endometriosis and adenomyosis Flashcards
How to diagnose endometriosis? (ESHRE + RANZCOG)
ESHRE (2022): Laparoscopy is no longer the diagnostic gold standard and it is now only recommended in patients with negative imaging results and/or where empirical treatment was unsuccessful or inappropriate.
RANZCOG (2021): Still considers laparoscopy and biopsy the gold standard. Can be reasonably suspected and empirically managed. Imaging is also used in the diagnosis - TVUS and MRI.
Abnormalities in the endometrium caused by adenomyosis
- Progesterone resistence (KRAS mutation caused reduced Progesterone receptors)
- Abnormal contractility (driven by Prog resistence)
- Hyperinflammation +/- chronic endometritis (Pro-inflam cytokines - IL-1beta, IL-6, IL-8 then increases STAT3)
- Impaired decidualisation (decreased HOXA10 HOXA11)
- Hyperproliferation - epithelial cells sustained (Ki67+ve)
Adenomyomectomy - what and pros and cons
Surigcal procedure to resect adenomyosis. Not performed in NZ or Australia.
Pros:
Decrease in pain symptoms, ?miscarriage, pPROM, PET, SGA, degeneration of adenomyosis.
Cons:
Increases placenta accreta spectrum quite considerably, increases caesarean and caesarean hysterectomy, clinical evidence on benefit in infertilty is poor, uterine ruptures increased.
How does endometriosis lead to infertility
Multifactorial,
Social determinants (pain, access to care, inability to engage in penetrative intercourse)
Factors associated with lesions (adhesions, inflammation, distortion of anatomy, tubal dysfunction)
Those not related with lesions – factors at the level of HPO and reproductive tract (decreased ovarian reserve, oocyte quality, sperm-oocyte interaction, decreased endometrial receptivity, increased uterine contractions).
Aetiology of adeomyosis
Poorly understood.
1. endomyometrial invagination of the endometrium.
2. de novo development from embryologically misplaced pleuripotent mullerian remnant
3. Invagination of the basalis proceeding along the intramyometrial lymphatic system.
4. Originating from bone marrow stem cells that are displaced through the vasculature.
Gut and uterine microbiome and endometriosis
Gut microbiome = shown to be changes in the gut microbiome in those with endometriosis
Disrupts immune function, exacerbates chronic inflammation, exacerbates gut symptoms.
Gut estrobolome – bacterial genes present within the gut are able to metabolise oestrogens, produce enzymes that can then modify the bioavailability of oestrogen.
Variations in the gut microbial community can impact oestrogen metabolism.
Uterine microbiome
Fusobacterium may facilitate endometriosis through inflammatory effects on eutopic endometrial fibroblasts.
High Hz of fusobaceterium in euptoic endometrial and ovarian endometriotic samples relative to those without endometriosis.
TVUS for endometriosis - key components
Must be experienced endometriosis scanner must include:
1. scans though the posterior vaginal forni
2. assessing the sliding sign
3. identifying the USLs.
proposed etiology theories of endometriosis development
Sampson’s theory (retrograde menstruation) (90% of women have retrograde menstruation and only 11% develop endometriosis - why? - likely immune abberations)
Coelomic metaplasia (originates from the metaplasia of specialised cells that are present in the mesothelial lining of the visceral and abdominal peritoneum).
Induction (results from the differentiation of mesenchymal cells, activated by substances released by the degenerating endometrium that arrives in the abdominal cavity)
Embryonic rest (defect of embryogenesis – mullerian duct maldevelopment could cause the spread of endometriotic cells across the posterior pelvic floor and the persistence of embryonic cell rests).
Stem cell theory (Stem cell theory posits that the cells responsible for the regeneration of the endometrial lining during one’s menstrual cycle play a role in the development of endometriosis. The spreading of these stem cells to ectopic regions can then lead to the differentiation of endometrial cells and cause endometriosis.)
pathophysiology of endometriosis and infertility
Distorted pelvic anatomy
Altered peritoneal function
Altered hormonal and cell mediated function
Endocrine and ovulatory abnormalities
Impaired implantation
Oocyte and embryo quality
Abnormal uterotubal transport
Drugs recommended for endometriosis-associated pain
ESHRE:
1. Analgesia (NSAIDs alone or in combo with other analgesia) (WEAK)
2. COCP (STRONG)
3. Progestogens (depot MPA, cyproterone acetate, MPA, northisterone acetate/norethindrone, desogesterl, dienogest, gestrinone. (NB - danazol no longer recommended).
4. LNG-IUS or etonogestrel-releasing subdermal implant (implanon)
(NB Jadelle is levonorgesterol and not recommended in guideline) (STRONG)
5. GnRH agonists as second line (due to side effect profile - VMS and BMD loss), add back combined therapy can reduced side effects and should be considered. (STRONG)
5. GnRH antagonists second line option -oral formulations now available (WEAK)
6. Aromatase inhibitors (STRONG???)
Surgical interruption of pelvic nerve pathways - two types used in endometriosis and ESHRE recommendation
Laparoscopic uterosacral nerve ablation (LUNA) - not recommended
Presacral neurectomy (PSN) - beneficial in treating midline pain as an adjunct to conventional laproscopic surgery, requires a high degree of skill and is assoc. with higher operative risk ( bleeding/constipation/urinary urgency/painless first stage of labour)
Evidence for surgically removing endometriosis to improve pain (stage 1/2)
Compared to diagnostic laparoscopy only, it is uncertain whether laparoscopic surgery reduces overall pain associated with minimal to severe endometriosis. (2 small RCTs only, very low quality evidence).
Currently a registered trial (Esprit2) looking at randomising patients with CPP and superficial endo to diagnostic lap versus.
Evidence in improvement in QoL scores have stronger evidence to support excision. Improved mental componenet score but not physical component score. Sexual satisfaction scores also improved.
Excision recommended over ablation
EHP-30 - what is it?
Endometriosis Health Profile is a health related Quality of Life (HRQoL) patient self-reported outcome tool. (Has been validated). Also a short version (EHP-5)
Covers;
Pain (11)
Control and powerlessness (6)
Social support (4)
Emotional well-being (6)
Self-image (3)
Evidence to support removal of advanced DIE/endometrioma for pain
Surgical removal of deep endometriosis may reduce endometriosis-assicated pain and improve QoL.
Removing endometrioma has not been studied using RCTs for reducing pain symptoms.
Nerve sparing operative laparoscopy should be performed and these surgeries should be done by experts.
No RCTs for hysterectomy improving pelvic pain, but ESHRE states can consider it (+/- ovaries) + all visible endometriosis. Must be aware it may not help cure the disease.
Ovarian suppression treatment to improve infertility in endometriosis
Based on the results of the Cochrane review, suppression of ovarian function (by means of danazol, GnRH agonists, progestogens, OCP) to improve fertility in women with endometriosis is not effective and should not be offered for this indication alone (strong recommendation).
Hormonal therapy post surgery in those TTC
Women seeking pregnancy shouldn’t be prescribed postoperative hormonal suppresion with the sole surpose to enhance future pregnancy rates.
Those not planning to conceive after surgery can be offered hormonal suppresion therpay as it doesn’t negatively impact future fertiltiy and improves the immediate outcome of surgery for pain.
Other medication treatments to improve fertility in those with endometriosis?
None that should benefit - pentoxifylline, NSAIds, letrozole outside of ovulation induction shouldn’t be prescribed to improve pregnancy rates.
Evidence of stage 1/2 excision and natural fertility
Peritoneal endometriosis
Although the Cochrane review does not specifically address endometriosis subtypes, it could only identify and include trials on rASRM stage I/II endometriosis (Bafort, et al., 2020). Therefore, their findings could be extrapolated to peritoneal endometriosis (or at least the absence of large endometrioma and/or deep lesions with extensive adhesions). Although laparoscopic surgery was found to increase (natural) viable intrauterine pregnancy rates, no data were found on live birth rates. It should also be noted that none of the studies discussed were stratified according to the Endometriosis fertility Index (EFI).
Endometrioma excision and natural fertility evidence
Known reduction in ovarian reserve (AMH/antral follicle count), most surgeons will leave these until after fertility treatment/family complete unless pain issues.
No RCTs comparing fertility outcomes after surgery for endometrioma in comparison
with expectant management, nor studies exploring the indication for surgery depending on the size of the cyst.
DIE excision and natural fertility - evidence
Although no compelling evidence exists that operative laparoscopy for DE improves fertility, operative laparoscopy may represent a treatment option in symptomatic patients wishing to conceive
Endometriosis Fertility Index
An end-of-surgery scoring system that predicts non-ART pregnancy rates (natural conception or IUI) after surgery. It was derived from prospective analysis of clinical data and has since been (externally) validated in over 30 studies, of which the majority were evaluated in a meta-analysis (Vesali, et al., 2020) confirming its good performance despite substantial heterogeneity between studies. By scoring patient-related factors (age, duration of subfertility and history of prior pregnancy) and surgical factors (‘least function score’ of the tubes and ovaries, endometriosis lesion and total score as extracted from the rASRM staging) factors, a score between 0 and 10 is generated. This score is strongly correlated with postoperative non-ART pregnancy rates and can therefore be used to counsel patients on their reproductive options, although it assumes normal gamete function.
IUI and endometriosis related infertility (stage 1/2 and then stage 3/4)
In infertile women with rASRM stage 1/2 endo, clinicians may perform IUI-OS instead of expectant management or IUI alone as it increases pregnancy rates.
Although the value of IUI in infertile women with rASRM stage 3/4 endo with tubal patency is uncertain, the use of IUI-OS could be considered.
IVF and endometriosis
- Stage1/2 endometriosis - same number of oocytes retrieved, lower fertilisation rates, no reduction in implantation, clinical pregnancy or live birth rates compared to women without endometriosis.
- Stage 3/4 endo - lower number of oocytes obtained, lower implantation, clinical pregnancy and trend to lower live birth was seen.
- Endometriomas - number of oocytes and M2 oocytes retrieved were lower, blastocysts, clinical pregnancy rates, live birth rates were all the same as controls.
Type of COS protocols and outcomes with endometriosis
RCT of 247 women with stage 1/2 endometriosis showed GnRH antagonist cycles were non-inferior to those for a GnRH agonist protocol. Retrospective data shows no different for stage 3/4 disease either.
Cochrane review updated 2019 - Long-term pituitary down-regulation before in vitro fertilisation (IVF) for women with endometriosis -
Uncertain effect on LBR
2 published in 2020 = no benefit.
Stress the paucity and low quality evidence
Note possible benefit of this in FET cycles for women with adenomyosis
GnRHa downreg in adenomyosis and IVF
Increased LBR – Hoe 2020, Lan 2021
GnRHa pretreatment before FET vs long or ultralong GnRHa protocol
Increased LBR
GnRHa may improve LBR in women with adenomyosis
Is there an increased risk of cancer with endometriosis?
Overall risk of cancer is not increased. Does seem to be associated with an increased risk of ovarian, breast and thyroid cancers (very small increased risk 0.5%). Probably increased risk of clear cell and endometrioid ovarian cancer in people with ovarian endometriosis (additional risk is very low)
Surgery prior to ART ESHRE recommendations
- Surgery not recommended prior to ART to improve LBR in women with rASRM 1/2 disease as potentail benefits are unclear (one retrospective study)
- Ovarian endometrioma surgery not recommended prior to ART to improve LBR as the current evidence shows no benefit and surgery is likely to have a negative impact on ovarian reserve.
- Surgery on DIE prior to ART should be guided by pain symptoms and patient preference as its effectiveness is uncertain
Fertility preservation and endometriosis
In cases of extensive ovarian endometriosis, clinicians should discuss the pros and cons of fertility preservation with women with endometriosis. THe true benefit of fertility preservation in women with endometriosis remains unknown.
– expensive
– exposes women to some clinical risk
– cost effectiveness unknown
– no evidence for criteria to select patients who may benefit
Risk factors for endometriosis in adolescents presenting with dysmenorrhoea
- Strong family history of endometriosis
- Obstructive genital malformations
- Early menarche
- Short menstual cycles
Should be considered in those with cyclical absenteeism from school, or with the use of COCP for treatment of dysmenorrhoea.
symptoms suggestive of endometriosis in adolescents
- chronic or acyclical pelvic pain particularly if combined with nausea.
- Dysmenorrhoea, dyschezia, dysuria, dyspareunia.
- Cyclical pelvic pain.
Types of pain with endometriosis
Various types of pain – visceral hypersensitivity and hyperalgesia (pelvic organ pain), somatic sensitisation = shooting and stabbing pains (pelvic floor muscles spasm) and referred pain down thighs. Central sensitisation = headache, nausea, anhedonia etc.
How does endometriosis cause pain
No consistent correlation between severity of symptoms and extent of disease
Nociceptive, inflammatory and neuropathic mechanism
Endometriosis generates inflammatory response - release of cytokines TNFa, IL6, IL8 with angiogenic and proimflammatory effects - activates macrophages and neutrophils
Effect of oestrogen on nerve growth factor
Release of prostaglandins E2 and F which are direct generators of pain
Adenomyosis -definition
Benign gynaecological condition characterised by invasion of endometrial glands and stroma from the basal layer of the endometrium into the myometrium with surrounding myometrial hyperplasia.
Can be focal or diffuse or an adenomyoma.
Focal - circumscribed nodular aggregates of endometrial glands surrounded by normal myometrium.
Diffuse - lesions spread throughout the myometrium.
Adenomyoma - focal adenomyotic lesions surrounded by hypertrophic myometrium,
Can be located within the internal or external myometrium or within the junctional zone between them.
Disease score calculated mild, moderate or severe.
Adenomyosis - diagnosis
Historically by histology after hysterectomy.
Can use TVUS and MRI but no standardised way to diagnose.
Morphological Uterus Sonographic Assessment criteria.
Features of adenomyosis on TVUS
-round cystic area within the myometrium surrounded by a hyperechoic halo;
- hyperechogenic islands;
- subendometrial hyperechogenic lines and buds.
Indirect features of adenomyosis
- fan shadowing
- globular uterus or asymmetry
Adenomyosis and infertility
Still not clearly linked.
Probably that asymptomatic mild adeno doesn’t have an affect on IVF outcomes.
Does appear to be an increased risk of miscarriage and particular with junctional zone adenomyosis and severe adenomyosis.
Also may be a trend to lower live birth rates.
WHat is the junctional zone
Junction between the endometrium and the inner myometrium.
MRI features of adenomyosis
RANZCOG guidelines - don’t use MRI as a first line method to diagnose adenomyosis - however it may be appropriate in some situations. Ultrasund should be used first line.
The most easily recognised feature is a thickening of the junctional zone ≥12 mm, either diffusely or focally (normal junctional zone thickness is up to ~5 mm).
T1
foci of high T1 signal are often seen, indicating menstrual haemorrhage into the ectopic endometrial tissues.
T2
typically a region of adenomyosis appears as an ill-defined ovoid/diffuse region of thickening, often with small high T2 signal regions representing small areas of cystic change the region may also have a striated appearance.
FIGO MUSA group features of adenomyosis on TVUS
Asymmetrical myometrial thickening
Myometrial cysts
Hyperechoic islands
Fan shaped shadowing
Echogenic subendometrial lines and buds
tranlesional vascularity
Irregular junctional zone
Interrupted junctional zone
*junctional zone may be best evaluated with 3D USS
* presence of 2 or more is highly associated with adenomyosis.
Ultrasound features of endometriosis
uterus
anteverted-retroflexed uterus (‘question mark sign’)
adenomyosis
nodules on the serosal surface - solid, hypoechoic masses
ovarian endometriomas
unilocular cystic lesions containing uniform low-level echoes (ground glass appearance)
no blood flow on colour Doppler
endometriomas occur bilaterally in approximately 50% of cases
‘kissing’ ovaries sign describes ovaries that are adherent to one another posterior to the uterus and is frequently seen with bilateral endometriomas
fallopian tubes: hydrosalpinx
urinary bladder
the appearance of nodules can be varied, including hypoechoic linear or spherical lesions
ureters: may appear dilated with deep endometriosis;
ureterovesical region
can be obliterated due to adhesions; should be assessed with the sliding sign (like the pouch of Douglas)
posterior vaginal wall/ posterior vaginal fornix
thickening of the vaginal wall
a discrete hypoechoic nodule in the vaginal wall
uterosacral ligaments
The uterosacral ligaments are the most common location to see deep endometriosis on transvaginal ultrasound
thickening of the white line of the uterosacral ligaments (>5.8 mm)
rectosigmoid colon
nodules can be single or multifocal
bowel nodules are hypoechoic
pouch of Douglas
the pouch of Douglas is considered obliterated if the sliding sign is negative (i.e. if the rectum and uterus do not slide apart)
obliteration can be partial or complete
the pouch of Douglas may also contain hypoechoic nodules of deep endometriosis
ENZIAN scoring system
comparing enzian, rASRM and EFI
rASRM
Separated into 4 stages:
Minimal (1-5) -
Mild (6-15) -
Moderate (16-40) -
Severe (>40) –
Broken down into endometriosis, posterior cul-de-sac obliteration, adhesions
Endometriosis further broken down into superficial or deep and into peritoneum, ovary.
Adhesions separated into filmy or dense and described for ovary and tubes. Broken down to <1/3 , 1/3-2/3 or >2/3
important endo questions
When did pain start, at menarche/before you were 20 or later?
Do you take time off work or school?
Did it progress from period pain to ovulation pain then all the time?
Do you have back pain?
Do you have bladder/bowel pain or pain with sex?
Do you have fatigue/headaches/nausea/difficulty sleeping?
Do you have family history of endometriosis?
Positive markers on eTVUS
endometrioma
Adenomyosis
Question mark sign (anteverted, retroflexed uterus)
Fixed or kissing ovaries
Fallopian tube distortion
The sliding sign (rectum glides freely over cervix)
Endometriosis nodules
Positive markers of eMRI
Endometrioma
Upper rectal distortion
Fixed uterine anteversion and/or retroflexion
Thickened USL
Haemtosalpinx
Posterior cul-del-sac obliteration
Uterine serosal plaques
Elevated vaginal fornices
Pain mx options on endometriosis
- reducing pain triggers
- pelvic organ visceral sensitisation
- pelvic muscle (somatic) sensitisation
- treatment for cerbral cortex (central) sensitisation
Pain triggers:
- menstrual suppression - COCP continuous, Progestogens (oral, implant, IUD), GnRH agonists/antagonists, SPRM, weak androgend)
- surgical removal of lesions
Pelvic organ visceral sensitisation:
- NSAIDs
-FODMAP diet
- regular bladder emptying
- Lubrication with sex
- neural modulators
-Dieticians
Pelvic muscle (somatic) sensitisation:
-Pelvic floor physiotherapy
- PR diazepam (acute spasm)
- Topical amitriptylline
- Botox
- Neural modulators
- Pain specialists
Treatment for cerbral cortex (central) sensitisation
- Paracetamol
- SNRIs
- behavioural modification
- self care/mindfulness
- pain specialists
- counselling/psychological support
