Endometriosis

Endometriosis is a chronic oestrogen-dependent condition characterised by the growth of endometrial tissue in sites other than the uterine cavity, most commonly:¹

• The pelvic cavity, including the ovaries
• The uterosacral ligaments
• The pouch of Douglas
• The rectosigmoid colon
• The bladder and distal ureter

Other sites are rarely involved but include:

• The umbilicus
• Scar sites, e.g. following Caesarean section² and laparoscopy
• The pleura and pericardium
• The central nervous system

Adenomyosis is the invasion of the myometrium by endometrial tissue. Extra-uterine endometrial tissue causes inflammation, pain and the formation of adhesions. Clinically its significance is as a cause of chronic pelvic pain (15% of cases attributed to endometriosis),³ dyspareunia and female infertility.

• Estimates of the prevalence of endometriosis vary from 2-22%.⁴ The prevalence can only be an estimate as diagnosis requires laparoscopic confirmation. Endometriosis has a much higher prevalence in infertile women, estimated as between 25 and 40%.⁵
• Endometriosis is found almost exclusively in women of reproductive age, with diagnosis usually during a woman's thirties. It is uncommon in the under-twenties.⁴

Risk factors

• Risk factors include: an early menarche, late menopause, delayed childbearing, short menstrual cycles or long duration of menstrual flow.
• Obstruction to vaginal outflow, e.g. hydrocolpos, or defects in the uterus or fallopian tubes.
• Genetic factors:
  • Risk for first-degree relatives of women with severe endometriosis is 6 times higher than that for relatives of unaffected women.
  • Familial aggregation has been shown in clinical and population-based samples and in twin studies.⁶
  • There is evidence of linkage to chromosomes 7 and 10, but no relevant genes have yet been identified.
• Multiparity and the use of oral contraceptives are protective.

The histological origin of endometriosis remains controversial. Suggested theories have included:

• Retrograde menstruation
• Lymphatic or haematogenous spread
• Metaplasia

To explain why only some women develop endometriosis, genetic defects or immunological abnormalities are often suggested in addition to the above.

The ovarian steroids oestrogen and progesterone are intimately involved in the development of endometriosis, as evidenced by the relationship of disease activity to uninterrupted menstrual cycles, onset following menarche and remittance of disease at menopause and the benefit of medical therapy which suppresses ovulation. Increasingly, the interactions of these sex steroids with the inflammatory cascades are being understood at a molecular level.⁷

Common symptoms include:

• Dysmenorrhoea
• Dyspareunia
• Cyclical or chronic pelvic pain
• Subfertility

The clinical presentation is variable, with some women experiencing several severe symptoms and others having no symptoms at all. The severity of symptoms tends to increase with age.¹ Traditionally, the diagnosis has not been commonly applied in adolescence but should be considered, as early recognition and treatment may be beneficial.⁸

• Women with endometriosis may have no symptoms and be diagnosed incidentally or during investigations for infertility.
• The appearance or worsening of symptoms at the time of menstruation, or just prior to it, suggests endometriosis.
• Other symptoms include dysuria, painful defecation, abdominal pain, backache, menstrual irregularity, and cyclical pain or bleeding (e.g. epistaxis, haemoptysis) at extrapelvic sites.

Signs

• Examination is often normal.
• However, there may be:
  • Posterior fornix or adnexal tenderness
  • Palpable nodules in the posterior fornix or adnexal masses (endometriosis can cause cystic lesions on the ovaries known as 'chocolate cysts')
  • Bluish haemorrhagic nodules visible in the posterior fornix

• Pelvic inflammatory disease
• Ectopic pregnancy
• Torsion of an ovarian cyst
• Appendicitis
• Primary dysmenorrhoea
• Adenomyosis
• Irritable bowel disease
• Uterine fibroids
• Urinary tract infection

• For a definitive diagnosis of most forms of endometriosis, laparoscopy is the gold standard investigation but it is invasive with a small risk of major complications, e.g. bowel perforation.⁶
• Symptoms and laparoscopic appearance do not always correlate.¹
• Transvaginal ultrasound scanning appears to be a useful test both to make and to exclude the diagnosis of an ovarian endometrioma.⁶
• MRI scan may be a useful non-invasive tool in diagnosis, especially for subperitoneal deposits.¹
• CA-125 measurement has limited value as a screening test or diagnostic test.⁶

In an acute setting, blood tests (e.g. FBC), urinalysis and MC&S, cervical swabs (MC&S, chlamydia testing) and βhCG may be helpful in excluding some important differentials.

Management needs to be individualised according to patient needs. For pain, the general principle is to create a pseudo-pregnancy or pseudo-menopause, whilst the treatment of infertility requires a different approach.

• For laparoscopically confirmed disease, suppression of ovarian function for 6 months reduces endometriosis-associated pain.
• All hormonal drugs are equally effective: the combined oral contraceptive pill, danazol, oral or depot medroxyprogesterone acetate and the levonorgestrel intrauterine system (IUS) are as effective as the gonadotrophin-releasing hormone (GnRH) analogues and can be used long-term.¹ Approximately 80-85% patients improve with treatment.
• Ablation of endometriotic lesions reduces endometriosis-associated pain. The smallest effect is seen in patients with minimal disease.

Drugs

• Non-steroidal anti-inflammatory drugs, e.g. naproxen, may be effective in reducing the pain associated with endometriosis, although the evidence to date is inconclusive.¹⁰ Paracetamol, with or without added codeine, is an alternative.
• If there is no evidence of a pelvic mass on examination, there may be a role for a therapeutic trial of a combined oral contraceptive (monthly or tricycling) or a progestogen to treat pain symptoms suggestive of endometriosis without a diagnostic laparoscopy first.⁶
• There is currently no evidence for any benefit of pre-operative or post-operative hormonal treatment.
• GnRH agonist therapy given for 3 months may be as effective as treatment given for 6 months in relieving endometriosis-associated pain. If longer or repeated treatment is required, GnRH agonist use can be extended with 'add-back' therapy (a low-dose oestrogen, progestin or tibolone to relieve menopausal side-effects and prevent bone loss).⁶

Surgical

• Laparoscopic excision or ablation at the time of diagnostic laparoscopy. The main conservative surgical techniques performed by laparoscopy are thermal or laser ablation, excision, ovarian cystectomy and denervation procedures.⁴
• Endometriomata (large cysts of endometriosis) are best stripped out instead of drainage and ablation.¹
• Hysterectomy with salpingo-oophorectomy is reserved for women as a last resort.
• Laparoscopic ablation of minimal-moderate endometriosis appears to relieve pain, although it is unclear whether laparoscopic uterine nerve ablation (LUNA) is required additionally.

Fertility⁹

• Medical treatment for endometriosis should be avoided for women who are trying to conceive.⁶
• In minimal-mild endometriosis, suppression of ovarian function to improve fertility is not effective, but ablation of endometriotic lesions plus adhesiolysis is effective compared to diagnostic laparoscopy alone.
• There is insufficient evidence available to determine whether surgical excision of moderate-severe endometriosis enhances pregnancy rates.
• IVF is appropriate treatment, especially if there are co-existing causes of infertility and/or other treatments have failed, but IVF pregnancy rates are lower in women with endometriosis than in those with tubal infertility.

• Women with endometriosis are at higher risk of developing ovarian cancer, particularly clear cell and endometrioid variants,¹¹ and they also may be at increased risk of breast and other cancers, autoimmune and atopic disorders.¹²
• Infertility: moderate to severe endometriosis can cause tubal damage leading to infertility. Lesser degrees of endometriosis, even in the absence of any obvious tubal damage, are also associated with sub-fertility and increased risk of ectopic pregnancy.
• Adhesion formation may occur due to the endometriosis or following surgery.

• The natural course of the disease is variable and may or may not be progressive. In 2 studies following the natural history of endometriosis over 6-12 months, endometrial deposits resolved spontaneously in a third of women, deteriorated in nearly half, and were unchanged in the remainder.¹
• In the five years after surgery or medical treatment, 20-50% of women will have a recurrence. Long-term medical treatment (with or without surgery) has the potential to reduce recurrence but there is no clear evidence for this.¹
• Relapse following surgical treatment is common.⁴ Surgical cohort studies report a 20% recurrence rate at 2 years and 40-50% at 5 years. Few risk factors for recurrence have been consistently identified. The use of biomarkers to identify recurrence is under investigation.¹³