W11 L1 Mon uterine disorder Flashcards
What is menstrual cycle
The regular renewal of the lining of the uterus (the endometrium) to prepare for potential embryo implantation.
Step in the menstrual cycle
- Menses – Thickened endometrium is eliminated
- Proliferative – Endometrium re-grows
- Secretory – Post-ovulation, the endometrium decidualises and prepares for implantation
Period pain is considered normal if
- Pain is present on the first 1 or 2 days of menses
- Pain is relieved by heat packs or mild medications
- Pain does not prevent you from doing day-to-day activities
Period pain is considered abnormal if
- Pain is severe enough to disrupt normal activities
- Pain persists beyond the menses period
- Pain is chronic and last more than 6 months
Primary Dysmenorrhea
- High prevalence (43-93%)
- Severe pain experienced (30%)
- Lasts 1-3 days
- Unknown cause – speculated hyperproduction of prostaglandins (induce uterine contractions)
- Treated with Non-steroidal anti-inflammatory drugs NSAID (aspirin, ibuprofen), COX inhibitors (naproxen)
Secondary Dysmenorrhea
- Pain due to an underlying pathology
- Common causes are endometriosis and adenomyosis
- Treatment is OCP (progestin) and/or surgery (removal of underlying cause)
Abnormal Uterine Bleeding (AUB)
occurs when menstrual bleeding falls outside normal parameters 25-80ml(for a period >6 months)
§ Causes: PALM-COEIN to investigate structural changes to uterus + non-structural issues
Ø PALM: Polyps, Adenomyosis, Leiomyoma (fibroids), Malignancy + hyperplasia
Ø COEIN: Coagulopathy (clotting disorders), Ovarian dysfunction, Endometrial dysfunction, Iatrogenic (nonmenstrual bleeding/spotting due to hormonal therapies), Not otherwise classified
Heavy Menstrual Bleeding (HMB)
§ HMB: excessive menstrual blood loss which interferes with physical, emotional, social + quality of life
Ø Normal 5-80mL blood loss (35mL average)
Ø >80mL causes anaemia + severe fatigue (27-54% of menstruating women)
pathology of HMB
uterine fibroids (30%) + polyps (10%) but most histologically normal
impact of HMB in QoL
bloodstains, pain, anxiety/depression, moodiness, interference w/ life
Treatment for HMB
- hormonal (OCP or progestagens to stop cycle)
- prostaglandin inhibitors (block prostaglandin production),
- anti-fibrinolytic agents (blocks fibrinolysis = removal of small clots),
- manage iron deficiency,
-surgery (ablation – removal of uterine lining but regrows under E; hysterectomy – remove uterus)
What is Uterine fibroids and the incident rate
“benign tumours of smooth muscle cells of the myometrium”
* Most common being tumour (77% of reproductive-aged women)
* Incidence and severity is higher in women of African descent
* Main indication for hysterectomy
Possible symptom for fibroids
- None
- Heavy menstrual bleeding
- Chronic pain, dysmenorrhoea and pressure symptoms
- Fertility and pregnancy problems
Characteristic of fibroids
- Firm, round, well separated from surrounding myometrium, non-invasive
- Occur as single or multiple tumours
- Vary in size and growth rates
- Vary in location:
– Submucosal
– Intramural
– Sub-serosal
– Pedunculated
Clonal origion of fibroids
derived from a single smooth muscle cell
* Although clonal, multiple cell types exist within the fibroid (SMC, fibroblasts, endothelial cells, immune cells)
* Fibroid cell sub-populations may be clonally expanded from a multipotent progenitor cell that undergoes differentiation.
* Fibroids are vascularized often with an avascular core (which stimulates more vascularization).
Treatment of Uterine Fibroids
§ Treatment:
-GnRH analogues (hypoestrogenism to shrink tumour before surgery; short term use only),
-hormone modulators (selecive oestrogen receptor modulators SERM + progesterone (SPRMs) to slow growth),
-progestins (reduce HMB by stopping cycle)
§ Surgical treatment:
-hysterectomy (remove uterus), myomectomy (remove uterine fibroid),
- uterine artery embolisation (block blood supply feeding fibroid),
-magnetic resonance-guided focused-ultrasound MRgFUS (untrasound energy heats + destroy fibroid)
Adenomyosis
presence of endometrial tissue wtihin myometrium
Ø Demarcation line b/w endometrium + myometrium destroyed
Ø 5-70%: mean frequency at hysterectomy 20-30%, coexists with other pathologies
Cause and symptom of adenomyosis
§ Causes: invasive endometrial tissue; unknown mechanism (may be overproduction of protein breakdown enzymes)
§ Symptoms: asymptomatic or pelvic pain, abnormal uterine bleeding, infertility
diagnosis of adenomyosis
-hysterectomy + histopathology,
-imaging (ultrasound, MRI)
Treatment of adenomyosis
-GnRH analogues (hypoestrogenism + antiproliferative effects)
- progestins (endometrial atrophy + hypoestrogenism),
- OCP (endometrial atrophy),
-NSAIDs (block prostaglandins, reduce pain)
what is endometriosis
Presence of estrogen-dependent endometrial- like lesions containing glands and stroma outside of the uterus
incidence of endometriosis
- 11.4% of reproductive-aged women
- 50-60% of women with pelvic pain
- 30-50% of women with infertility
Cost of endometriosis
High personal (quality of life) and healthcare costs (7 billion AUD annually)
-burden of disease
-direct healthcare cost
-productivity loss
-taxation
lesion of endometriosis
contains glands + stroma (similar to normal endometrium);
-hormonally responsive + bleed/wound repair like endometrium,
- scarring/adhesion formation
possible location of lesion for endometriosis
-uterus,
-fallopian tubes (can cause blockage),
-ovaries,
-ovarian fossa,
-uterosacral ligaments,
-rectovaginal septum,
-pouch of Douglas + uterovesical fold
stage of endometriosis
- Stage I & II (minimal to mild)
– More common
– Superficial - Stage III & IV (moderate to severe)
– Deep infiltrating / ovarian
– Adhesions
Symptoms of endometriosis
- Pain symptoms include (but not limited to):
– Dysmenorrhea (menstrual period pain)
– Dyspareunia (pain during sexual intercourse)
– Chronic non-menstrual pelvic pain
– Lower back pain
– Ovulation pain - Bowel and Bladder symptoms
- Infertility issues
- Increased risk of adenomyosis, autoimmune disease, ovarian cancer
theory of endometriosois
There are several different theories about the aetiology of endometriosis, but no one theory can explain all aspects of the pathology
Genetics of Endometriosis
- Endometriosis is a complex disease caused by interactions of many genetic and environmental factors
- Environmental factors (eg. pesticides and toxins), that affect estrogen metabolism play a part in endometriosis – Also consider smoking and diet
- Aggregation of endometriosis cases within families & increased prevalence of endometriosis among related vs unrelated women strongly suggest the presence of predisposing genetic (heritable) factors
Diagnosis of endometriosis
- Delay in diagnosis - from symptom onset to diagnosis - mean delay of 6.7 years
- Definitive diagnosis requires surgery (laparoscopy)
Treatment of endometriosis
- Multi-disciplinary: Surgical, medical and management approaches
- Surgery
– Removal of lesions and adhesions (by laparoscopy)
– Sometimes hysterectomy - Medical
– Manipulation of hormones to produce a pseudo-pregnant or pseudo-menopausal state (amenorrhea) - Androgens (eg. Danazol), GnRH antagonists (eg. Zoladex),
Progestogens (eg. Mirena), OCP - Pain relief
- analgesics, non-steroidal anti-inflammatory drugs
- Side effects have to be considered
- Desire for pregnancy
- Symptoms often recur after treatment
Problem with endometriosis
- “It is evident that endometriosis can have a profound impact on women, girls, their families, partners and carers, and society as a whole”
- “There is significant frustration with the under-recognition and misdiagnosis of endometriosis, and the subsequent delays from onset to diagnosis and treatment”
Clinical database for endometriosis
1100s Women undergoing laparoscopy for pelvic pain and treatment for endometriosis and infertility are recruited
-have follow up questionnaire and look at genetic and molecular data for identification of possible bio marker
Endometriosis Research result VEZT in endometriosis
- VEZT encodes the adherens junction protein VEZATIN
- Vezatin is essential to life (knockout is embryo lethal)
Ø Expressed on endometriosis lesions, leucocytes + endothelial cells
Ø Hormonally regulated in endometrium (high in secretory phase)
Ø Essential for blastocyst integrity + sperm maturation; binds to Myosin VII (essential for listeria infection)
The Functional Role of
VEZT in Endometriosis
Over expression of VEZT in HESC significantly altered the expression of 6,594 genes
Ø Significantly upregulated: role of pattern recognition receptions, neuroinflammation signalling pathway,
dendritic cell maturation, interferon signalling
§ RSAD2 gene x8 encodes viperin that inhibits viral infections as part of interferon gamma pathway + innate immune system; elevated in secretory phase
Ø Significantly downregulated: LXR/RXR activation, leucocyte extravasation pathway
§ PTGES3L-AARSD1 gene x7
Conditional Overexpression
of VEZT in a murine model
- CRISPR-CAS9 technology was used to generate a conditional knock-in VEZT mouse
- CTV-VEZT mice were then crossed with a Tamoxifen inducible Cre mouse (UBC-Cre-ERT2) to produce the conditionally overexpressed VEZT mouse (TgCre)
- VEZT overexpression at 12 weeks significantly dysregulates hormone receptor expression and increase cytokine gene expression
- increases lesion formation in WT and TgCre mice
