SECTION 1: EPIDEMIOLOGY AND AETIOLOGY
Endometriosis is defined as the presence of endometrial tissue outside the uterus. It is an estrogen-dependent condition that usually affects women of reproductive age. It is rarely found before menarche and tends to regress after the menopause. Women from all ethnic and social backgrounds are affected. There are few studies on the prevalence of endometriosis. It is estimated that 10% of women of reproductive age are affected.1
Endometriosis can be found almost anywhere within the body apart from the spleen, but is most commonly located within the pelvis. The lesions may be in the form of pigmented or non-pigmented superficial lesions, ovarian cysts or deep nodules.
Superficial lesions are found on the peritoneal or ovarian surfaces. The pigmented lesions appear dark blue or brown due to haemosiderin content, and nonpigmented lesions are usually white in colour and may show vesicular or fibrotic appearances. There may be new vessel formation around these superficial lesions.
Ovarian cysts (endometriomas) contain thick, brown-coloured old haemorrhagic fluid and are frequently called chocolate cysts. Deep nodules of endometriosis are often found in the rectovaginal space, uterosacral ligaments, pelvic side walls and uterovesical area. There is quite often adhesion formation, resulting in adherence of pelvic structures to each other and significant distortion of the pelvic anatomy in more advanced forms of the condition.
Some groups consider peritoneal, ovarian and rectovaginal endometriosis as different entities. However, they are often found together and it is possible they have a common aetiology. Common theories on the aetiopathogenesis of endometriosis include retrograde menstruation, coelomic metaplasia, lymphatic/vascular dissemination or differentiation of circulating bone marrow cells into endometrium.2 The latter two theories are useful in explaining the endometriosis at distant sites and the first two are more applicable to pelvic endometriosis.
Menstrual blood containing endometrium is found in the pelvis in most women in general. These cells may implant and survive in ectopic locations, either due to an intrinsic abnormality of the eutopic endometrium resulting in increased implantation ability, or to inability of the immune system to clear them from the peritoneal cavity in some women.
Endometriosis may be inherited in a polygenic manner; it is up to seven times more common in women with a family history.2
Nulliparous women and women with short cycles and heavy menstrual bleeding are more likely to develop endometriosis.1 These facts are consistent with the retrograde menstruation theory.
It is possible that the prevalence of endometriosis is related to age, with a peak age of diagnosis at 40-44 years. Current oral contraceptive pill use reduces risk, but this is possibly due to postponement of diagnosis secondary to improved pain symptoms while using it.3
SECTION 2: MAKING THE DIAGNOSIS
Endometriosis commonly presents with pain and/or infertility, although some women have no symptoms. The pain may be in the form of dysmenorrhoea, deep dyspareunia or non-menstrual pelvic pain.
Empirical treatment of pain presumed to be due to endometriosis is frequently employed. NSAIDs and the combined oral contraceptive pill (COC) are used in dysmenorrhoea, which may be secondary to endometriosis.4,5 It is important to explain the rationale of this approach and possible diagnoses such as endometriosis, adenomyosis and primary dysmenorrhoea should be discussed at this stage.
Empirical treatment is particularly helpful in teenagers with dysmenorrhoea. However, if there is no improvement, a further discussion should take place on the possibility of laparoscopy as up to 50-70% of teenagers who do not respond to initial medical treatment are reported to have endometriosis.
Some women may have cyclical intestinal symptoms (diarrhoea, constipation or painful defecation – that is, dyschezia, cyclical rectal bleeding) or fatigue. There may be additional symptoms when endometriosis is in unusual locations; cyclical haematuria, cyclical haemoptysis, cyclically enlarging painful and tender masses in the umbilicus, caesarean section and other laparotomy scars. Severe dysmenorrhoea in an infertile woman is highly suggestive of pelvic endometriosis. The symptoms of endometriosis are not specific and there is considerable overlap with other conditions such as primary dysmenorrhoea, PID, adenomyosis and irritable bowel syndrome.4
While clinical examination may be normal in women with minimal-mild endometriosis, abnormal findings, such as a retroverted uterus with reduced mobility, painful rectovaginal or uterosacral nodules, or the presence of adnexal masses, are not rare with more advanced endometriosis. Umbilical, abdominal or episiotomy scar nodules may easily be detected, particularly at the time of menstruation.
Pelvic ultrasound is usually the first-line investigation. The presence of persistent haemorrhagic ovarian cysts with ground glass echogenicity is highly specific and sensitive for the diagnosis of pelvic endometriosis. In experienced hands, adherence of the ovaries and deep endometriotic nodules may also be detected on ultrasound. MRI has a similar accuracy.
There are no reliable biochemical markers for endometriosis as yet. CA125 may be elevated in women with endometriosis, but is non-specific.4
Laparoscopy may be required when diagnosis is uncertain, symptoms are severe or surgical treatment is planned. Laparoscopy is highly accurate for excluding or confirming endometriosis. However, it is an invasive diagnostic tool with potential morbidity. Histological confirmation may be useful, but negative histology does not exclude the diagnosis.
There is often a delay between the beginning of symptoms and establishment of diagnosis. This may be due to a number of factors, including significant overlap of symptoms with other conditions, requirement of a laparoscopy for diagnosis, lack of awareness of the condition among women and healthcare professionals, and inadequate use of diagnostic tools.
SECTION 3: MANAGING THE CONDITION
Management is tailored according to symptoms, age, reproductive plans and extent/location of the lesions. The treatment of pain may involve medical therapy, surgery, or both.
NSAIDs and the COC are used for the treatment of endometriosis-associated pain in confirmed disease. NSAIDs have not been shown to be significantly better than placebo for this purpose in RCTs, but COCs have been shown to be superior to placebo.6
COCs may be taken cyclically, but when dysmenorrhoea persists it may be useful to take them tricyclically or continuously to avoid periods.
Depot medroxyprogesterone acetate may also be helpful, especially if the woman becomes amenorrhoeic, although evidence for its use in the treatment of endometriosis-associated pain is lacking. The levonorgestrel intrauterine system (LNG-IUS) has been shown to be effective in the control of endometriosis-associated pain after surgery, in small RCTs.
Other medical treatment options, such as the gonadotrophin-releasing hormone analogues (GnRHa) and high-dose progestogens, are also effective in the treatment of endometriosis pain, but duration of their use is limited because of their side-effects.7,8 After treatment with these agents, one of the contraceptive options mentioned above should be started as maintenance therapy. Danazol and gestrinone are also effective, but they are rarely used in the UK due to unacceptable side-effects. Dienogest, a lower-dose progestin, is not licensed in the UK. Aromatase inhibitors, such as anastrozole, in combination with the COC should only be used when other treatment options fail.
It has to be emphasised that medical therapies do not eliminate the disease.
Surgical treatment of endometriosis is beneficial both for pain and infertility associated with endometriosis.9 Surgery is usually carried out laparoscopically and aims to eliminate endometriosis by excising or ablating it, to divide adhesions and to restore pelvic anatomy.
A number of RCTs demonstrated surgery to be more effective than diagnostic laparoscopy only for the control of pain and chances of spontaneous pregnancy. Surgical treatment of advanced endometriosis should ideally be carried out in centres of expertise where a multidisciplinary team is present, including gynaecologists experienced in advanced minimal access surgery, fertility specialists, colorectal surgeons, urologists and pain management specialists.
Surgical treatment of severe endometriosis is complex and may carry significant risks and long-term side-effects.
Endometriosis-associated infertility may require additional fertility treatment as well as or instead of surgery, such as IVF.
The efficacy of complementary therapies in endometriosis is questionable, but some women find them helpful.
SECTION 4: PROGNOSIS
Endometriosis is a potentially chronic condition and may require long-term treatment.
Medical treatment does not eliminate endometriotic lesions and symptomatic recurrence rates after discontinuation of treatment are in excess of 75-80%. Prospective RCTs reported long-term (at least six to 12 months) improvement of pain after surgery in more than 60% of patients. However, recurrence rates after surgery are in the region of 30-40%.
For this reason, long-term hormonal maintenance treatment should be recommended to women who are not trying to become pregnant.
SECTION 5: CASE STUDY
A 33-year-old woman and her partner of three years presented to their GP with an 18-month history of primary infertility.
The woman had been on the oral contraceptive pill for 15 years. She was first prescribed it due to severe period pains and decided to discontinue it two years ago to start a family.
After stopping the oral contraceptive pill, her periods started becoming very painful again and heavier; she also described occasional deep dyspareunia. She had no history of PID. She was not on any medication. Her partner had no significant past medical history.
Initial investigations showed ovulatory range luteal progesterone levels and a normal semen analysis.
They were referred to the fertility clinic at the local hospital, where hysterosalpingography showed bilateral patent fallopian tubes. Three cycles of superovulation and intrauterine insemination treatment were unsuccessful and a referral was made to the assisted conception unit for IVF treatment at the tertiary-level hospital. Pelvic examination showed a retroverted fixed uterus and a palpable rectovaginal nodule. A diagnosis of endometriosis was made.
The woman chose to undergo laparoscopic surgery due to worsening dysmenorrhoea, dyspareunia and dyschezia. At laparoscopy, which was performed as a joint procedure by the gynaecologist and the colorectal surgeon, she was found to have severe endometriosis, which included adherent ovaries and bowel obliterating the pouch of Douglas. The fallopian tubes were patent. The adhesions were separated, the ovaries freed and the rectovaginal nodule, which was protruding into the posterior vaginal fornix, was excised without opening the rectosigmoid.
The patient tried for pregnancy unsuccessfully, then underwent IVF treatment which was successful at the first attempt. An LNG-IUS was inserted three months after normal vaginal delivery for contraception and future prevention of endometriosis-related pain.
SECTION 6: EVIDENCE BASE
- Marcoux S, Maheux R, Berube S. Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis. N Engl J Med 1997, 24; 337(4): 217-22.
This article gives the outcome of the EndoCan trial, which compared the outcome of laparoscopic surgery for minimal-mild endometriosis-associated infertility to diagnostic laparoscopy only. Women were more likely to achieve spontaneous pregnancies after laparoscopic surgery.
- Seracchioli R, Mabrouk M, Frasca C et al. Long-term cyclic and continuous oral contraceptive therapy and endometrioma recurrence: a randomized controlled trial. Fertil Steril 2010; 93(1): 52-6.
This RCT from Italy showed that both cyclical and continuous use of the COC reduced the risk of endometrioma recurrence after surgical treatment compared with no treatment.
- Duffy JMN, Arambage K, Correa FJS et al. Laparoscopic surgery for endometriosis. Cochrane Database Syst Rev 2014, Issue 4. Art.No.: CD011031. DOI: 10.1002/14651858.CD011031.pub2.
This Cochrane review included 10 RCTs and concluded that laparoscopic surgery to treat mild and moderate endometriosis reduces overall pain and increases live birth or ongoing pregnancy rates.
The European Society of Human Reproduction and Embryology (ESHRE) guideline for the management of women with endometriosis was re-written in 2013 and is available online. A concise version was also published (Reference 4). It was developed by 12 experts in the field of endometriosis, a patient representative and a research specialist.
Key text and online
- Sutton C, Jones K, Adamson GD (editors). Modern management of endometriosis. London, Taylor & Francis, 2006.
- Endometriosis UK
Mr Ertan Saridogan is consultant in reproductive medicine and minimal access surgery, University College London Hospitals, London.
- This is an updated version of an article that was first published in September 2012
- Vigano P, Parazzini F, Somigliana E et al. Best Pract Res Clin Obstet Gynaecol 2004; 18(2): 177-200.
- Bulun SE. N Engl J Med 2009; 360(3): 268-79.
- Vercellini P, Eskenazi B, Consonni D et al. Hum Reprod Update 2011; 17(2): 159-70.
- Dunselman GA, Vermeulen N, Becker C et al. Hum Reprod 2014; 29(3): 400-12.
- Giudice LC. N Engl J Med 2010; 362(25): 2389-98.
- Davis L, Kennedy SS, Moore J et al. Cochrane Database Syst Rev 2007; 18(3): CD001019.
- Brown J, Kives S, Akhtar M. Cochrane Database Syst Rev 2012; Issue 3 CD002122.
- Brown J, Pan A, Hart RJ. Cochrane Database Syst Rev 2010; 8(12): CD008475.
- Duffy JMN, Arambage K,Correa FJS et al. Cochrane Database Syst Rev 2014, Issue 4. Art.No.: CD011031. DOI: 10.1002/14651858.CD011031.pub2.