosis, improvement of symptoms, pregnancy rates, and overall tolerability.

Pre-surgical medical treatment (goserelin) improved fertility compared with surgery alone (one study, n = 80; weighted mean difference [WMD] –9.60, 95% CI –11.42 to –7.78).

Post-surgical medical treatment

Compared with surgery alone, post-surgical medical treatment with danazol, a low-dose combined oral contraceptive, or a gonadotrophin-releasing hormone analogue (leuprolide, triptorelin, goserelin) was no better at 12 months (five studies, n = 567; relative risk [RR] 0.76, 95% CI 0.52 to 1.10). However, the results neared statistical significance at 24 months (five studies, n = 567; RR 0.70, 95% CI 0.47 to 1.03). There was no significant difference in disease recurrence (five studies, n = 567; RR 1.02, 95% CI 0.27 to 3.84) or pregnancy rates (five studies, n = 567; RR 0.78, 95% CI 0.50 to 1.22).

After surgery, post-surgical treatment with nafarelin, medroxyprogesterone, or danazol (three studies, n = 244) showed no difference from post-surgical placebo with regard to pain. There was no difference in pregnancy rates between the groups (RR 1.05, 95% CI 0.44 to 2.51).

Pre-surgical medical treatment compared with post-surgical medical treatment (intranasal nafarelin) did not differ in regard to pelvic pain (one study, n = 53; RR 1.01, 95% CI 0.49 to 2.07).

HRT after oophorectomy

Evidence on the effects of hormone replacement therapy after oophorectomy

Although there is a risk that hormone replacement therapy (HRT) might cause recurrence of endometriosis, evidence from two small randomized controlled trials (RCTs) is not strong enough to deprive severely symptomatic women of HRT.

A Cochrane systematic review (search date: March 2008) [Al Kadri et al, 2009] examined whether HRT in women who had undergone bilateral oophorectomy for endometriosis (and therefore had a surgically-induced premature menopause) induced a recurrence of the disease and its symptoms. Two RCTs were found.

One trial [Fedele et al, 1999] in women with a conserved uterus (n = 21) compared tibolone (2.5 mg per day) with transdermal 17 beta-estradiol (0.05 mg per day) plus medroxyprogesterone acetate (10 mg per day for 12 days a month). Recurrence of pain was found in 1/11 women in the tibolone group and 4/10 women in the progestogen group. This was not statistically significant.

The second trial (n = 172) compared no treatment with treatment with oestrogen plus progestogen (transdermal patches released 0.05 mg of 17 beta-estradiol per day, and micronized progestogen [200 mg per day] was taken orally for 14 out of 30 days).

There was no statistical difference between the groups in the recurrence of pain (0/57 in the treatment group and 4/115 in the no-treatment group).

Recurrence of endometriosis was not reported in the no-treatment group and 2/115 of women had recurrence in the treatment group.

This trial was not sufficiently powered to detect a difference.

The authors concluded that although HRT might cause recurrence of endometriosis and pain, there is insufficient evidence to deprive women with severe menopausal symptoms following bilateral oophorectomy of this treatment.

Search strategy

Scope of search

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of Endometriosis.

Search dates

January 2005 – January 2008

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

endometriosis/, endometriosis.tw.

Table 1 . Key to search terms.
Search commands Explanation
/ indicates a MeSH subject heading with all subheadings selected
.tw indicates a search for a term in the title or abstract
exp indicates that the MeSH subject heading was exploded to include the narrower, more specific terms beneath it in the MeSH tree
$ indicates that the search term was truncated (e.g. wart$ searches for wart and warts)
Topic specific literature search sources

Royal College of Obstetricians and Gynaecologists

Sources of guidelines

National Institute for Health and Care Excellence (NICE)

Scottish Intercollegiate Guidelines Network (SIGN)

National Guidelines Clearinghouse

New Zealand Guidelines Group

British Columbia Medical Association

Canadian Medical Association

Institute for Clinical Systems Improvement

Guidelines International Network

National Library of Guidelines

National Health and Medical Research Council (Australia)

Alberta Medical Association

University of Michigan Medical School

Michigan Quality Improvement Consortium

Royal College of Nursing

Singapore Ministry of Health

Health Protection Agency

National Resource for Infection Control

CREST

World Health Organization

NHS Scotland National Patient Pathways

Agency for Healthcare Research and Quality

TRIP database

Patient UK Guideline links

UK Ambulance Service Clinical Practice Guidelines

RefHELP NHS Lothian Referral Guidelines

Medline (with guideline filter)

Sources of systematic reviews and meta-analyses

The Cochrane Library :

Systematic reviews

Protocols

Database of Abstracts of Reviews of Effects

Medline (with systematic review filter)

EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

NIHR Health Technology Assessment programme

The Cochrane Library :

NHS Economic Evaluations

Health Technology Assessments

Canadian Agency for Drugs and Technologies in Health

International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

The Cochrane Library :

Central Register of Controlled Trials

Medline (with randomized controlled trial filter)

EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

Bandolier

Drug & Therapeutics Bulletin

MeReC

NPCi

DynaMed

TRIP database

Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

Department of Health

Health Management Information Consortium (HMIC)

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