L21: Endometriosis Research Flashcards
What is endometriosis? What does it cause?
- a condition when cells similar to the lining of the uterus, or endometrium, grows outside of uterus.
- Often involved pelvic tissue, can envelop ovaries and fallopian tubes
- Affects nearby organs, bowel and bladder
- This tissue during menstrual cycle responds to hormones, due to its location, might result in pain
- Causes surrounding tissues to be irritated and potentially causes scars
What are endometriomas?
cysts, lumps of endometrial tissue outside of uterus
What are the risk factors for endometriosis?
Risk factors of endometriosis
- Never giving birth
- More frequent menstrual cycles
- Heavy and prolonged menstrual periods
- Higher levels of oestrogen
- Low BMI
- Structural issue with vagina, cervix or uterus (that prevents passage of the blood from the body)
- Family history
- Starting period on an early age
- Or starting menopause on a later age
What are the symptoms of endometriosis?
Symptoms
- Pelvic pain – during or outside normal menstrual period, beyond normal cramping
- Lower back abdominal pain
- pain with intercourse
- pain with bowel movements or urination
- infertility
- fatigue
What is a common place for endometrial tissue to settle?
Pouch of Douglas
What are the theories of causes of endometriosis?
Theories of causes:
- during menstruation endometrial tissue does not go down through vagina, but back through Fallopian tubes and into the pelvis – retrograde menstruation -> and seeds itself
- could be through lymphatic system as well, like cancers metastasise
- or cell metaplasia occurs -> cells change from normal cell type to endometrial cell
- genetic link, but no genes found yet
What are adhesions in endometriosis?
Adhesions and endometriosis
- this localised bleeding and inflammation can lead to adhesions
- damage to the tissue, as they heal they develop scar tissue that binds them together
- result: different organs attaching to each other
- example: ovaries can be attached to lining of the bladder (peritoneum)
- this results in chronic non-cyclic abdominal pain
How is dichloroacetate (DCA) important in treatment of endometriosis?
- DCA
- Used clinically to treat rare metabolic disorders in children
- Effects of DCA on mesothelial cell – lactate secretion reduced
- Testing DCA in mice induced endometriosis, lactate reduction successful/significant
How are macrophages involved in endometriosis?
Macrophages in endometriosis
- Abundant in lesions and peritoneal fluid
- Promote lesion growth and vascularisation
- Important in development of pain symptoms
- Pro-repair phenotype
- Decreased phagocytosis
What is RRx-001 (nibrozetone)?
- Anti-cancer drug in phase I-III trials
- Multiple anti-cancer pathways
- Differing activity in normoxic/hypoxic environments
i) Inflammasome inhibition
ii) Nrf2 upregulation
iii) Macrophage upregulation
iv) Macrophage repolarisation
v) Enhanced phagocytosis
vi) Vascular normalization
How is RRx-001 useful in endometriosis?
RRx-001 modulates peritoneal macrophages
- 10x Multiome analysis of sn-RNA/ATAC data
- Increased monocyte-derived subpopulation – pro-resolving LpM
- Reduction in pro-disease LpM
- Preservation of proliferating populations
RRx-001 reduces endometriosis lesion growth and pain
- Pre-treatment in mouse model
i) Reduces lesion development
ii) Reduces lesion number and size
iii) Attenuates evoked pain-like responses
What are cannabinoids?
Cannabinoids
- Class B illegal drug
- Contains phytochemical called cannabinoids
- Two most well studied:
i) THC acts on CB receptors – major psychoactive component of cannabis
ii) CBD works via alternate mechanisms
What is CBD? Where is it used as a treatment?
Cannabidiol (CBD)
- Available from health stores
- Licensed for certain forms of epilepsy
- Being studied as a treatment for a wide range of conditions: Parkinson’s, schizophrenia, diabetes, multiple sclerosis and anxiety
- 31% endometriosis patients responded to use CBD to reduce pain
What is the evidence of CBD efficacy against endometriosis in animal models?
CBD and endometriosis: animal models
- In vitro reduced proliferation
- THC reduced lesion size; improved pain behaviour
- CBD reduced lesion size, inflammation and scarring; reduced pain mediators and improved pain behaviour
- CBD reduced lesion size, inflammation and new blood vessel growth
