lecture 31: diseases and disorders 3: uterine Flashcards Preview

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Flashcards in lecture 31: diseases and disorders 3: uterine Deck (28):
1

What is gynaecology?

  • gynaecology is a medical speciality focued on women's health, in particular the genital tract in non-pregnant women (ovaries, uterus, vagina) 
  • a gynaecologist manages medical and surgical problems affecting women's reproductive and urological systems 
  • problems with menstruation 
  • lower abdominal pain
  • gynaecologic malignancies 
  • fertility problems 
  • sexual health 
  • sexually transmitted diseases 
  • urinary incontinence 

2

What is the human menstrual cycle?

3

What are normal limits for menstrual bleeding?

  • frequency of menses (days)
    • frequent: less than 24
    • normal: 24-38
    • infrequent: more than 38
  • regularity of menses: cycle-to-cycle variation over 12 months, days 
    • absent: no bleeding 
    • regular: variation ± 2-20 
    • irregular: variation more than 20
  • duration of flow, days
    • prolonged: more than 8.0
    • normal: 4.5 - 8.0 
    • shortened: less than 4.5 
  • volume of monthly blood loss, mL 
    • heavy: more than 80
    • normal: 5 - 80
    • light: less than 5
  • abnormal uterine bleeding (AUB) occurs when menstrual uterine bleeding falls outside normal parameters
  • unscheduled bleeding between menstrual cycles is also categorised as abnormal

4

What is PALM-COEIN?

  • classification system for causes of abnormal uterine bleeding in the reproductive years 
  • women may fit into more than one category 
  • Polyps
  • Adenomyosis 
  • Leiomyoma (uterine fibroids) 
  • Malignancy and hyperplasia 
  • Coagulopathy (clotting disorders e.g. von Willebrand disease)
  • Ovulatory disorders
  • Endometrium 
  • Iatrogenic (non-menstrual bleeding or spotting due to hormonal therapies) 
  • Not classified 

5

What is Heavy Menstrual Bleeding (HMB)?

  • Menorrhagia definition: excessive menstrual blood loss which interferes with the woman's physical, emotional, social and material quality of life 
  • normal average monthly menstrual blood loss (MBL) = 35 mL
    • HMB usually defined as MBL more than 80ml (=90th per centile) 
    • HMB: increased incidence of iron deficiency and anaemia 
  • incidence:
    • affects 10-30% of menstruating women 
    • increases up to 50% peri-menopause 
  • costs: 
    • social, medical and public health issue 
    • economic implications (e.g. treatment costs, lost work days) 

6

What are treatments for HMB?

  • treatment depends on cause and life stage of the women
  • medical:
    • hormonal:
      • combined oral contraceptive pill
      • progestogens e.g.: Mirena - intrauterine device that releases Levonorgestrol 
    • prostaglandin synthetase inhibitors (e.g. megenamic acid) 
      • block prostaglandin production (prostaglandins have roles in inflammation, vessel function, platelet aggregation etc) 
    • anti-fibrinolytic agents (e.g. Tranexamic acid)
      • fribrinolysis: process that dissolves fibrin resulting in removal of small blood clots 
  • surgical:
    • endometrial ablation: removal of lining of uterus 
    • hysterectomy: surgical removal of the uterus 
  • management of iron deficiency 

7

Why is HMB research difficult?

  • limited research - no animal models
  • observation studies using human tissue samples
  • basic studies on mechanisms of mesntruation 
  • clinical trials comparing treatments 
  • NHMRC Funding Research Project: Mechansisms of Heavy Menstrual Bleeding (Hickey, Rogers and Girling) 
    • Aim: understand the molecular mechanisms playing a role in HMB associated with common clinical presentations:
      • regular menstrual cycles with/without uterine fibroids 
  • investigate pathways already known to have a role in HMB
  • identify novel pathways involved in HMB 

8

What are uterine fibroids?

  • Leiomyoma: benign clonal tumours of the smooth muscle cells of the uterine muscle wall (myometrium) 
  • incidence: 
    • most common benign tumour in fertile women 
    • affect around one third of women aged 18-30 years and 50-80% of women by age 50 
    • incidence and severity is higher in women of african descent 
    • main indication for hysterectomy 
  • key symptoms 
    • not all fibroids are symptomatic 
    • heavy menstrual bleeding 
    • pain symptoms 
    • fertility and pregnancy problems 
  • costs 
    • negative effects on quality of life 
    • high personal and healthcare costs 

9

What are features of fibroids?

  • fibroids are heterogeneous 
  • firm, round outline well demarcated from surrounding myometrium 
  • single or multiple 
  • vary in size 
  • variable in location:
    • submucosal
    • intramural
    • subserosal
    • pedunculated 
  • bundles of differentiated smooth muscle cells (SMC), fibrous tissue, sparse vasculature, few mitotic figures 

10

Images of fibroids 

11

What are symptoms of uterine fibroids?

  • approximately 25% of women with fibroids have clinical symptoms 
  • incidence and severity of symptoms depends on size, number and location of fibroid 
  • distortion of uterine cavity or surface 
  • irregular or excessive/heavy menstrual bleeding (which may be associated with anaemia)
  • pelvic pain or pressure 
  • bowel and bladder dysfunction
  • fertility problems 
  • recurrent miscarriage 

12

What are non-surgical treatments of uterine fibroids?

  • treatments tailored to individual patient based on severity of symptoms, and age and proximity to menopause 
    • is fertility preservation required?
    • side effects
  • medical treatments:
    • GnRH analogues: may be used to induce hypoestrogenic state to shrink tumours before surgery 
      • short term use only 
      • effects on fibroid growth temporary 
      • side effects
    • progestins (e.g. mirena): to reduce HMB 
    • hormone modulators e.g. SERM, SPRMS 

13

What are surgical interventions used to treat uterine fibroids?

  • hysterectomy: removal of uterus
  • myomectomy: removal of uterine fibroid 
  • uterine artery embolization: delivery of particulate material through the uterine arteries to block the blood supply to vessels of the uterine fibroid 
  • magnetic resonance-guidance focused-ultrasound (MRgFUS): application of high-intensity focused ultrasound energy to locally heat and destroy diseased or damaged tissue through ablation 
    • leads to thermal destruction of fibroid 
    • only suitable for certain types of fibroid 

14

What are fundamental factors involved in myometrial physiology and uterine leiomyoma formation and growth?

  • genetic factors: 
    • chromosomes 2, 3, 6, 7, 8, 10, 11, 12, 13, 14, 22 
    • genes - MED12, HMGA2, HMGA1, FH, BHD, TSC2, PCOLCE, ORC5L and LHFPL3 
  • risk factors:
    • early menarche
    • age (late reproductive years) 
    • heredity 
    • nulliparity 
    • obesity 
    • PCOS 
    • diabetes 
    • hypertension 
  • cytokines 
    • IL1, 6, 11, 13, 15
    • TNFalpha
    • GM-CSF
    • erythropoietin 
  • epigenetic factors:
    • DNA methylation, histone modifciation, miRNA (let7, miR-21, miR-93, miR-106b, and miR-200) 
  • ECM components:
    • collagen, fibronectin and proteoglycans 
    • chemokines:
      • MIP1alpha, MIP-1beta 
      • RANTES 
      • eotaxin, eotaxin-2
      • IL-8
      • CCR1, CCR3, CCR5
      • CXCR1, CXCR2 
      • MCP-1
  • growth factors 
    • EGF, HB-EGF, PDGF, IGF, TGF-alpha, TGF-beta, VEGF, aFGF, bFGF
    • activin and myostatin 
  • progesterone
  • oestrogen 

15

What is research on uterine fibroids?

  • despite scale of problem - limited research 
  • heterogeneity not necessarily recognised in study design 
  • lack of suitable animal models 
  • observational studies:
    • comparing fibroid and host myometrium, regressing and growing fibroids for expression of growth factors, receptors etc
  • in vitro studies:
    • using cultured fibroid and host myometrial SMCs for examining interactions between ER, PR and growth factors etc 
    • But! cultured cells may not be representative of what goes on in vivo 
  • examples of our research:
    • retinoid pathway: Zaitseva et al 
    • differential gene and protein expression - contribution to mechanisms? Zaitseva et al
    • fibroid heterogeneity: zhao and rogers, tsiligiannis 
    • using MRgFUS to investigate how symptomatic fibroids cause heavy menstrual bleeding 

16

What is endometriosis?

  • presence of oestrogen-dependent endometrial lesions containing glands and stroma outside of the uterus 
  • incidence
    • 6-10% of reproductive-aged women 
    • 50-60% of women with pelvic pain 
    • 30-50% of women with infertility 
  • key symptoms
    • various pain symptoms 
    • fertility problems 
  • costs 
    • negative effects on quality of life: mental, social and physical wellbeing 
    • high personal and healthcare costs 

17

What are common locations for endometriosis?

  • endometrial implants/lesions
  • endometrial nodules
  • endometriomas 
  • umbilicus 
  • coecum
  • peritoneum
  • appendix
  • bladder
  • uterine serosa
  • uterovesical fold 
  • rectovaginal septum and uterosaccral ligaments 
  • sigmoid colon
  • ovary
  • ureter
  • fallopian tube 
  • small bowel 

18

What are the symptoms of endometriosis?

  • complicated range of pain symptoms - symptoms can overlap with other disorders 
  • women may be asymptomatic or symptomatic 
  • key symptoms: pain, infertility and/or HMB
  • pain symptoms include (but not limited to):
    • dysmenorrhea (menstrual period pain)
    • pyspareunia (pain during sexual intercourse) 
    • non-menstrual pelvic pain
    • lower back pain
    • ovulation pain
  • bowel and bladder symptoms
  • fatigue 
  • fertility problems 
  • women with endometriosis are at increased risk of autoimmune disease, ovarian cancer (endometriod and clear-cell), and other cancers (e.g. non-Hodgkin's lymphoma, melanoma) 

19

How is endometriosis diagnosed?

  • often a delay from onset of symptoms until diagnosis of endometriosis. Research suggests a mean delay of 6.7 years 
  • definitive diagnosis requires surgery (laparoscopy) to visualise the lesions

20

How can endometriosis be treated?

  • multi-disciplinary: surgical, medical, and management approaches (e.g. psychology, physiotherapy)
  • surgery:
    • removal of lesions and adhesions - often by laparoscopy 
    • sometimes hysterectomy 
  • medical:
    • manipulation of hormones to produce a pseudo-pregnant or pseudo-menopausal state (amenorrhea)
      • androgens e.g. danazol
      • GnRH antagonists e.g. zoladex 
      • progestogens e.g. Mirena 
      • combined oral contraceptives 
  • pain relief: analgesics, NSAIDs 
  • side effects have to be considered 
  • symptoms often recur after treatment 

21

What are theories about the aetiology of endometriosis?

  • no one theory can explain all aspects of the pathology 
  • mesothelium, other cell types → metaplasia 
  • mullerian rests → induction 
  • E2 
    • environment 
    • inflammation 
    • genetics
  • lymphatic spread, haematogenous spread 
  • bone marrow
    • mesenchymal
    • haematopoietic stem cells
    • endothelial precursors 
    • endometrial tissue and cell reflux 

22

Do implants arise from uterine endometrium?

  • retrograde menstruation theory: explains physical displacement of endometrial fragments into the peritoneal cavity, but not the development of lesions 
  • retrograde menstruation occurs in 90% of women, but endometriosis only develops in 10% 
  • also need:
    • escape from immune clearance 
    • attachment to peritoneal epithelium 
    • invasion of the epithelium 
    • establishment of blood vessels and innervation 
    • continued growth and survival 

23

Do implants arise from tissues other than uterus?

  • coelomic metaplasia: transformation of normal peritoneal tissue to endometrial tissue 
  • induction theory: an endogenous stimulus, such as hormone, promotes differentiation of cells in the peritoneal lining to endometrial cells
  • embryonic mullerian rests: cells residual from embryologic mullerian duct migration maintain the capacity to develop into endometriotic lesions under the influence of oestrogen 
  • extrauterine stem or progenitor cells from bone marrow may differentiate into endometriotic tissue
  • benign metastasis: lesions result from lymphatic or haematogenous (via blood) transport of endometrial cells 

24

What are features of the pathophysiology of endometriosis?

  • genetics vs environment
    • hereditable component to endometriosis 
    • risk for first-degree relatives of women with severe endometriosis is 6 times higher than relatives of unaffected women 
  • increased endometrial cell survival 
    • acquired genetic alterations – endometrial cells have high turnover and are therefore vulnerable to genetic recombination errors 
  • altered hormonal activity
    • oestrogen (E) dependence 
    • localised E production by lesions 
    • progesterone (P) resistance - deregulated activity of P in lesions and uterus 
  • dysregulation of immune clearance and refluxed endometrial cells
  • endometrial cell invasion and attachment 
    • shares features with malignancy 
    • matrix metalloproteinase activity 
  • angiogenesis and neuroangiogenesis 
    • growth of blood vessels into lesions 
    • growth of nerve fibres/axons into lesions 
  • inflammation 
    • increased number of activated macrophages in women with endometriosis 
    • altered cytokine/chemokine profile 
    • increased prostaglandins in peritoneum 

25

What are endometriosis research directions?

  • epidemiology 
    • environment
    • BMI
    • diet
    • genetic studies
  • diagnosis
    • biomarkers 
    • imaging
  • classification and prognosis 
    • clinical staging 
    • phenotype symptoms 
  • clinical trials, treatment and outcomes 
    • multi-centre RCTs
    • defined outcome measures 
    • pelvic pain
    • novel medical treatments
  • pathophysiology 
    • immunomodulators 
    • inflammatory mediators 
    • macrophage 
    • oxidative stress
    • pain
    • angiogenesis 
    • lymphangiogenesis 
    • stem cells
    • apoptosis 
    • miRNA 
    • animal and in vitro models
    • transgenic models 
    • progestins and SPRMs 
    • ovary 
    • microbiome 
  • research policy 
    • data regestries and Biobanks
    • centres of expertise 
    • multidisciplinary approaches 
    • lobbying 
    • national endometriosis organisations 
    • WES and WERF

26

What is their research into genetics and endometriosis?

  • large genome-wide association studies (GWAS) have been conducted by various international groups including collaborators at the queensland institute of medical research 
    • uno et al
    • painter et al
    • nyholt et al
  • GWAS is a very powerful approach to discover genes influencing risk for endometriosis 
  • the studies have identified several association loci (i.e. loci linked with endometriosis risk) and potential candidate endometriosis genes
  • next step: how do we use results from the GWAS studies to identify disease mechanisms and drugable targets?

27

What is their research into nerve fibres and pain in endometriosis?

  • there is relatively little fundamental or applied research aimed at understanding endometriosis associated pain
  • aims:
    • to determine whether aberrant innervation is present in the uteri of women with endometriosis, or more broadly in women with pelvic pain
      • nerve fibre distribution, density and phenotype in women with different pathologies and pain symptoms 
    • to investigate how endometriotic lesions alter the interaction of neurons with the central nervous system 
      • mechanistic studies investigating how endometriotic lesions affect the cell bodies in the dorsal root ganglia 

28

What are the key points?

  • HMB occurs in 10-30% of women
    • multiple causes
    • mechanisms responsible for HMB are not understood
  • uterine fibroids are common benign tumours of the uterine muscle wall
    • heterogeneous tumours - size, shape, location, molecular and histological characteristics 
    • aetiology unknown 
  • endometriosis is a common gynacological disorder causing pain and fertility problems 
    • presence of endometrial tissue outside of the endometrium 
    • delay until definitive diagnosis, which requires laparoscopy 
    • variable treatments, but disease commonly recurs