Endometriosis: symptoms, diagnosis and management

Endometriosis can be a chronic and debilitating condition. It is often difficult to diagnose, taking an average of 7.5 years for a complete diagnosis to be made, owing to the non-specificity of presenting symptoms^[1]
. This delay can result in decreased quality of life for patients. Healthcare professionals, including pharmacists, have an important role to play in identifying the signs and symptoms of endometriosis to support diagnosis at the earliest possible opportunity.

The Royal College of Obstetricians and Gynaecologists defines endometriosis as “the growth of endometrial-like tissue (the womb lining) outside the uterus (womb)”^[1]
. In the UK, it is estimated that endometriosis affects 10% of women from their first menstrual period to menopause and it is the second most common gynaecological condition after fibroids^[1]
. Any woman of reproductive age, regardless of race or ethnicity, can be affected by the condition^[2]
.

This article will describe the diagnosis and management of endometriosis, as well as the referral process.

Signs and symptoms

Endometriosis can be difficult to diagnose, not only because of the wide variety of symptoms and their different presentations (see Box 1), but also because of the non-specific nature of presenting symptoms (e.g. general malaise and sleep disturbance)^[3]
.

Pathophysiology

Although it is well recognised that endometriosis is mediated by cyclical hormonal fluctuations, the exact pathophysiology is not fully understood^[8]
. The monthly hormonal changes that normally cause proliferation of the endometrium also cause the ectopic endometrial cells (endometriosis) to proliferate, resulting in inflammation, pain and adhesions (scar tissue formation)^[2]
.

Most of the ectopic endometrial-like tissue deposits in the pelvis. Endometriomas (ovarian cysts) may also develop when the ovaries are affected (see Figure)^[4]
.

Aetiology

The aetiology of endometriosis is not fully understood; however, there are several potential causes:

• Retrograde menstruation — the backwards flow of menstrual debris through the fallopian tubes into the pelvic cavity — leads to the possible implantation of refluxed endometrial tissue outside the uterus^{[9],[10],[11],[14]}
  .
• Metaplasia (an abnormal change in the tissue, i.e. cells in the pelvis differentiating into endometrial cells) has also been proposed. Alternatively, lymphatic or vascular spread of the endometrial cells may occur;
• Immune dysfunction, or altered immune-surveillance, which may allow the proliferation of endometriosis (i.e. the patient’s immune system does not repress endometriosis)^[5]
  .

Patients may also have a genetic predisposition because familial clusters of endometriosis have been demonstrated in several studies; however, some have shown that any potential inheritance mechanism does not fit the Mendelian model of inheritance (i.e. where any hereditary component is likely to be polygenic in nature)^[12]
. Further research is ongoing to identify specific gene groups that may be implicated that may also form potential drug targets^[13]
.

Risk factors

There are several risk factors that may increase the chance of developing endometriosis. These include, but are not limited to:

• Having a first-degree relative with the disorder (e.g. mother, sister, daughter);
• Primigravida (being pregnant for the first time) above the age of 30 years;
• Ethnicity — Caucasian women are thought to be at a greater risk of developing endometriosis;
• Anatomical abnormalities (e.g. women with an abnormal uterus or fallopian tubes);
• Menstrual cycle factors (e.g. early age of first menstrual period, dysmenorrhoea, short menstrual cycle [i.e. less than 27 days], long periods [i.e. more than 7 days]);
• Allergies (e.g. food, eczema, hay fever);
• Obesity;
• Exposure to toxins — research suggests that dioxins may contribute to the development of endometriosis^{[8],[14],[15]}
  .

Diagnosis

While there are several procedures that can be used to aid the diagnosis of endometriosis (see Table 1), the only definitive way to confirm it is to carry out a full, systematic laparoscopy^[15]
. If the results are normal, endometriosis can be excluded and alternative symptom management should be offered^[6]
.

While serum cancer antigen 125 (CA125) should not be used to diagnose endometriosis, raised levels (≥35IU/mL) may be consistent with having endometriosis^[6]
. Elevated CA125 can also be indicative of malignancy^[6]
.

Women are most commonly diagnosed with endometriosis between the ages of 30 years and 40 years^[4]
. Although endometriosis is uncommon among women aged 20 years and younger, it should not be excluded^[6]
. Endometriosis should also not be excluded in women who have returned a normal abdominal or pelvic examination, ultrasound or MRI^[4],[6]
. A pelvic examination is unlikely to be abnormal because most cases of endometriosis are usually mild to moderate in severity^[4]
.

The National Institute for Health and Care Excellence (NICE) also recommends that the patient should keep a pain and symptom diary to aid discussions about suspected or confirmed endometriosis^[6]
.

Differential diagnosis

The symptoms of endometriosis can be indistinguishable from other conditions, including:

• Pelvic adhesions, functional or neoplastic ovarian cyst, adenomyosis and uterine fibroids;
• Malignancy (e.g. colorectal, ovarian, cervical or bladder cancer);
• Dysmenorrhoea, ectopic pregnancy, ovarian torsion, uterine malformation;
• Irritable bowel syndrome, inflammatory bowel disease, chronic constipation;
• Appendicitis, cystitis, diverticulitis, pelvic inflammatory disease, serositis;
• Urinary tract infections (UTIs), chlamydia, gonorrhoea;
• Degenerative disc disease and congenital abnormalities of the reproductive tract (e.g. hemivagina, vaginal septum)^{[4]
  ,[8]}
  .

A full blood count may rule out infection and inflammation, and may distinguish pelvic inflammatory disease from endometriosis. Urinalysis, urine culture and blood serology can rule out UTIs and sexually transmitted infections (STIs)^[8]
.

Pharmacological management

The treatment choice for endometriosis depends on the individual patient’s needs and preferences, such as their age and whether they wish to conceive (see Table 2)^[4]
.

Analgesia

Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen and mefenamic acid, should be offered unless contraindicated. 

NSAIDS inhibit the synthesis of prostaglandins via cyclo-oxygenase and should be commenced prior to pain or menstrual onset^[16]
. Prostaglandins have been implicated in the modulation of pain response, inflammation, dysmenorrhoea and menorrhagia (heavy menstrual bleeding)^[17]
.

Ibuprofen has a licensed indication for dysmenorrhoea in women of all ages and has a relatively superior gastrointestinal (GI) safety profile^[4]
. Naproxen is licensed for patients aged 16 years and over, and is associated with an intermediate risk of GI side effects. While mefenamic acid is licensed for the treatment of dysmenorrhoea, there are concerns about its narrow therapeutic window and its propensity to cause seizures in overdose^[4]
. For example, a woman weighing 50kg would only need to ingest an extra 500mg dose in 24 hours (total 2,000mg) for her to be considered at risk of toxicity^[4]
.

Paracetamol should be given when NSAIDs are contraindicated or in addition to an NSAID when treatment response is insufficient. Analgesics should be trialled alone or in combination for a period of three months. If they prove to be ineffective, a referral should be considered^[6]
.

When response to individual therapy is insufficient, analgesia in combination with hormonal treatment is another option.

Hormone treatment

If conception is not desired, hormonal treatment (e.g. combined oral contraceptives [COCs] or progestogens) should be trialled in suspected, confirmed or recurrent endometriosis. If hormonal treatment is ineffective, not tolerated or contraindicated, a referral should be made to gynaecology services (paediatric, adolescent or adult depending on age) or specialist endometriosis services^[6]
.

Combined oral contraceptives

Although COCs are not licensed for the treatment of endometriosis, they are widely used to treat the associated pain, offer contraceptive protection and control the menstrual cycle, without permanent negative effects on subsequent fertility^[6]
.

Monophasic COCs (e.g. 30–35 micrograms of ethinylestradiol and norethisterone, norgestimate or levonorgestrel) are usually prescribed first line^[4]
. The NICE clinical knowledge summary recommends that a conventional regimen of three months should be trialled, although tricycling or continuous use is recommended when control of symptoms is inadequate, or if there is a symptomatic flare while off active treatment^[4]
. The Faculty of Sexual and Reproductive Health reports that evidence suggests that a continuous rather than a cyclical COC regimen is advantageous in the management of endometriosis^[18]
.

COCs are usually prescribed first line; however, oral progestogens (see below) should be offered when hormonal contraception has been declined.

Progestogens

Progestogen-only contraceptives (e.g. intrauterine levonorgestrel, oral desogestrel 75 micrograms, depot medroxyprogesterone and subdermal etonogestrel) may also be considered^[4]
. Meanwhile, oral non-contraceptive options include medroxyprogesterone and norethisterone^[4]
.

By inhibiting ovulation, progestogens reduce oestrogen levels and induce endometrial atrophy^[4]
.

Other hormone treatments

Secondary care treatment options include gonadotrophin-releasing hormone (GnRH) agonists (e.g. goserelin) and androgens (e.g. danazol). GnRH agonists inhibit pituitary secretion via negative feedback, while androgens directly inhibit pituitary gonadotrophins, both causing amenorrhoea and inducing a reversible menopausal state that results in the regression of endometriosis^[4]
.

Furthermore, the addition of HRT to GnRH agonists can be considered to reduce side effects (e.g. loss of bone density) of GnRH agonists — this is known as ‘add-back therapy’. However, the re-introduction of oestrogen may result in a reactivation of endometriosis symptoms, so women need to be monitored carefully^[4]
(see Table 2).

Tricyclic neuromodulators

Neuromodulators (such as tricyclics, serotonin and norepinephrine reuptake inhibitors, local anaesthetics, capsaicin patches, N-methyl-D-aspartate antagonists, anticonvulsants, and nerve blocks) have been used for symptom control in both primary and secondary care^[19]
.

NICE recommends a choice of amitriptyline, duloxetine, gabapentin or pregabalin be trialled in the first instance, and if it is not effective or tolerated, any of the other three options should be considered^[6]
.

For further guidance, please refer to the NICE clinical guideline on neuropathic pain in adults

.

Referrals

Recurrent, persistent or severe signs of endometriosis require referral to a gynaecologist. NICE currently recommends that if pelvic signs of endometriosis are present, or if initial management is contraindicated, ineffective or not tolerated, women should be referred^[6]
. Furthermore, specialist endometriosis services should also be enlisted if women have suspected or confirmed deep endometriosis involving the bowel, bladder or ureter or in women aged 17 years and under^[6]
.

Hormonal treatment should not be offered to women with endometriosis who are trying to conceive because it does not improve spontaneous pregnancies — surgical management is preferred when fertility is a priority^[6]
.

Non-pharmacological management

Lifestyle advice can be provided to patients with endometriosis to aid symptom relief (see Box 2).

Surgical treatment is an option for patients who do not respond to pharmacological treatment or lifestyle interventions. Laparoscopic treatment with prior patient consent should be considered during diagnostic laparoscopy for peritoneal endometriosis (not involving the bowel, bladder or uterus) or uncomplicated ovarian endometriomas^[6]
. However, laparoscopic uterine nerve ablation for chronic pelvic pain is not recommended by NICE.

Further surgery may be required for recurrent endometriosis, deep endometriosis (bowel, bladder or ureter involvement) or when complications arise^[6]
. For patients with deep endometriosis, three months of taking a GnRH agonist should be considered prior to surgery as an adjunct. Excision should be considered rather than ablation of endometriomas, and fertility should be conserved if desired^[6]
. Hormonal treatment (e.g. COCs) should be considered after excision or ablation to prolong surgical benefits and to manage symptoms^[6]
.

If a hysterectomy is indicated, for example if a woman has adenomyosis or menorrhagia that has not responded to other treatments, this should be combined with laparoscopic excision of all visible endometriotic lesions at the time of the hysterectomy. Laparoscopic hysterectomies should be performed when combined with surgical treatment of endometriosis, with or without oophorectomy (removal of one or both ovaries), unless there are contraindications. Patients may still require further surgery after a hysterectomy owing to endometriosis recurrence.

Complications and prognosis

Studies have found that diagnosis of endometriosis can be delayed for up to ten years owing to diagnostic and clinical challenges, resulting in both disease progression and a decrease in quality of life^[7]
.

Around 30–50% of women with endometriosis have sub-fertility^[4]
. Fertility problems can occur as a result of damage to the ovaries or fallopian tubes, or changes to the pelvic anatomy as a result of adhesions causing inappropriate fusion (e.g. of organs) or endometriomas^[11]
. 

Endometriomas can develop depending on the proximity of the endometriosis tissue to the ovaries. These fluid-filled cysts can become enlarged and painful^[11]
. Although pharmacotherapy will not improve fertility, surgery to remove visible patches of endometriosis tissue can be beneficial^[11]
.

Infertility is uncommon in women with mild-to-moderate endometriosis, with eventual resultant pregnancies without the requirement for treatment. Although IVF may be an option in those who find it difficult to conceive, success tends to be limited in those affected by endometriosis^[11]
.

The prognosis of endometriosis is variable; in 20–50% of women, symptoms will recur after medical or surgical intervention. Deposits can also spontaneously regress in up to 30% of women after 6–12 months^[4]
.

Role of the pharmacist

NICE recommends that analgesics, such as NSAIDS and paracetamol, are trialled alone or in combination for three months in patients with endometriosis^[6]
. Pharmacists should check the following:

• There is an appropriate supply of the medicine;
• The correct dose is prescribed depending on any existing disease state;
• There are no drug–drug or drug–disease state interactions;
• There are no contraindications.

The same applies for hormonal treatments and neuromodulators. Advice should also be given on administration and adverse effects (see Table 2).

For an example case study, see Box 3.