chronic endometritis/microbiome Flashcards
Definition chronic endometritis
chronic inflammatory state of the endometrium caused by abnormal endometrial microbiome.
* Characterised by presence of oedema, increased stromal cell density, dissociated maturation of the stroma and epithelium.
* Presence of plasma cell infiltrate in the stroma.
* ~8% of endometrial biopsies.
normal endometrium is lactobacillus predominant, CE displaces lactobacilli with other bacteria.
*Ureaplama urealyticum detected commonly.
Theories behind CE causing imparied ER
- Activation of local inflammatory processes – altered chemokine and cytokine secretion (innate immune system)
- Abnormal leucocyte infiltration within the endometrium
- Altered uterine contractility
- Defective decidualisation
- Defective endometrial vascularisation
- Proliferative phenotypic change of the endometrium when it should be secretory
- Oestrogen receptor expression and PR expression increases
- Inc expression of apoptosis genes BCL2 BAX
- Cell proliferation
Linked with Infertility (particularly unexplained), RPL and RIF.
Associations/causes of CE
- Infection - Chlamydia, TB, past PID or cervicitis
- IU pathology (polyps, submucous fibroids)
- IUDs
- Radiation
- RPOC
- Unknown
Diagnosis
Not standardised.
- Hysteroscopy
a. Features include:
i. Micropolyps/microvesicles– especially when blood supply demonstrated.
ii. Hyperemia (focal or diffuse).
iii. Mucosal oedema. - Hysteroscopy and endometrial biopsy (GS) – ideally in the follicular phase
a. Plasma cell identification (mild 104, severe >/= 5) achieved with Haemtoxylin and eosin staining (H&E), or in combination with immunohistochemical examination for CD-138+.
The amount of plasma cells to diagnose is controversial (some say even 1 plasma cell is diagnostic.
1-4 plasma cells = mild CE
>/= 5 = severe CE
Not validated:
b. Molecular profiling (16SRNA analysis specific for different bacteria can be used to diagnose (not validated yet)
c. Culture (done to identify possible pathogens)
*Can not use genital swab and culture to diagnose.
Evidence for CE and infertility/IVF.
SR and MA of chronic endometritis and IVF outcomes.
Vitagliano
2022
Diagnostics
Studies - prospective cohort (4) , retrospective cohort (5) and cross-sectional (1)
Findings:
* CE significantly reduces OPR/LBR and CPR in women undergoing IVF (OR 1.97).
* Cured CE improved OPR/LBR (OR 5.33).
* IVF outcomes the same between cured CE and those without CE.
* The negative effects of CE on IVF outcome may be restricted to severe disease, whereas mild CE may have no influence on IVF success.
CE and RIF
Evidence not as convincing
Outcomes following Ab therapy for CE in RIF patients
* Demirdag et al, Obstet Gynecol 2021, Kato et al 2022
* CE frequently found in patients with RIF, outcomes didn’t appear to improve with ab treatment
(Cheng et al., 2022).
* LBR/OPR was not significantly higher in RIF patients with cured CE (after oral antibiotics) compared to those with persistent CE (OR 2.90; 95% CI 0.65–12.98; I2 = 77%; 4 studies) The reviewers did report higher CPR in cured compared to persistent CE.
CE and RPL
Pirtea – 2021
Fert Ster
SR and MA
(observational, Cross-sectional, case control, retrospective)
Findings:
* 30% incidence of CE in women with RPL
* Oral antibiotics to treat (doxycycline 100mg bd 14 days) – estimated cure rate 88%
* Fertility outcome improved after treatment (LBR increased in those with cured CE)
CE and RPOC
* Elder et al, Am J Reprod Immunol 2021
* 1 in 4 with RPOC have CE
* Not clear if causative or a response to the pregnancy loss.
* Dx of CE did not negatively impact subsequent reproductive outcomes
EMMA and ALICE
Endometrial Microbiome metagenomic analysis
- commercially available kit (igenomix) that analyses the endometrial microbiome as well as pathogenic bacteria that can cause chronic endometritis
Analysis of infectious chronic endometritis
Neither validated and cost $900 NZD
Definition of microbiome
“the ecological community of commensal, symbiotic, and pathogenic microorganisms that literally share our body space”
Human microbiome project set up to gather a deeper knowledge of microbiota in different body sites.
Sources of possible colonisation of endometrium
Uterine colonisation:
Bloodstream
Gut
Oral cavity
Vaginal ascension
Uterine seeding:
semen
IUDs
ART devices (embryo catheters)
Two main types of endometrial colonisation
Lactobacillus dominant (>90%)
Non-Lactobacilli (<90% LB)- gardenerlla, prevotella, streptococcus
Determined by:
Age, hormonal changes, ethnicity, IUD presence,
How might microbiome affect implantation
increase in pH
Change in protein expression/receptivity
Changes in metabolic composition of endometrium
Proinflammatory environment
Lactobacilli play an important role in maintenance of vaginal
bacterial communities through production of bacteriocins, hydrogen peroxide, pribiotics and lactic acid which decreases the vaginal pH and impairs growth of pathogenic bacteria. Thought to promote a supportive environment for embryonic implantation and survival.
A nonLB environment associated (correlation not causation) with reduced IVF success.
However, assessment of pH value as a potential predictor of endometrial microbiota in
14 endometrial fluid samples revealed a wide range of pH values regardless of the bacterial
composition, suggesting that the abundance of Lactobacilli alone is not enough to change
the uterine pH.
Endometriosis patients have a distinct uterine microbiome.
Tools for management of microbiome
Antibiotics = most commmon but cant rule out some negative effects
Probiotics
Microbiota transplantation
Systematic reviews: no strong evidence for these in ART
Can increase lactobacillus with them though
Technology to test for uterine colonisation - issues with assessing uterine microbiota
NGS of bacterial 16S rRNA genes enables many studies to describe different microbial communities inside the endometrial cavity.
Contamination with cervix, vaginal and external exposures.
Endometrial microbiota and miscarriage - potential mechanisms
To date, most evidence linking the endometrial microbiota with
early pregnancy loss is associative. Whether reported relationships are causal or a consequence of physiological changes leading to miscarriage remains to be elucidated.
Potential mechanisms:
Dysregulation of inflammatory pathways
Affects invasion, artery remodelling, endometrial senescence
Altered receptivity and function may predispose to pregnancy loss.
Overall get more proinflammatory cytokines, chanhges in T cell from more 2 to 1, abnormal uNK cells, plasma cell infiltraion = abnormal immune repsonse and defects in implantaion and immune tolerance
