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March 2007: Tailor treatment to the patient in endometriosis

When should endometriosis be suspected as a cause of pelvic pain?

When should women with pelvic pain be referred to secondary care?

What are the most effective treatments for endometriosis?

When should endometriosis be suspected as a cause of pelvic pain?

When should women with pelvic pain be referred to secondary care?

What are the most effective treatments for endometriosis?

Endometriosis is a common gynaecological condition found almost exclusively in women of reproductive age. It is most common in patients aged 25 to 35 years. The signs and symptoms are diverse and the clinical course is highly variable and unpredictable. Endometriosis has been defined as the presence of endometrial-like tissue outside the uterus, which induces a chronic inflammatory reaction. The pathogenesis is still hugely debated, hence the condition has been known as a ‘disease of theories'; the most widely accepted theory is retrograde menstruation and implantation of viable endometrial cells.

41136034The prevalence of endometriosis in the general female population is not known. Diagnosis is confirmed by the presence of endometrial implants at surgery, and until a simple screening test is developed the true incidence will remain unknown. The prevalence of endometriosis at surgery varies according to the indication for the operation (see table 1, above).

Costs incurred

The annual incidence of pelvic pain in the UK is estimated at 14,000 with a prevalence of 345,000.1 The estimated total annual cost to society for all women with pelvic pain is £158.4 million (direct) and £24 million (indirect). The estimated total lifetime treatment costs for a one-year incidence cohort of women with pelvic pain are £10.5 million (direct) and £2.6 million (indirect).

The contribution of endometriosis to these costs is impossible to calculate because not every woman with pelvic pain will have a laparoscopy, but an estimate is 20–30 per cent. The economic burden of endometriosis can be calculated directly in terms of the cost of healthcare resources consumed, and indirectly in terms of lost work capacity. The cost of intangibles such as suffering and reduced quality of life is impossible to quantify.

Delay in diagnosis

There is considerable delay between the onset of symptoms and diagnosis. There is often a delay of up to 12 years between symptom onset and a definitive diagnosis.2 This delay may be due to the fact that the predictive value of any symptom(s) remains uncertain and symptoms of endometriosis overlap with normality such that dysmenorrhoea requiring simple analgesia, or the occasional ‘ouch' during sexual intercourse, is probably normal and these symptoms can be overlooked by both the woman and her GP. There is also considerable overlap between the symptoms of endometriosis and those of other conditions such as irritable bowel syndrome and pelvic inflammatory disease.

Psychosocial impact

In addition to the physical effects of the disease, the psychosocial impact of endometriosis is also a cause for concern. Every doctor should be aware of the feelings of frustration at the delay in diagnosis and consequent depression experienced by women with endometriosis.

Symptoms and signs

An accurate clinical assessment is essential to identify women at risk of endometriosis and those who require further evaluation. The symptoms are variable and often unrelated to the extent of the condition. Endometriosis can also be present without any symptoms and only discovered coincidentally.

The most common symptoms of endometriosis are listed in table 2, attached.3

A diagnosis of endometriosis should be considered in all women of reproductive age who have cyclic pelvic pain. Dysmenorrhoea typically begins one to two days before menstruation, lasts throughout the flow and necessitates time off work or school.

Deep dyspareunia relates to adhesions and rectovaginal endometriosis. It may be unilateral due to the presence of an endometrioma. The pain occurs during intercourse, is worst in the premenstrual phase and may be so severe that the couple avoid intercourse. A postcoital ache does not appear to be specific for endometriosis.

Dyschezia is a deep-seated pelvic pain on defecation and usually relates to a deep nodule of endometriosis between the vagina and rectum. The passage of stool produces a deep-seated pelvic pain. Women may describe clutching onto the toilet in pain. The pain is worst during the premenstrual phase and throughout the period. If the nodule penetrates the rectum it will produce rectal bleeding. The blood is mixed with the motion rather than on the toilet paper.

Pelvic examination is generally unhelpful, but endometriosis should be suspected if any of the following specific or non-specific findings are encountered during examination:

• Nodularity and tenderness behind the cervix

• Adnexal masses that may represent endometriomas

• A fixed retroverted uterus

• Pelvic discomfort to a degree that makes the woman too uncomfortable to be examined.

The presence of such signs should prompt early hospital referral.

Investigations

Investigations should be undertaken to exclude other treatable causes of pelvic pain.

Swabs for gonorrhoea and chlamydial infection should be taken. The existence of a nucleic acid amplification technique for chlamydial infection and gonorrhoea means that these infections can be identified on vaginal and endocervical swabs and urine. A speculum examination is no longer required and the test is highly sensitive and specific. Any identified infection should be treated and the woman and her partner referred to the genitourinary clinic for contact tracing and test of cure. Gonorrhoea is not always sensitive to ciprofloxacin and swabs for culture and sensitivity are required.

Trichomonas and candidal infection produce discharge and soreness, but not pelvic pain.

In the absence of infection, it is worthwhile addressing constipation (a common cause of dyspareunia) and irritable bowel syndrome (symptoms overlap with endometriosis) with empirical or ‘try it and see' treatment.

Transvaginal ultrasound (TVS) is of value in detecting ovarian endometriotic cysts (endometriomas). These typically have a ‘ground glass' appearance because of the presence of altered blood within the cyst. Haemorrhagic functional cysts and corpus luteal cysts have a similar appearance, but will disappear in subsequent cycles. Negative ultrasound findings do not exclude the disease as TVS has limited value in diagnosing peritoneal endometriosis.

Who to refer

Although there are no specific guidelines on which women need secondary care, those in the following groups should be considered for referral:

• Abnormal signs such as endometriotic nodules and adnexal mass

• Failed empirical treatment

• Age >40 years, previously fit and well, presenting with significant pelvic pain

• Pain and infertility

• Irregular bleeding over the age of 45 years.

Second-line investigations

Serum CA125 is not specific for endometriosis. It is a marker for coelomic irritation and may be elevated in endometriosis, as well as in peritonitis, pericarditis, ovarian cysts and pregnancy. In a meta-analysis of 23 studies investigating CA125 levels in women with surgically confirmed endometriosis, the estimated sensitivity was 28 per cent for a specificity of 90 per cent.4

Magnetic resonance imaging (MRI) has greater sensitivity and may aid the evaluation of deep lesions.

Laparoscopy is the most important method of evaluating the pelvis and should be considered the gold standard investigation when endometriosis is suspected.2 Laparoscopy is not always essential before treatment, especially when a patient presents with two or more characteristic symptoms, such as those in table 2, attached.

Empirical treatment

Empirical treatment with simple painkillers, combined oral contraceptives (COCs) or progestogens can be considered at this stage if swabs for infection are negative, bowel symptoms are absent and scan is normal.

Medical treatment

Medical treatment is highly effective in treating the pain of endometriosis. All medical treatments except painkillers have a contraceptive action, hence there is no place for medical treatment when the priority is to conceive.

The majority of therapies cause ovarian suppression and induce amenorrhoea. Treatment for six months produces pain relief in 90 per cent of women. Treatment (and amenorrhoea) for three months should produce a dramatic improvement in pain relief; if not, alternative causes of the pain should be considered.

All the treatments described below have similar efficacy, but differ in their side-effects. The woman's individual circumstances and preferences should be considered when selecting appropriate treatment. Duration of treatment should be determined by the choice of drug, response to treatment and adverse effect profile.

NSAIDs

NSAIDs are used widely but the evidence showing whether they are effective in managing endometriosis-associated pain is inconclusive. It is important to note that NSAIDs have significant adverse effects, including gastric ulceration and an anti-ovulatory effect when taken mid-cycle. These drugs offer a non-hormonal approach and are particularly useful in women who are trying to conceive. NSAIDs can be taken regularly and be combined with paracetamol (1g qds po).

Combined oral contraceptives?(COCs)

In comparative trials with gonadotropin-releasing hormone (GnRH) agonists, COCs were equally effective in the treatment of pelvic pain caused by endometriosis.2 COCs have never been assessed with ‘before and after' laparoscopy, but it is assumed that the effect on the laparoscopic appearance of the disease is similar. This evidence supports the use of COCs as first-line therapy. It is suitable for women who need contraception and treatment for endometriosis-associated pain.

If period pain is severe, the COC can be taken in a bicyclic or tricyclic regimen or even continuously. Some women will get breakthrough bleeding (and associated pelvic pain) if they try to take several courses of the COC continuously. If this occurs, they should take the seven-day break and restart.

Progestogens

Progestogens, in particular the long-acting depot injections, have an important role in the long-term management of endometriosis because of their low cost and good safety profile.

Progestogens have been widely used for the treatment of endometriosis. They are given continuously and at high dosage to suppress ovulation. This results in decidualisation, growth and then atrophy of the endometrial implants. High-dose oral medroxyprogesterone acetate (MPA 30mg daily) and depot MPA (150mg every three months) are both effective for pain relief. This can be continued long-term.

Commonly reported side-effects are breast tenderness, weight gain caused by fluid retention, breakthrough bleeding and bloating.

Desogestrel 75µg can be used in women who cannot take oestrogen-containing contraceptives. It prevents ovulation more reliably than other progestogen-only pills.

The levonorgestrel intrauterine system has been shown to reduce endometriosis-associated dysmenorrhoea, although studies involved small numbers and a heterogeneous group of patients.5,6

Danazol and gestrinone

Both danazol and gestrinone are effective treatments, but the listed side-effects of irregular bleeding, weight gain and an increase in unwanted hair limits their acceptability.

Gonadotropin-releasing hormone agonists

Treatment with GnRH agonists results in a ‘menopause-like' hormone state. Treatment is effective for endometriosis-associated pain, with 90 per cent of women experiencing improved pain relief after six months' treatment. The addition of ‘add-back' hormone replacement therapy (HRT, continuous combined) reduces menopausal side-effects and the loss of bone density without reducing efficacy. The addition of add-back HRT does not appear to be associated with an increase in breast cancer because it is simply replacing, rather than prolonging, ‘hormone life'.

Treatment with GnRH agonists is usually started during a period. As part of their mechanism of action, there is an initial stimulation of the ovaries and then suppression. The initial stimulation, or ‘flare effect', occurs in the first month, and a worsening of symptoms, and even emergency hospital admission, have been reported. It is normal to have one period after starting treatment, and for amenorrhoea and menopause side-effects to start after this period.

Aromatase inhibitors

The development and growth of endometriosis is oestrogen-dependent, hence there are studies suggesting that aromatase inhibitors, for example letrozole and anastrozole, may be effective in the treatment of endometriosis-associated pain. Treatment is associated with bone density loss.

Complementary therapy

The role of complementary therapy in the treatment of endometriosis-associated pain is unclear.2

Surgical treatment

Surgical treatment of minimal to mild endometriosis improves pregnancy rate. Surgical treatment of moderate to severe disease improves pain but the benefit for fertility is uncertain.2 Laparoscopy to confirm a diagnosis of endometriosis can also be used as an opportunity for treatment. Surgical destruction of endometriotic implants by diathermy, laser and excision all appear equally effective. Ovarian endometriomas can be removed. More severe degrees of endometriosis may require further surgery with medical treatment first and bowel preparation. The treatment carried out at laparoscopy will depend on the woman's wishes, her priorities and her desire for children.

Long-term prognosis

The natural history of endometriosis is uncertain. In the placebo groups of randomised controlled trials, endometriosis deteriorated in 50 per cent of women, while remaining in a steady state or even resolving spontaneously in the other 50 per cent.7,8 In the treatment groups, disease did not deteriorate in any woman. In studies comparing GnRH agonists with placebo, treatment significantly improved endometriosis-associated pain. Most women in the placebo groups discontinued treatment because of persistent pain.9,10

Endometriosis is a progressive disease that tends to recur after treatment. Treatment inactivates rather than removes local implants, and symptoms may recur once treatment is complete and the menstrual cycle resumes. It is estimated that by four years 27 per cent of women with minimal to mild endometriosis need further treatment for recurrence of pain, and 12 per cent require hysterectomy.11 Treatment, whether surgical or medical, should therefore be considered to produce a remission from symptoms rather than a permanent cure.

Recurrent endometriosis usually presents with pain. Repeat laparoscopy is not always required, because a diagnosis has already been made. Medical treatment is the same as initial treatment and is measured against improvement in symptoms.

Many women with recurrent endometriosis wish for children. However, where fertility is no longer required, radical surgery is an option. Treatment with the GnRH agonists results in a medical oophorectomy and improvement on treatment suggests that radical surgery will be successful.

Hysterectomy and oophorectomy provide the nearest thing to definitive treatment. If the ovaries are conserved, estimates of risk of recurrence are up to 10 per cent.12 Current practice is to recommend bilateral oophorectomy at the time of hysterectomy. Most women with endometriosis can take HRT without problems, but there is a small risk of recurrence with HRT. If this occurs, HRT should be withdrawn.

Endo key points Key points Table 2: Common symptoms of endometriosis Authors

Mr Paul K Fiadjoe
MRCOG
specialist registrar in obstetrics and gynaecology, St Michael's University Hospital, Bristol

Mrs Caroline E Overton
MD MRCOG
consultant obstetrician and gynaecologist,
St Michael's University Hospital, Bristol

endometriosis_tab1

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