Endometriosis is a chronic inflammatory disease characterised by the growth of ectopic endometrial-like tissue outside of the uterus. These lesions most commonly occur on the ovaries, fallopian tubes and broad ligaments.

Endometriosis affects an estimated 10% of women in the UK, mainly of reproductive age, and is the second most common gynaecological condition after fibroids. While it remains unknown exactly why these ectopic endometriotic lesions appear, it is known that the lesions grow in response to oestrogen release much like normal endometrial tissue. As a result of the oestrogen dependent nature of these lesions, signs and symptoms are often associated with menstruation.

Common symptoms include chronic pelvic pain, painful periods and subfertility. Management is based upon the severity of these symptoms with treatment options encompassing pharmacological treatments (analgesia and hormonal) and surgery (to remove endometriotic lesions).

As with its pathophysiology, the exact aetiology of endometriosis remains unclear and is an area of active research. Despite this, it is known that there are several risk factors which are associated with an increased incidence of the disease:

• Menstrual history: women with the following risk factors in their obstetric history experience a higher number of menstrual cycles, which is associated with an increased risk of endometriosis. This is thought to be due to increased overall oestrogen release over their lifetime.
  • Early menarche
  • Prolonged menstrual periods (longer than 7 days)
  • Shorter interval between cycles (27 days or shorter)
  • Nulliparity
  • Increasing age
• Family history: patients with a family history of endometriosis have a higher risk of developing the condition themselves. Due to this it is widely believed that there may be a genetic mode of inheritance for the disease

Endometriosis is a chronic inflammatory condition characterised by the growth of endometrial-like tissue outside of the uterus.

Endometriotic lesions most commonly develop on the surface of the uterus, the ovaries, fallopian tubes, broad ligaments, pelvic peritoneum, and more rarely the bladder, ureters, bowel, pleura, pericardium etc.

While the exact pathophysiology of the condition is unknown, the most widely accepted hypothesis is Sampson’s theory of retrograde menstruation (1927). Retrograde menstruation is the flow of menstrual tissue and endometrial cells through the fallopian tubes during menstruation. Sampson postulates that retrograde flow enters the peritoneal cavity where endometrial cells subsequently become implanted, leading to endometriotic lesions. Other popular theories regarding the pathophysiology of endometriosis include coelomic metaplasia, reduced immunosurveillance and haematogenous and lymphatic spread.

The complex pathophysiology discussed in the remainder of this section is combined from a number of papers and reviews including Brosens et al. (1997, 2013), Tanbo et al. (2017) & Lin et al. (2018).

There are 3 main types of endometriotic lesions:

• Superficial lesions
  • These lesions are primarily situated in the peritoneum and are often highly vascular and have a tendency to bleed
• Deep lesions
  • These lesions involve the deeper structures of the pelvis, the pelvic ligaments, the rectovaginal septum and inside the walls of muscular organs

Both superficial and deep lesions may lead to adhesions, fibrosis, thickening of the pelvic ligaments and a fixed retroverted uterus

• Endometriomas
  • Endometrial cysts and chocolate cysts (endometriomas) are the final type of endometriotic lesion and are present on the ovary. These cysts can grow and release inflammatory cytokines. This can lead to adhesions, damage to the follicles of the ovary and ovarian torsion
  • Chocolate cysts in particular are pathognomonic for endometriosis, they are a type of non-cancerous ovarian endometrioma containing old blood, their contents appearing tar-like and brown giving them their name

Endometriotic lesions function much like normal endometrial tissue, responding to oestrogen release in the proliferative stage of the menstrual cycle by growing and being shed during menstruation. Due to their dependence on oestrogen to grow, endometrial lesions mainly affect women of reproductive age and are rarely found in childhood or after menopause, when oestrogen from the menstrual cycle is no longer as present.

The symptoms of chronic pelvic pain and period pain likely come from these endometriotic lesions growing and shedding. This shedding causes pelvic irritation, particularly in the perineum/ bottom of the perineal cavity where the blood collects. Lesions in contact with the bowel, bladder or ureters lead to bowel and urinary symptoms which are precipitated by the same process.

Subfertility and infertility are key concerns with endometriosis. The pathophysiology is not fully understood however current theories suggest that endometriotic lesions cause subfertility via:

• The release of cytokines causing acute and chronic inflammation in the fallopian tubes and ovaries, as a result these tissues become scarred and fibrosed, rendering them unable to function
• The formation of adhesions and fibrosis due to lesions between the uterus, ovaries, fallopian tubes and surrounding structures leading to a distortion of the pelvic anatomy
• Ovulatory dysfunction. This is thought to occur due to the formation of endometriomas, chronic inflammation or the surgical removal of deep-rooted endometriomas, which has been linked to destruction of primordial follicles and scarring of the ovaries

These features can also cause chronic pelvic pain and deep pain during sex (dyspareunia).

Endometriosis is thought to affect an estimated 10% of women of reproductive age (15-49 yrs old) in the UK. These women can present with a range of different features.

The 2017 National Institute for Health and Care Excellence (NICE) guidelines and 2014 European Society of Human Reproduction and Embryology (ESHRE) guidelines state that the clinical features associated with endometriosis include:

• Chronic pelvic pain lasting more than 6 months
• Cyclical pelvic symptoms i.e. symptoms that may only present or worsen during menstruation, including
  • Cyclical pelvic/period pain (dysmenorrhoea) - typically beginning 1-2 days before menstruation. This is one of the most common symptoms
  • Cyclical GI symptoms - painful defecation/ bowel movements
  • Cyclical urinary symptoms - pain passing urine (dysuria), blood in the urine (haematuria)
  • Depending on the severity of the disease these symptoms may or may not be present during the rest of the menstrual cycle
• Dyspareunia (deep pain during or after sexual intercourse)
• Subfertility in up to 30-50% of women

It is important to consider a diagnosis of endometriosis in women presenting with at least one of the above signs or symptoms and to take full history to elicit the severity and scope of these symptoms.

Following a detailed history, it is important to perform a pelvic and/or abdominal examination to look for any physical signs of endometriosis. The key positive findings are detailed below:

Pelvic examination

• Potential positive findings:
  • Painful examination (from insertion of equipment)
  • Tenderness in the posterior vaginal fornix
  • Reduced organ mobility
  • Large cysts/ endometriomas felt in adnexa

Abdominal examination (indicated either as an additional examination or if pelvic examination is refused)

• Potential positive findings:
  • Large cysts/ endometriomas may be felt on palpation

As many patients may not have obvious physical signs, further imaging is often required based on a suggestive history and examination.

It is also prudent to note that some patients with mild symptoms may not choose to present at all, and may later be diagnosed with endometriosis based on incidental findings on scans and during surgery.

Refer to gynaecology if:

• Initial management in primary care (analgesia and hormonal treatments) is not effective, not tolerated or is contraindicated
• Pelvic signs of endometriosis are present i.e. on examination or USS
• Persistent severe symptoms suggestive of endometriosis
• If fertility is a priority for a patient who is not responding to pain management. These patients should be managed in a multidisciplinary team

Refer women to a specialist endometriosis service (endometriosis centre) if:

• They have suspected or confirmed deep endometriosis involving the bowel, bladder or ureter. This type of endometriosis is much more difficult to treat

Refer to a paediatric and adolescent gynaecology service, gynaecology service or specialist endometriosis service (endometriosis centre), depending on local service provision:

• Young women (aged 17 and under) with suspected or confirmed endometriosis

Monitoring

Consider gynaecological outpatient follow-up for women with confirmed endometriosis, particularly women who choose not to have surgery, and if they have:

• Deep endometriosis involving the bowel, bladder or ureter or
• 1 or more endometrioma that is larger than 3 cm

Endometriosis is a condition that is difficult to diagnose definitively without invasive methods (laparoscopic surgery) to visualise the lesions. In practice there is a hierarchy of investigation from history and examination to transvaginal USS/MRI to diagnostic laparoscopy.

For the majority of patients who experience mild/moderate symptoms (predominantly managed in primary care) surgery is not indicated, for these patients diagnosis can be made on strong clinical suspicion from the history or evidence from the imaging.

The small proportion of patients who show extensive disease or severe symptoms based upon their USS and history/examination will then progress to surgery. Laparoscopic surgery is the gold standard investigation for endometriosis, which confirms it’s presence without a doubt, for these patients it acts as diagnosis and treatment for severe disease.

In this section, we will focus on the investigations for endometriosis set out by the 2017 NICE guidelines and the key findings that are compatible with a positive diagnosis, these are shown below:

History and examination

Take a full history and perform a pelvic and/or abdominal examination to elicit symptoms (see “Clinical features” section).

Imaging modalities

Transvaginal ultrasound

• First line imaging investigation
• Used to investigate suspected endometriosis through identification of:
  • Endometriomas (endometrial cysts on the ovary), superficial peritoneal lesions, and deep endometrial lesions involving the bowel, bladder or ureters
• The limitation of transvaginal USS is that it is best used for identifying deep endometrial lesions (usually only present in about 1/5 of women with endometriosis) and large endometriomas. Therefore the majority of women with more superficial lesions (which are much more difficult to visualise) often receive a negative test result

Abdominal ultrasound

• Used if transvaginal ultrasound is refused

Pelvic MRI

• Not used as primary investigation but may be considered to assess the extent of deep endometriosis involving the bowel, bladder or ureters

Do not exclude endometriosis if the abdominal or pelvic examination, ultrasound or MRI are normal. If symptoms continue or there is sufficient clinical suspicion, consider referral for further investigation.

Diagnostic laparoscopy

• Definitive gold standard for diagnosis and treatment
• Involves systematic inspection of the pelvis and biopsy of any suspected endometriotic lesions (to confirm diagnosis of endometriosis and/or exclude malignancy)
• Surgical removal of these lesions acts as treatment leading to the reduction of symptoms and improving fertility
• Findings include: a fixed retroverted uterus, endometrial cysts and chocolate cysts (endometriomas), adhesions, thickening behind uterus, peritoneal deposits on the ovary, pelvic ligaments, bowel etc
• If a full laparoscopy is performed and is normal, this excludes endometriosis and an alternative diagnosis and management should be offered

Staging:

The American Society for Reproductive Medicine (ASRM) criteria is used widely amongst clinicians to classify the severity of endometriosis. The ASRM criteria stage endometriosis from stage I (minimal) to IV (severe) based on operating room findings of the appearance, location, size and number of endometriotic lesions.

Additional tests:

Serum CA125

• This is not used to diagnose endometriosis. A raised serum CA125 (> 35 IU/ml or more) may be consistent with having endometriosis however endometriosis can still occur despite a normal serum CA125

Delayed diagnosis is a significant problem for women with endometriosis. Delays of up to 4 to 10 years can occur between first reporting symptoms and confirmation of the diagnosis as many women perceive symptoms to be part of their normal menstrual cycle.

The key features of endometriosis are symptoms of dysmenorrhoea, pelvic pain and subfertility and pelvic findings include the presence of superficial lesions, deep lesions and endometriomas. There are several conditions which can present similarly and are important to exclude during diagnosis.

The most common differentials are detailed below, with key differentials including description of their positive (+) traits shared with endometriosis and their negative (-) traits that distinguish them from endometriosis:

For patients with dysmenorrhoea (most common symptom of endometriosis):

• Primary dysmenorrhoea – recurrent painful periods: (+) pelvic pain (-) nil pelvic findings on examination or imaging
• Secondary dysmenorrhoea – recurrent painful periods due to secondary reproductive disorders:
  • Adenomyosis (presence of endometrial tissue within the myometrium of the uterus): (+) pelvic pain (-) USS/MRI detect endometrial tissue in myometrium only, nil pelvic findings outside of uterus, presence of enlarged boggy uterus
  • Pelvic inflammatory disease (PID): (+) pelvic pain, pelvic/fallopian tube inflammation on USS, adhesions (-) fever, abnormal cervical discharge, positive chlamydia/ gonorrhoea swab
  • Cervical stenosis
  • Fibroids
  • Ovarian cyst: (+) pelvic pain, cyst on USS (-) simple follicular cyst not chocolate cyst/ endometrioma, unlikely to cause adhesions or other deposits in pelvic cavity
  • Endometrial polyps

For patients with chronic pelvic pain:

• Ovarian cyst
• Polycystic ovarian syndrome (PCOS): (+) pelvic pain, subfertility (-) irregular & less frequent periods, multiple cysts on USS, presence of simple follicular cysts rather than chocolate cysts/ endometriomas, nil other pelvic findings
• PID
• Fibroids
• Adenomyosis
• Adhesions secondary to other abdominal/pelvic surgery
• Irritable bowel syndrome (IBS)
• Inflammatory bowel disease (IBD)
• Interstitial cystitis: (+) suprapubic pain, urinary symptoms (-) negative findings on imaging, positive urine dipstick

For patients with subfertility:

• PCOS
• Fibroids
• Adhesions secondary to other abdominal/pelvic surgery

Ovarian/ Colon cancer

Whilst not the most common differential, ovarian cancer and colon cancer are important to exclude after evidence is found of growths and adhesions in the pelvis. Patients with these cancers will also present with discomfort in the pelvis and non-specific symptoms of bloating and altered urinary frequency, advanced cancer can also present with pain during sex or even affect periods. One of the key differences between cancer and endometriosis is the age of presentation, ovarian and colon cancer tend to present most commonly in menopausal/post-menopausal women, and thus endometriosis is significantly less likely in these patients. It is however important to remember that ovarian and colon cancer can still occur in younger women and so it is essential to investigate these lesions thoroughly when found.

In this section, we will discuss the different forms of management for endometriosis, when to refer, who to monitor and what extra support can be offered. This section is based upon 2017 NICE guidelines, NICE CKS and BNF treatment summaries for endometriosis.

The management of endometriosis can be divided into pharmacological (analgesic and hormonal treatment) and surgical treatments. Analgesia aims to relieve symptoms of pelvic pain, hormonal treatment suppresses oestrogen release to reduce symptoms (utilising the oestrogen-dependent nature of the endometriotic lesions), and surgical treatment aims to remove or destroy lesions and improve fertility. Surgery is the only potentially curative management of the options listed.

Treatment is offered to those with suspected, confirmed or recurrent endometriosis. The choice of treatment depends on severity of symptoms and the patient’s choices around contraception and fertility.

Analgesia

• Used to relieve symptoms of dysmenorrhoea, chronic pelvic pain, dysuria, painful bowel movements
• A short trial (3 months) of paracetamol or an NSAID alone or in combination should be considered for first-line management of endometriosis-related pain
• If pain relief is inadequate, consider hormonal treatments or referral to secondary care for further assessment

Hormonal treatment

• Aims to reduce pain by suppressing ovarian function and oestrogen release, reducing the heaviness of periods and thus limiting growth and activity of the lesions. This also acts as a contraceptive, which should be discussed with the patient beforehand
• A combined oral contraceptive (oestrogen + progesterone) or a progestogen only contraceptive (pill, implant, IUS, etc.) should be offered
• If this fails or is not acceptable to the patient consider referral to secondary care for further assessment
• Other hormonal treatments are available outside of the NICE guidelines (at the discretion of specialist providers). These include GnRH agonists and antagonists and androgenic agents. GnRH agonists can be used for a short period to halt the menstrual cycle which can be used to relieve symptoms. This can be an option for women who have failed other hormonal treatment and do not wish to have surgery

Laparoscopic surgery

• This is the gold standard treatment that can be used to manage symptoms and is the only form of treatment that may improve fertility
• Involves systematic inspection of pelvis for lesions (diagnostic laparoscopy), with gynaecological surgeons subsequently removing these lesions in order to improve symptoms. Techniques used include excision and ablation
• Patients with extensive deep endometriosis involving the bowel, bladder or ureter may require additional pre and post-surgical treatment. This includes:
  • Pelvic MRI, to map lesions before surgery
  • GnRH agonists, for 3-6 months before surgery to shrink lesions
  • Simple hormonal treatment after deep surgery to prolong the beneficial outcomes and manage symptoms

Hysterectomy

• Abdominal hysterectomy with or without bilateral salpingo-oophorectomy is considered to be the most effective and last-line treatment available for treating the symptoms of endometriosis, however it is important to recognise that this is a significant operation with long-lasting effects
• Hysterectomy may be indicated in patients with chronic debilitating symptoms or adenomyosis where all other treatments have been unsuccessful and the patient does not want to retain fertility
• Workup for this treatment must include specific discussion of effects on fertility, possibility of early menopause, the (minor) potential for recurrence of lesions and the impact on future health

Support

Endometriosis is a long-term condition which can have complex psychological, sexual, social and physical effects. It is important to recognise the need for long-term support and to assess individuals needs and desires particularly in relation to fertility, pain management and the impact on daily activities. Provide information for patients and offer referral to local support groups and charities.

Endometriosis is a chronic condition which can result in a number of complications over a patient's lifetime. Patients with moderate to severe endometriosis are more likely to experience complications. Physicians should be aware of the following complications which have been organised into the groups below:

Complications which arise from the presence of the endometriotic lesions alone. These include:

• Infertility, as explained in the “Pathophysiology” section
• Adhesions, due to the “sticky” nature of endometriotic lesions, leading to inflammation and obstruction of fallopian, GI, and ureteric tracts
• Endometrioma/ chocolate cyst rupture, leading to acute pain and peritoneal signs

Complications which may arise as damage secondary to laparoscopic removal of the endometriotic lesions, these include:

• Infection
• Bleeding
• Perforation
• Chronic and acute pain
• Failure to remove all lesions
• Recurrence of lesions after they have been removed
• Further damage to fertility, due to damage of the reproductive organs during surgery or secondary complications such as adhesions

Complications which can arise during pregnancy, these include:

• Early miscarriage
• Endometrioma/ chocolate cyst rupture

• Patients with endometriosis can present with a wide spectrum of symptoms. While most will present with mild symptoms that respond readily to management in primary care, a minority experience debilitating symptoms on a daily basis.

• While the exact pattern of disease is relatively unknown, it does appear that many women experience a stable or regressive pattern of symptoms throughout their fertile years with only a minority of women experiencing severe or progressive symptoms. The most severely affected patients obtain limited relief from surgery and live with the psychological and surgical complications of their disease for the rest of their lives. This is in stark contrast to the majority of women, who are able to control their symptoms in primary care, allowing them to live a normal life. Despite this, it is important to note that statistically 30-50% of women with endometriosis will experience some form of subfertility or infertility and so various options for fertility treatment should be offered.

• Regardless of the severity of symptoms, the majority of sufferers will experience remission of their symptoms after the menopause. This is due to the reduction in baseline oestrogen levels in the body after menopause and the end of the menstrual cycle. In a minority of women with severe disease, adhesions and anatomical distortions of the pelvic cavity may remain after the menopause and may continue to cause symptoms.