endometriosis

Question 1

How to diagnose endometriosis? (ESHRE + RANZCOG)

Answer 1

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.

Question 2

Abnormalities in the endometrium caused by adenomyosis

Answer 2

1. Progesterone resistence (KRAS mutation caused reduced Progesterone receptors)
2. Abnormal contractility (driven by Prog resistence)
3. Hyperinflammation +/- chronic endometritis (Pro-inflam cytokines - IL-1beta, IL-6, IL-8 then increases STAT3)
4. Impaired decidualisation (decreased HOXA10 HOXA11)
5. Hyperproliferation - epithelial cells sustained (Ki67+ve)

Question 3

Adenomyomectomy - what and pros and cons

Answer 3

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.

Question 4

How does endometriosis lead to infertility

Answer 4

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).

Question 4

Aetiology of adeomyosis

Answer 4

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.

Question 5

Gut and uterine microbiome and endometriosis

Answer 5

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.

Question 6

TVUS for endometriosis - key components

Answer 6

Must be experienced endometriosis scanner must include:
1. scans though the posterior vaginal forni
2. assessing the sliding sign
3. identifying the USLs.

Question 7

proposed etiology theories of endometriosis development

Answer 7

Sampson’s theory (retrograde menstruation) (90% of wmen 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.)

Question 8

pathophysiology of endometriosis and infertility

Answer 8

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

Question 9

Drugs recommended for endometriosis-associated pain

Answer 9

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???)

Question 10

Surgical interruption of pelvic nerve pathways - two types used in endometriosis and ESHRE recommendation

Answer 10

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)

Question 11

Evidence for surgically removing endometriosis to improve pain (stage 1/2)

Answer 11

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

Question 12

EHP-30 - what is it?

Answer 12

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)

Question 13

Evidence to support removal of advanced DIE/endometrioma

Answer 13

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.

Question 14

Ovarian suppression treatment to improve infertility in endometriosis

Answer 14

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).

Question 15

Hormonal therapy post surgery in those TTC

Answer 15

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.

Question 16

Other medication treatments to improve fertility in those with endometriosis?

Answer 16

None that should benefit - pentoxifylline, NSAIds, letrozole outside of ovulation induction shouldn’t be prescribed to improve pregnancy rates.

Question 17

Evidence of stage 1/2 excision and natural fertility

Answer 17

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).

Question 18

Endometrioma excision and natural fertility evidence

Answer 18

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.

Question 19

DIE excision and natural fertility - evidence

Answer 19

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

Question 20

ART and endometriosis surgery

Answer 20

Not really answered in ESHRE guidelines, seems to be a growing body of evidence that better to do IVF prior to endometriosis surgery. As surgical resection doesn’t appear to improve success of ART.

If surgery has occurred - Women should be counselled of their chances of becoming pregnant after surgery. To identify patients that may benefit from ART after surgery, the Endometriosis Fertility Index (EFI) should be used as it is validated, reproducible and cost-effective. The results of other fertility investigations such as their partner’s sperm analysis should be taken into account.

Question 21

Endometriosis Fertility Index

Answer 21

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.

Question 22

IUI and endometriosis related infertility (stage 1/2 and then stage 3/4)

Answer 22

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.

Question 23

IVF and endometriosis

Answer 23

1. 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.
2. Stage 3/4 endo - lower number of oocytes obtained, lower implantation, clinical pregnancy and trend to lower live birth was seen.
3. Endometriomas - number of oocytes and M2 oocytes retrieved were lower, blastocysts, clinical pregnancy rates, live birth rates were all the same as controls.

Question 24

Type of COS protocols and outcomes with endometriosis

Answer 24

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

Question 25

Is there an increased risk of cancer with endometriosis?

Answer 25

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)

Question 26

Surgery prior to ART ESHRE recommendations

Answer 26

1. Surgery not recommended prior to ART to improve LBR in women with rASRM 1/2 disease as potentail benefits are unclear (one retrospective study)
2. 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.
3. Surgery on DIE prior to ART should be guided by pain symptoms and patient preference as its effectiveness is uncertain

Question 27

Fertility preservation and endometriosis

Answer 27

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

Question 28

Risk factors for endometriosis in adolescents presenting with dysmenorrhoea

Answer 28

1. Strong family history of endometriosis
2. Obstructive genital malformations
3. Early menarche
4. Short menstual cycles

Should be considered in those with cyclical absenteeism from school, or with the use of COCP for treatment of dysmenorrhoea.

Question 29

symptoms suggestive of endometriosis in adolescents

Answer 29

1. chronic or acyclical pelvic pain particularly if combined with nausea.
2. Dysmenorrhoea, dyschezia, dysuria, dyspareunia.
3. Cyclical pelvic pain.

Question 30

Types of pain with endometriosis

Answer 30

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.

Question 31

How does endometriosis cause pain

Answer 31

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, IL* 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

Question 32

Adenomyosis -definition

Answer 32

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.

Question 33

Adenomyosis - diagnosis

Answer 33

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

Question 34

Adenomyosis and infertility

Answer 34

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.

Question 35

WHat is the junctional zone

Answer 35

Junction between the endometrium and the inner myometrium.

Question 36

MRI features of adenomyosis

Answer 36

Pelvic MRI is the modality of choice to diagnose and characterise adenomyosis. MRI has a sensitivity of 78-88% and specificity of 67-93%.

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.

Question 37

TVUS features of adenomyosis

Answer 37

Although pelvic ultrasound is the primary imaging modality employed to investigate menorrhagia and dysmenorrhoea, the sonographic features are variable and the sensitivity is operator and technique dependent. For example, the sensitivity and specificity of transabdominal ultrasound were 32-63% and 95-97%, respectively 7. Yet transvaginal ultrasound is reported to be as sensitive (89%) and specific (89%) as MRI.

In 2021 a consensus on revised definitions of the uterine morphological features of adenomyosis was published 21.

It may be useful to categorise ultrasound findings into three groups that mirror the histological findings 15-17:

“adeno”: ectopic endometrial glands

subendometrial echogenic linear striations and/or nodules (specific sign), extending from the endometrium and into the inner myometrium

hyperechoic islands 19

irregular endometrial–myometrial junction 19

tiny (1-5 mm) anechoic myometrial and subendometrial cysts (specific sign): reflecting glands filled with fluid

cystic striations

“myosis”: muscular hyperplasia +/- hypertrophy, which may be hypoechoic

focal or diffuse myometrial bulkiness, which may be asymmetric 5

typically of the fundal region and posterior wall

focal lesions have relatively indistinct borders, compared to leiomyomas

asymmetrical myometrial thickening

thickening of the transition zone can sometimes be visualised as a hypoechoic halo surrounding the endometrial layer of ≥12 mm thickness (less specific)

vascularity: flow on colour Doppler

generally increased

increased number of tortuous vessels penetrating the myometrium

areas of increased vascularity reciprocate the distribution of lesions