endometriosis

see also

• gynaecology
• RIF or pelvic pain
• LIF or pelvic pain
• dysmenorrhoea
• chronic pelvic pain in women
• Endometriosis Care Centre Of Australia
• Epworth Julia Argyrou endometriosis centre

• endometriosis is defined as the presence of endometrial glandular and stromal tissue outside the uterine cavity.
• it is dependent upon oestrogen
• clinical flare ups tend to have a catamenial (cyclical) pattern, occurring between 24h before and 72h after the onset of menses, and are typically recurring
• pregnancy itself slows or stops the growth of endometriosis
• endometriosis affects about 10-20% of all women of reproductive age and up to 50% of those with infertility
• 2 main phenotypes:
  • superficial endometriosis (SE)
    • black, white, or red implants, depending on the degree of fibrosis, scarring, and haemorrhage within the tissue
    • only red or clear blisters respond well to drug therapy ¹⁾
  • deep endometriosis (DE)
    • invasion of endometrial-like glands and stroma at least 5 mm beneath the peritoneal surface
    • often associated with fibrosis and/or smooth muscle proliferation and are most frequently associated with pelvic pain and infertility
• it is the most common cause of chronic pelvic pain in adolescent girls, especially those whose pain is not relieved by medical therapy.
• endometriosis is usually found in the pelvis – particularly in the Pouch of Douglas, on the ovaries, on the bladder and on the surface of the bowel (including the appendix).
• the ectopic endometrial tissue is functionally active, invasive, hormone dependent and shows regression with anti-oestrogen therapy.
• endometriosis is an enigma - the severity of the disease is not necessarily matched by the extent of the symptoms.
  • it is not uncommon to find severe endometriosis in asymptomatic women who are being investigated for infertility and yet there are some patients with minimal disease who suffer intense pelvic pain.

• even minimal disease can cause infertility, but the mechanism by which this happens is still poorly understood.
• the quality of an embryo (ie, its ability to develop and implant normally) is reduced by the presence of endometriosis.
• This phenomenon appears to be related to altered concentrations of progesterone, interleukin-6 and vascular endothelial growth factor (VEGF) within the follicle itself. It should be noted that VEGF is vital to the successful implantation of an embryo because it is primarily responsible for the growth of new blood vessels.

• endometriosis-associated malignancy (EAM)
  • while there is an increased risk of cancers, mainly ovarian cancers, the absolute risk of cancer in women with endometriosis is still considered low but warranting monitoring
  • risk factors for EAM ²⁾:
    • ovarian endometrioma tumor size ≥ 9 cm in diameter (although in this USS based study some may have been ovarian cancers to start with)
    • hyperestrogenism, both endo- and exogenous
    • unopposed estrogens after hysterectomy
    • obesity
    • postmenopausal status
    • possibly gene factors such as:
      • mutations in the ARID1A gene
      • loss of BAF250a gene expression
  • protective factors which reduce risk of EAM:
    • hormonal contraception
    • childbearing
    • tubal ligation
    • hysterectomy
  • endometriosis-associated ovarian cancer (EAOC):
    • Ovarian Cancer Association Consortium (OCAC) study published in 2012 suggests patients with a history of endometriosis have:
      • 3x risk of clear-cell ovarian cancers
      • more than double the risk of endometrioid tumours
      • 2x risk of low-grade serous ovarian cancers
    • EAOC is characterized by an early onset of the disease, on average 5-10yrs younger than in those without endometriosis, and EAOC is commonly a low-stage and low-grade disease usually without ascites at initial presentation and may have a better prognosis than non-EAOC ³⁾

• a 2024 Danish study suggests it appears to confer 35% greater risk of acute myocardial infarction, 20% greater risk of cardiac arrhythmias and heart failure, and 20% greater risk of ischaemic stroke compared with women without endometriosis ⁴⁾

• largely unknown
  • the aetiology, pathophysiology and natural history of this disease are still poorly understood despite extensive research
  • the two most popular theories of causation are that:
    1. nests of embryonic cells in the pelvic peritoneum become transformed into islands of ectopic endometrium, which then become active after menarche
    2. reverse menstruation carries small pieces of endometrial tissue into the pelvis via the Fallopian tubes and this tissue becomes implanted into the peritoneum of genetically susceptible individuals.
    3. see also Cells. 2022 The Role of the Immune System in the Development of Endometriosis:
       1. immune cells, such as neutrophils, macrophages, NK cells and dendritic cells, may play a special role in the angiogenesis, growth, and invasion of endometriotic cells.
       2. immune cells secrete cytokines and defensins, which also affect the endometriosis environment.
       3. immune checkpoint inhibitors should be responsible for controlling the immune response, but in patients with endometriosis their levels are observed to differ from those in healthy patients
  • possible Fusobacterium bacterial role
    • a 2023 study showed 64% of women with endometriosis in the study had Fusobacterium infiltration in the endometrium whereas only 7% of controls had this, and it appears that activated transforming growth factor–β (TGF-β) signaling resulting from Fusobacterium infection of endometrial cells led to the transition from quiescent fibroblasts to transgelin (TAGLN)–positive myofibroblasts, which gained the ability to proliferate, adhere, and migrate in vitro. A mouse study appeared to show that inoculation of Fusobacterium into the endometrium could cause endometriosis and that antibiotics could prevent this. ⁵⁾
• genetic factors
  • having a first-degree family member with endometriosis is a risk factor
    • the relative risk for women who have immediate relatives with endometriosis was estimated at 2.3 in a study on Australian twins and their families, while the overall heritability has been estimated at ~50%, as shown from monozygotic twin studies
  • Mendelian randomization analysis (MR) suggests a causal effect of depression on endometriosis, and it was found that at least 22 genes associated with both endometriosis and depression (which is twice as high in these patients) appear to be related to genes linked to conditions involving the gastric mucosa, like gastritis, peptic ulcer and gastroesophageal reflux disease, or GERD. These genes were related to 'cell-cell adhesion', 'inositol phosphate metabolism', 'Hippo-Merlin signaling dysregulation' and 'gastric mucosa abnormality'. ⁶⁾
  • some single nucleotide polymorphisms have been found to be associated with endometriosis ⁷⁾
• other risk factors for developing endometriosis appear to include⁸⁾:
  • early menarche
  • shorter cycle length
  • long and heavy menstrual flow
  • lean body size
  • reduced gravidity/parity
  • nickel allergy ⁹⁾
  • high trans-unsaturated fatty acid intake ¹⁰⁾
  • low vitamin D levels ¹¹⁾
  • alcohol consumption ¹²⁾

• it can take a number of forms, such as:
  • flare up of pelvic pain due to active lesions (which look like blood blisters) especially around the time of menstruation
  • large blood collections (endometriomas) - these are often within the ovarian tissue
  • adenomyosis - an enlarged uterus due to endometrial glands infiltrating deep into the uterine muscle
  • extragenital endometriosis which may involve:
    • uterosacral ligaments (70% of cases of extragenital endometriosis)
    • vagina (14%)
    • rectum (10%)
      • adhesions (especially around the sigmoid colon and the left adnexae), this may cause an angulated colon which may cause chronic constipation
    • rectovaginal septum or bladder (6%)
      • urinary tract involvement occurs in 0.3-12% of all cases but in 20-50% of patients with deep endometriosis, and most cases occur in those aged 25–40 years
      • in those with urinary tract involvement, 85% are bladder, 10% ureter, 4% kidney and 2% urethra ¹³⁾
      • bladder endometriosis may be more prevalent amongst women with previous Caesarean section(s) and less prevalent in those with retroverted uteruses while ureteral endometriosis is more common on the left side ¹⁴⁾
      • women with bladder DE typically present with dysuria but may also have urinary frequency, recurrent urinary tract infections [10,18] and hematuria, and, more atypically, urinary incontinence
      • ureteral DE may present as flank pain or haematuria or sterile pyuria but is commonly asymptomatic
      • ureteral DE is often associated with extensive pelvic disease
      • hydronephrosis in women with ureteral DE is generally asymptomatic and hence a renal USS is advisable
    • peritoneal distortion due to the presence of deep deposits (pocket formation)
    • extra-pelvic involvement is rare:
      • in an abdominal scar usually following Caesarean section, laparoscopy or abdominal hysterectomy - mean time to presentation after surgery is 3.6yrs ¹⁵⁾
        • The appearance of scar endometriosis at ultrasound, CT, or MRI depends on the phase of the patient’s menstrual cycle, the chronicity of the process, the number of stromal and glandular elements, and the amount of bleeding and associated inflammation (Chamie, et al., 2018, Gidwaney, et al., 2012, Yarmish, et al., 2017).
      • within the bowel itself can cause rectal bleeding, or outside of the bowel can cause adhesions and constipation
        • involvement proximal to terminal ileum is rare indeed as it mainly affects rectosigmoid > appendix > caecum > distal ileum
      • involvement of liver / diaphragm which may cause referred pain to shoulders
      • rarely, pulmonary (almost exclusively R sided, and may even cause pneumothorax)
        • pleural form with catamenial pneumothorax, non-catamenial endometriosis-related pneumothorax, catamenial haemothorax
          • chemical pleurodesis, pleural abrasion or pleurectomy may be helpful for recurrent pneumothorax or haemothorax
        • pulmonary form with catamenial haemoptysis and lung nodules
          • persistent haemoptysis due to parenchymal lesions may be treated by lobectomy or segmentectomy
      • rarely, may present as a benign renal mass with flank pain and haematuria
      • rarely, spinal, CNS and other seeding

• most commonly causes:
  • dysmenorrhoea
  • pelvic pain which may radiate to the low back
  • deep dyspareunia
  • infertility
• less commonly causes:
  • mid-cycle bleeding
  • gastrointestinal triad of bloatedness, gassiness, and cramps with or without diarrhoea and constipation, usually worse during mestruation
    • painful bowel movement may be due to endometriosis in the rectovaginal septum and pelvic lateral walls
  • painful orgasms
  • hydrosalpinx
  • urinary symptoms
  • neuropathic pain to thighs, buttocks especially if there is involvement of retroperitoneum / nerves or referred pain from the ovarian nerves
    • tends to be a throbbing or stabbing sensation, often worse when walking or exercising and worse around the time of menstruation
    • the ovaries have 3 nerve supplies:
      • two sources of sympathetic innervation:
        • the ovarian plexus which arises from the renal plexus which also innervates parts of the fundus of the uterus. The suspensory ligament of the ovary carries this plexus to the ovaries.
        • the superior ovarian nerve, carried within the ovarian ligament
      • parasympathetic innervation (provides pain sensation) is from the uterine (pelvic) plexus, which arise from the pelvic splanchnic nerves (S2-S4 ventral rami)
    • other sensory nerves within the pelvis:
      • sensation to the pelvis itself is S2-S4
      • ilioinguinal nerve supplies cutaneous sensation to labia, and the upper anterior-medial thigh (T12,L1)
      • genitofemoral nerve (L1-L2):
        • femoral branch supplies cutaneous sensation to the inner aspect of the upper thigh
      • lateral femoral cutaneous nerve provides sensation to the anterior and lateral aspects of the thigh (L2,L3)
      • femoral nerve supplies sensation to the anterior and medial aspects of the thigh (L2-L4)
      • obturator nerve supplies sensory innervation to the medial upper thigh and provides articular branches to the hip and knee (L2-L4)
      • sciatic nerve roots (L4-S3)
      • posterior femoral nerve supplies the skin of the posterior thigh, buttock, posterior aspect of the labia and a variable area of the posterior calf (S1-S3)
      • pudendal nerve supplies sensation to the external genitalia and the skin around the anus, anal canal and perineum (S2-S4)
• may have other rare symptoms depending on its involvement elsewhere
• endometriosis is a risk factor for ovarian cancer
  • 10x risk overall for severe endometriosis (19x risk of type 1 ovarian cancer), while any severity of endometriosis conveys a 4x risk ¹⁶⁾
• endometriosis is a risk factor for Sjögren's syndrome (SS) and appears to have a hazard ratio of 1.4-1.57, highest amongst age group of 20-39 ¹⁷⁾
• endometriosis is a risk factor for ankylosing spondylitis (AS)
  • endometriosis and AS share the same immunologic characteristics such as TNF-α and Th17 pathway
  • although a relatively long list of genes identified to be involved in the development either of endometriosis or AS is available, thus far there appears little overlap between genetic factors affecting susceptibility to both diseases. ¹⁸⁾
  • one study found a statistically significant association between endometriosis and the risk of AS (HR = 1.59, 95% CI = 1.09–2.31, p = 0.016). Endometriosis patients without the use of NSAIDs were found to have a significantly higher incidence of AS compared with NSAID users (HR = 4.57, 95% CI = 1.41–14.84, p = 0.011). As such, we infer that endometriosis is probably an independent risk factor for AS ¹⁹⁾

• unfortunately no blood tests are currently available to detect endometriosis reliably
• in 2019, a new DNA blood test, the Mitomic Endometriosis Test, is said to be 90% sensitive in detecting endometriosis even in its early stages HOWEVER it needs further validation studies before its use can be recommended
  • this test looks for specific biomarkers of endometriosis in the blood by examining mutations in mitochondrial DNA
• NB. serum Ca125 may be elevated in endometriosis but is neither sensitive nor specific for endometriosis

• patients with endometriosis have the protein HMGB1 in there menses at much higher levels than those who do not have it
• no current test available as yet
• in 2025, a borophene-based lateral flow immunoassay (LFIA) HMGB1 antibody test was invented which only takes 10 minutes for results with a limit of detection of 40 pg/mL and is said to have “500% higher sensitivity than existing laboratory approaches” ²⁰⁾

• Transabdominal US has limited utility but may detect ovarian endometriomas, and a good quality transabdominal ultrasound can reveal deep endometriosis affecting the bowel and bladder with similar sensitivity to MRI
  • may detect adenomyosis and focal adenomyomas (these usually have vessels running through the lesion on Doppler ultrasound and are more poorly defined, unlike fibroids where vascularity is mostly at the periphery in 85% of cases, and fibroids often have a pseudocapsule of compressed myometrial tissue surrounding them)
    • ultrasound with Doppler resulted in a sensitivity of 69.56%, specificity of 87.1%, positive predictive value (PPV) of 76.1% and a negative predictive value (NPV) of 82.92% for adenomyosis, and 87.1% sensitivity, 69.56% specificity, 82.92% PPV, and 76.1% NPV for fibroid ²¹⁾
• Transvaginal ultrasound has been shown to have sensitivities and specificity above 90% for deep endometriosis, depending on location, IF it is looked for
  • Whilst a high quality transvaginal scan can almost always detect (or exclude) ovarian endometriomas and other pelvic masses, it cannot accurately define adhesions and it cannot 'see' smaller lesions.
  • it is the 1st line for diagnosing bladder DE, however, routine US does not specifically look for this and US needs to specifically evaluate the bladder wall and ureteral size and position ²²⁾

• the only way to prove its presence is by direct visualisation and this is usually achieved by laparoscopy.

• MRI has high sensitivity (90%) and specificity (91%)
  • much better than USS for accurate diagnosis of adenomyosis (US is correct in only 50% of cases)
• MRI scans may be very useful to detect extragenital endometriosis lesions
• MRI has a low sensitivity (33%) for detecting rectal lesions due to artefacts related to rectal content;
• MRI is extremely useful in the detection of deeply infiltrating endometrial implants, even in the setting of diffuse adhesions that may result in complete obliteration of the posterior cul-de-sac ²³⁾
• see also https://radiopaedia.org/articles/endometriosis

• response to a 2 month trial of a GnRH agonist such as inhaled Nafarelin which induces a menopause-like state may be a useful diagnostic option in the older patient
• risk of osteoporosis which is largely reversible upon cessation
• small risk of pulmonary fibrosis

• HCG to exclude pregnancy
• consider Ix to exclude pelvic inflammatory disease (PID)
• pelvic USS to exclude other gynaecologic causes

• if symptoms are suspicious of endometriosis then referral to gynaecology for consideration for diagnostic laparoscopy with uterine biopsy (to detect adenomyosis) +/- laparoscopic Rx of endometriosis lesions.
  • The major advantage of laparoscopy is that conservative surgical treatment can be undertaken at the same time during the procedure, but the operation does carry with it a small risk of significant complications, such as an injury to bowel or a ureter.
  • If endometriosis is suspected, a pelvic ultrasound scan is normal and the patient does not wish to conceive, then a trial of drug therapy may be offered as an alternative to laparoscopy
  • There is no role for hormonal drug therapy in the treatment of endometriosis-related infertility
    • This is not only because such treatment does not improve fertility, but also because it prevents ovulation, which only further delays conception.
  • drug therapy is not useful for disease involving the Pouch of Douglas (this may involve utero-sacral ligaments, posterior cervix and vagina and the anterior wall of the rectum) ²⁴⁾
• women should be referred to a gynaecology service if initial hormonal treatment for endometriosis is not effective, not tolerated or contraindicated ²⁵⁾
• women with suspected or confirmed deep endometriosis involving the bowel, bladder or ureter are referred to a specialist endometriosis service. ²⁶⁾

• Unfortunately, there is often a significant wait for surgical treatment in a public hospital and thus many patients will require pain management in the meantime.
• use of non-steroidal anti-inflammatory drugs and simple pain, analgesia and analgesics is the most appropriate therapy in these circumstances
• If menorrhagia is an accompanying symptom, then the use of tranexamic acid to reduce blood loss during menstrual periods is also appropriate.

• The amenorrhoea produced by pregnancy and lactation is very effective in suppressing endometriotic deposits and may lead to long-term relief of symptoms.
• The use of a progestogen-only pill, such as norethisterone, as a contraceptive during lactation adds to this effect.
• However, endometriosis is notorious for being a recurring problem and the remission may only be temporary.

• The primary aim of hormone therapy is to suppress the activity of endometriotic implants but this treatment can also lead to atrophy of these deposits in the long term. Unfortunately, all of the available drugs have the potential to cause significant side effects, which can result in non-compliance and thus limit their long-term usefulness.

• combined OCP used continuously
  • to produce amenorrhoea although breakthrough bleeding may occur
• progestogen such as dydrogesterone or dienogest
  • This therapy lacks the potential side effects of oral oestrogen but significant breakthrough bleeding is common, and, if that occurs, most women will stop using the drug.

• Danazol and gonadotrophin releasing hormone agonists (GnRH agonists) are very effective drugs but they are also quite expensive and they are only subsidised through the PBS for visually proven endometriosis.
• Their use is therefore usually limited to those women who have already had a laparoscopy and where there has been a recurrence of symptoms such as dysmenorrhoea. Because the long-term use of these drugs causes osteoporosis, they are generally taken for no longer than 6 months.

• levonorgestrel inter uterine device (Mirena) may be beneficial
• surgical excision may be possible for more rare circumscribed lesions (adenomyoma)
• in severe cases, hysterectomy may be indicated, preferably with preservation of at least one ovary

• the prevalence amongst post-menopausal women is said to be 2-5% as either a new diagnosis (perhaps delayed or missed earlier diagnosis) or a recurrence
• unfortunately there appears to be a paucity of research in endometriosis in post-menopausal women
• risk of endometriosis is particularly in those with a PH of endometriosis and associated with either:
  • oestrogen therapy
  • dietary phyto-oestrogens
  • high endogenous oestrogen levels (in post-menopausal women this is mainly from non-ovarian sources such as skin and adipose)
  • and there may be a role for genetic factors and inflammatory mediators in increasing risk.
• post-menopausal women with endometriosis is a risk factor for endometriosis-associated malignancy (EAM)
• endometriosis may present with an asymptomatic mass in which case the finding is usually an endometrioma, and a third may have pre-malignant histology while some will also have a co-existing pelvic malignancy
• oestrogen replacement therapy should generally be ceased
• use of GnRh analogues, danazol and progesterone, appears to be ineffective in postmenopausal endometriosis ²⁷⁾
• Rx is thus primarily surgical although there may be a role for aromatase inhibitors but these increase risk of osteoporosis which needs to have additional preventive Rx
  • aromatase inhibitors (AIs) are able to block extraovarian oestrogen production which is the main oestrogen source for most postmenopausal women not taking exogenous oestrogen
    • also P450 aromatase - the central enzyme converting androgens into estrone and estradiol - appears to be overexpressed in endometriotic tissue

• https://www.eshre.eu/Guideline/Endometriosis
• NICE quality standards on endometriosis
• endometriosis.org - useful site for patients