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As many as 15 per cent of women of child-bearing age are estimated to suffer from endometriosis ­ Mr Janesh Gupta and Mr Rajesh Varma take an in-depth look at a condition which severely affects the patient's quality of life

Endometriosis is defined as the ectopic implantation of viable endometrium-like glands and stroma outside the uterine cavity and myometrium.

Endometriotic lesions usually involve uterine or pelvic peritoneum, but have been known to occur at unexpected distant sites within the body.

Endometriotic lesions may be superficial or deep; haemorrhagic, fibro-nodular, or adhesion-like; or involve the ovaries and result in endometriomas.

The detection of 'kissing ovaries' (closely opposed) at ultrasound is strongly associated with the presence of endometriosis and is a marker of the most severe form of this disease. See page 52 for a scan of what is seen. A common site for lesions is the pouch of Douglas­ see right.

The presence of endometriosis is strongly associated with infertility, chronic pelvic pain (CPP), dyspareunia and dysmenorrhoea. These, and other less common symptoms, are listed in table 1.

Endometriosis and

ovarian cancer

Although endometriosis is a benign disorder, there is also a marginally increased risk of developing malignancy in women with long-standing endometriosis, particularly ovarian endometrioid and ovarian clear cell cancers, with the ovarian cancer appearing to arise directly from the endometriotic lesion in some cases.

The risk of malignant transformation of endometriosis is estimated at 0.3-0.9 per cent. The pathophysiological mechanism for this association is unknown, but its existence is important when seeking consent from women for radical or conservative surgical treatment of endometriosis and other risk factors for cancer.

Endometriosis and irritable bowel syndrome (IBS)

Chronic pelvic pain, genitourinary symptoms and irritable bowel syndrome (IBS) often co-exist. Some 39 per cent of patients with CPP have been reported to have IBS and 24 per cent of patients with CPP also have genitourinary symptoms.

A summary comparing the diagnostic parameters of IBS and CPP is given in table 2.

Impact of endometriosis in

primary and secondary care

Symptoms like infertility and CPP adversely impact on health-related quality of life, health care utilisation, and workplace absenteeism. CPP is the reason for 10-20 per cent of all outpatient visits to a gynaecology clinic and is responsible for approximately 40 per cent of laparoscopies and 10-15 per cent of hysterectomies. Endometriosis is diagnosed in 30 per cent of cases referred for infertility investigations and in 10-70 per cent of women with CPP. Overall, studies estimate that endometriosis may affect around 7-15 per cent of women of reproductive age, thus making this a common and important condition.

Examination and investigations

In most cases clinical abdominal and pelvic examination reveals no abnormality. In a minority of cases of endometriosis, pelvic examination may reveal: fixed and tender retroverted uterus; nodules on the uterosacral ligaments; or adnexal mass consistent with ovarian endometrioma. Laparoscopy is considered the key investigative tool for endometriosis, as both diagnostic staging and surgical treatment may be undertaken. Preoperative pelvic ultrasound is useful to diagnose ovarian endometriomas.

How is endometriosis classified?

The revised American Fertility Society Score uses a points system to designate disease extent based upon visual interpretation of depth of lesion invasion, bilaterality, ovarian involvement, presence of adhesions, and extent of pouch of Douglas involvement.

From this system, 1-15 represents minimal or mild disease, 16-40 moderate, and >40 severe. Importantly, this staging system was established to predict fertility outcomes, but does not correlate with the more common symptom of pelvic pain.

What causes endometriosis?

Endometriosis remains as enigmatic and poorly understood since Sampson's seminal recognition of it in 1925. The most likely explanation is that there is spillage and implantation of menstrual debris via the fallopian tubes in to the pelvic cavity ­ a process termed retrograde menstruation.

This has been shown to occur in around 10-20 per cent of normally menstruating women, but not all these women will develop endometriosis, and not all women with endometriosis undergo retrograde menstruation. It has been suggested that women with endometriosis may also be unable to recognise and destroy these endometrial cells thereby allowing them to implant and proliferate to form pelvic endometriotic lesions.

There is an inheritable component to endometriosis, although these genes are multiple and have low-penetrance. Furthermore, abnormalities in endocrine, metabolic, angiogenic and immunological factors have been identified in the endometriotic lesions and surrounding peritoneal fluid. However, a unifying mechanism remains elusive. Importantly, the extent of endometriosis does not correlate with symptoms experienced. This, along with other findings, casts doubt as to the nature of any direct causal relationship between endometriosis and symptomology.

Treatments in primary care

For women in whom endometriosis is suspected, laparoscopic confirmation is not always necessary. A trial of medical therapy is reasonable assuming that there are no other indications for surgery, such as the presence of a suspicious adnexal mass or positive infective screen from urine or genital tract, or if malignancy is suspected. If CPP is secondary to endometriosis, pelvic pain symptoms should subside with the trial of medical treatment.

The treatment can then be continued indefinitely (allowing for risk factors for taking the COC) or referral made to a gynaecologist. If CPP continues while being amenorrhoeic then this could still indicate endometriosis, but may also suggest the presence of other pathology such as IBS or urological tract disorders.

Both pain (eg using non-steroidal anti-inflammatory agents), and the underlying disorder, need to be treated. If IBS is suspected, it is important to avoid opiate analgesia, as this could worsen IBS and cause constipation. Women with IBS should be given advice to increase dietary fibre and water content. We often cite the breakfast cereal story outlined in the box below.

Drugs that target endometriosis have been shown to reduce related pelvic pain and dyspareunia. However, medical treatments are either neutral or counterproductive on correcting subfertility. Meta-analyses have shown there is little difference in the effectiveness of the various medical treatments, which only lasts while patients remain on the treatment. In addition, women may be advised not to conceive while taking these drugs, thereby prolonging the period of subfertility.

These drugs act by suppressing the oestrogen-mediated growth signal that sustains endometriotic lesions, and include:

·Progestogens (eg norethisterone)

Side-effects include bloating, fluid retention, breast tenderness, nausea.

·Gonadotrophin-releasing hormone analogues GnRHa (eg buserelin, goserelin) Side-effects include menopausal symptoms (hot flushes, night sweats, vaginal dryness, mood swings) and osteoporosis. Adding hormone replacement therapy (eg oestrogen patches) reduces these side-effects without causing reactivation of endometriosis.

·Combined oral contraceptive pill

We recommend a six-month trial that is continuous and without a pill-free break. The induction of amenorrhoea suggests adequate therapeutic level of oestrogen suppression

Surgical treatment ­

conservative or radical

Surgical treatment can be either conservative or radical. Conservative surgery aims to retain the reproductive potential of the patient. Radical surgery is hysterectomy and bilateral salpingo-oophorectomy. Removal of the ovaries is an important consideration in women with endometriosis as this reduces the risk of endometriotic recurrence, although it gives the woman a 'surgical' menopause earlier than expected. Most authorities consider surgical treatment, ideally via laparoscopy, as a second choice option.

For minimal or mild endometriosis, surgical ablation (by laser or electrocautery) or excision of endometriotic lesions (usually performed at laparoscopy) compared with expectant management, improves fertility and reduces pelvic pain. Furthermore, where endometriosis is minimal and without tubal damage, intrauterine insemination with superovulation is a reasonable option to achieve conception.

For severe endometriotic disease, surgery remains effective in reducing pelvic pain, but is limited by case selection and operator experience and type of surgery (conservative or radical) being undertaken. Not all women will have improved fertility or less pain after surgery and this should be clearly stated in the patient consent process, along with the attendant surgery-related risks. It has been argued that in cases of infertility it may be more cost-effective and safer for women with severe endometriosis to proceed directly to

in vitro fertilisation.

Inconsistencies in surgical standardisation have led to controversies as to the best surgical treatment for endometriosis. Robust trials are under way to determine some of these answers (eg ELITE ­ Effectiveness of Laparoscopic Interventions in the Treatment of chronic pelvic pain associated with Endometriosis co-ordinated in Birmingham by ourselves).

Latest medical treatments

under study

·Aromatase inhibitors (eg letrozole, anastrozole) Aromatase P450 converts androstenedione and testosterone to oestrone and oestradiol (E2). In premenopausal women ovaries are the major sites of oestrogen production, while in postmenopausal women oestrogen is produced by aromatisation of ovarian and adrenal androgens in extragonadal sites, mostly in adipose tissue.

Aromatase inhibitors have been used in combination with GnRHa to successfully treat endometriosis refractory to medical and treatment in premenopausal women. The GnRHa is needed in premenopausal women because the ovary can overcome the oestrogen blockade from the aromatase inhibitor by inducing compensatory increases in luteinising hormone and follicle stimulating hormone. These increases are prevented by addition of a GnRH agonist.

·Levonorgestrel-releasing intrauterine system (Mirena coil) The continuous local exposure of the endometrium and genital tract to progesterone, coupled with anovulation, has been effective at reducing endometriotic disease and symptoms.

·Selective progesterone receptor modulators (eg Asoprisnil) These may function both as progesterone receptor antagonists and agonists. These drugs display antiproliferative effects in the endometrium without effecting serum oestradiol levels. These drugs are being evaluated for: the treatment of endometriosis, fibroids, and menorrhagia; aids for in vitro fertilisation to prevent a premature LH surge and to delay the emergence of the implantation window; as contraceptive and abortive agents; labour induction and cervical ripening agents.

·Selective oestrogen receptor modulators (SERMS) (eg raloxifene and arzoxifene) and antagonists (eg Fulvestrant) Tamoxifen was the first-generation SERM. Tamoxifen has oestrogen antagonist effects on breast cancer but weak agonists effects on uterine endometrium. Numerous related compounds with greater uterine antagonistic profile have been developed and are being tested.

The challenge

Women with endometriosis are a diagnostic and management challenge. The key to successful outcome is individualised care and a biological-psychological-social approach.

Complete symptomatic relief of CPP is likely to be an unrealistic goal so be honest from the outset. A 30 per cent improvement in symptoms should be regarded as a success and should be the aim. Improvements of up to 50-70 per cent can be possible, but it depends on the woman's motivation and commitment, together with the success of treatment strategies initiated.

There still remains considerable controversy in how to treat infertility associated with endometriosis. Nonetheless, for both infertility and chronic pelvic pain, women should be advised that the positive effects from any treatment strategies may take up to six months.

Table 1 Symptoms of

endometriosis

·Pain before or during menstruation

·Pain during or after sexual intercourse

·Infertility

·Painful urination during menstruation

·Painful bowel movements during menstruation

·Gastro-intestinal disturbances

such as nausea, diarrhoea, constipation

The breakfast cereal story

we tell patients with IBS

Imagine eating breakfast cereal and leaving your bowl unwashed overnight. The following morning the cereal has dried solid to the bowl. The easiest way to remove this is by soaking the bowl in water. The same principles apply to your bowels. Unless you drink at least eight to 10 glasses of water per day, the increased fibre intake may 'cake' in the bowels and worsen constipation. However, it is important to realise that caffeine-related drinks such as tea and coffee are not suitable fluids as they can 'dehydrate' you and similarly make matters worse. Therefore, drinking plenty of clear water is necessary to bulk the stool fibre. Remember this regime may take three to six months to become effective. So persist with the fibre and fluid supplement.

Take-home points

·Understand and accept that the patient has genuine pain

·The association between endometriosis and IBS is common

·Aim for diagnosis and management that will improve the quality of life of the patient

·Management strategy for tackling endometriosis and IBS should be honest and realistic

·Multidisciplinary holistic management approach to history, investigation and treatment

·The use of opiate analgesics should be avoided

Useful websites

www.endo.org.uk

National Endometriosis Society (UK) ­ Helpful clear advice, with chat room and interactive advice

www.pelvicpain.org

International Pelvic Pain Society (US)

www.obgyn.net/cpp/cpp.asp

www.familydoctor.org

www.rcog.org.uk/guidelines.asp?PageID=

106&GuidelineID=10

The Investigation and management of endometriosis (24) ­ Jul 2000. Royal College of Obstetricians and Gynaecologists (UK) guidelines for endometriosis

www.emedicine.com/med/topic2939.htm

A well-written review of CPP

www.merck.com/mrkshared/mmanual/section18/

chapter237/237a.jsp

www.update-software.com/abstracts/AB000387.htm

Definitive Cochrane abstract on interventions for treating CPP in women

Janesh Gupta is expert panel member of the National Endometriosis Society and senior lecturer/consultant academic, department of obstetrics and gynaecology, University of Birmingham, Birmingham Women's Hospital

Rajesh Varma is Medical Research Council clinical fellow researching the genetic and molecular aspects of endometriosis, academic department of obstetrics and gynaecology, University of Birmingham, Birmingham Women's Hospital

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