Endometriosis is a common, and potentially debilitating disease. It is thought to affect approximately 6-10% of the population, although prevalence rates may be much higher since a significant proportion of patients are asymptomatic.[1] It is defined as the presence of endometrial-like tissue outside of the uterus, which can result in local inflammatory reactions, the formation of scar tissue and adhesions.[2] The symptoms and severity of endometriosis can vary considerably. The most common features are dysmenorrhoea and chronic pelvic pain, which can occur fairly soon after the start of menarche, and deep dyspareunia. More rarely it can affect the lower gastrointestinal tract and urinary system, resulting in symptoms such as tenesmus, fresh rectal bleeding and painful micturation.[3] Infertility occurs in 30-50% of cases, and infertile women are thought to be 6-8 times more likely to have endometriosis than fertile women. The exact mechanism for this reduced fertility is hotly debated and is thought to be related to both anatomical and endocrine factors.[3] Many women often report co-existent fatigue, and endometriosis can result in physical, sexual and physiological dysfunction leading to significant absences from work.[4]

In September 2017 NICE produced its first specific guidance on the disease.

Initial assessment and investigation

The most important factor in assessing endometriosis is to consider the diagnosis in the first place. Diagnosis can take up to 10 years from first presentation of symptoms, partly due to the ‘normalisation’ of pelvic pain by patients and partly due to falsely reassuring initial investigations.[5] This delay in diagnosis has been reported to result in increased personal suffering, prolonged ill health and a disease state that is more difficult to treat.[4] Given that up to half of all patients presenting with chronic pelvic pain potentially have an underlying diagnosis of endometriosis, having a high level of suspicion is important in making the diagnosis.[5]

Taking a full history with particular regard to key symptoms of endometriosis is vital. A pain diary can be helpful in highlighting a cyclical element to the pain, and this may be a useful initial tool when assessing a patient. An abdominal examination should be carried out on all patients to exclude an abdominal mass. Where appropriate, a pelvic examination should be performed in order to identify abdominal masses and pelvic signs, such as reduced organ mobility and enlargement, tender nodularity in the posterior vaginal fornix, and visible vaginal endometriotic lesions.[4]

Investigations

According to the new NICE guidance, transvaginal and transabdominal ultrasound scanning should be considered as the first line investigation in patients with symptoms of endometriosis, with or without pelvic signs on examination.[4]

Ultrasound scans are able to identify endometrial deposits measuring 1cm or more in the ovaries, bowel, bladder or ureter, as well as adhesions and free fluid.6 Studies show the specificity of transvaginal ultrasound scans to be high (in the region of 95-100%), but negative findings are less reliable and do not rule out the disease. CA125 blood testing is not recommended, since both elevated and normal levels can be associated with the condition.[4] Pelvic MRI imaging may have a role in the diagnosis of endometriosis, but should not be used first line. Current NICE guidance advocates the use of MRI to asses the extent of deep endometriosis involving bowel, bladder or ureter.

Referral to secondary care is usually indicated if patients are suffering with severe, persistent or recurrent symptoms where initial medical managements have been ineffective or not tolerated. Other indications for specialist referral include either confirmed or suspected deep endometriosis, doubt regarding diagnosis and young women under the age of 17 with endometriosis. Laparoscopy is regarded as the gold standard for the investigation of endometriosis. It can be used to make a visual and histological diagnosis, exclude malignancy and used for treatment purposes.[4]

Pharmacological treatment

Treatment should be based on a woman’s symptoms rather than grade of endometriosis, and simple pain relief should be offered in the first instance. This should initially be in the form of paracetamol and anti-inflammatories, either alone or in combination. A three-month trial of analgesics is appropriate before considering alternative pharmacological treatments. If these simple measures fail to improve symptoms, neuromodulators (such as amitriptyline, duloxetine, gabapentin or pregabalin) may be considered.[4]

Combined oral contraceptives (COC) have been long used to help control symptoms of endometriosis, and their continued use is supported by NICE.

Historically, it was noted that the clinical symptoms of endometriosis improved during pregnancy, and this lead to the utilisation of oral contraceptives to mimic this state. By inhibiting the production of gonadal oestrogen and suppressing ovarian activity, there is a reduction in prostaglandin release resulting in decreased local inflammation.[7] There is good evidence that the COC reduces dysmenorrhoea, dyspaerunia and chronic pelvic pain in patients with endometriosis.[8]

Some specialists advocate using low oestrogen COCs, with only a 4-day pill-free break rather than the usual 7-day break or, indeed, continuous administration of COCs. It would appear that these regimens result in a more even suppression of endometrial growth and is associated with better pain control. However, these benefits may be offset by the fast recovery of disease after ceasing treatment and the increased risk of thromboembolic events in higher risk patients.[7]

Progestogens, in its many forms, have been used in the treatment of endometriosis for the past 30 years and there is robust evidence that they are effective in reducing pain secondary to endometriosis. The mechanism of action is primarily due to reduced endometrial proliferation and the creation of an atrophic endometrium and a so-called ‘pseudopregnancy’ state. In a similar way to COCs, they also appear to reduce local inflammation which gives rise to endometrial deposits. They can be given orally, via depot, implant or via a levonorgestrel-releasing intrauterine system.

Other progestogens, including medroxyprogesterone acetate, norethisterone, cyproterone acetate, or dienogest, may also used to treat pain associated with endometriosis. However, current advice does not support the use of danazol or gestrinone due to their severe anti-androgenic side effects.[8,9]

Gonadotrophin releasing hormone (GnRH) agonists suppress ovarian activity and induce a hypo-oestrogenic state, which has a beneficial effect on endometriosis symptoms. However, this ‘pseudomenopausal’ state can precipitate vasomotor symptoms as well as irreversible bone demineralisation. So-called ‘add back’ treatment is usually recommended in the form of low dose oestrogen and progesterone HRT to counteract these negative side effects.[9]

On balance, there is no evidence to suggest that one form of hormonal treatment is more effective than another in treating the symptoms of endometriosis. In practice the clinical decision to use one drug over another is dictated by the risk profile of the patient, side effect tolerability and patient personal preference.[8]

Newer treatments are on the horizon, but have not been endorsed in the recent NICE guidance. Aromatase inhibitors prevent the conversion of testosterone to oestrogen and have been shown to effectively reduce endometriosis-related pain.[9] Selective oestrogen and progesterone receptor modulators, as well as immunotherapies, are also being explored with the potential to alter current established treatments regimens in the future.[9]

The recent NICE guidance states that there is currently no evidence to support the use of traditional Chinese medicine for the treatment of endometriosis.[4]

Surgical treatments

If medical treatments fail to achieve satisfactory symptom control, referral to secondary care services is warranted. In the case of suspected deep endometriosis involving the bowel, bladder or ureter, referral to a specialist endometriosis service is suggested by NICE. Young adults under the age of 17 years with suspected disease should be referred to either local paediatric or adolescent gynaecology services or a specialist endometriosis centre.

Initial surgical management usually involves a laparoscopy. This allows for confirmation of diagnosis in addition to treatment, either in the form of excision or ablation of endometrial lesions. Women should be counselled regarding this ‘see and treat’ approach prior to laparoscopy. In patients where previous treatments have failed and who are not looking to conceive, hysterectomy may be considered. Removal of the ovaries at the time of surgery is shown to result in more effective symptom control, but this must be balanced with the consequences of the resultant surgically induced menopause. Careful consideration and counselling should be administered prior to surgery. Given the potential widespread nature of endometriosis, patients must be made aware that hysterectomy with or without oophrectomy may not eliminate symptoms or disease.[4,8]

Hormonal treatments may be offered post-surgery as either a short term adjunct, or a longer term treatment to reduce disease recurrence.[8]

Treatment where fertility is a priority

The treatment for infertility secondary to endometriosis should be managed by a specialist multidisciplinary team. Medical treatments are not recommended as there is no evidence they result in improve fertility and ultimately delay potential conception.[4] Treatment options differ depending upon the extent and location of the endometriosis, but the aim is to remove or reduce endometrial deposits, hence restoring normal pelvic anatomy. Excision or ablation of endometriosis plus adhesiolysis has been shown to improve spontaneous pregnancy rates, as can cautious ovarian cystectomy.

Patients with advanced disease may be guided towards considering IVF treatment sooner rather than later. Since the most effective treatment for endometriosis-associated infertility is IVF, acting promptly can reduce the time to pregnancy in these cases. This should be kept in mind when considering referral to secondary care infertility services.[9]

References

1. Giudice LC, Kao LC. Lancet. 2004;364(9447):789–799. doi: 10.1016/S0140-6736(04)17403-5.
2. Kennedy S, Bergqvist A, Chapron C, D’Hooghe T, Dunselman G, Saridogan E, et al. Hum Reprod. 2005;20(10):2698–2704. doi: 10.1093/humrep/dei135.
3. Bulletti C, Coccia ME, Battistoni S, Borini A. Journal of Assisted Reproduction and Genetics. 2010;27(8):441-447. doi:10.1007/s10815-010-9436-1.
4. Endometriosis: diagnosis and management NICE guideline [NG73] Published date: September 2017
5. Pugsley Z, Ballard K. The British Journal of General Practice. 2007;57(539):470-476.
6. Holland, Cutner, Saridogan et al. BMC Women’s Health. October 2013. 13:43 https://doi.org/10.1186/1472-6874-13-43
7. Zito G, Luppi S, Giolo E, et al. BioMed Research International. 2014;2014:191967. doi:10.1155/2014/191967.
8. Guideline on the management of women with endometriosis. European society of human reporoduction and embryology.
Issued : 18 September 2013
9. Hickey et al. BMJ 2104;348:g1752 doi: 10.1136/bmj.g1752