lecture 30: disease and disorders 2: ovarian Flashcards

1
Q

What is ovarian follicle development?

A

preantral follicle growth (4 months)

  • primordial follicles
  • initial recruitment
  • primary follicles

Antral follicle growth (2 cycles)

  • antrum formation
  • cyclic recruitment
  • some undergo atresia
  • selection and dominance
  • ovulation
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2
Q

What are genes involved in fertility?

A
  • primordial follicles
    • KITL, KIT, AMH
  • primary follicle
    • GDF9, KITL
  • secondary follicle
    • FSH, FSHR, IGF1, CCND2, TAF4B
  • early antral follicle
    • INHA, INHBA, CX37
    • ERalpha, ERbeta
  • ovulation
    • LHR, COX2, PR, CEBPB, NRIP1
  • COC integrity
    • GDF9, BMP15, PTGER2, PTX3, AMBP
  • fertilisation and pre-implantation development
    • ZP1, ZP2, ZP3, MATER, DNMT1o, PMS2, HSF1
  • implantation
    • COX2, HOXA10, HOXA11, LIF, IL11R, HMX3, PR, ERalpha
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3
Q

What are examples of people purporting bizarre reasons for ovarian disorders?

A
  • women drivers could suffer damage to ovaries, says Saudi Sheikh
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4
Q

What are normal levels of follicles?

A
  • foetus at 20 weeks’ gestation: each ovary contains about 4 million follicles
  • term: 1-2 million follicles
  • puberty: 300,000 - 400,000
  • 37 years: 100,000 then rapid loss
  • perimenopausal threshold less than 1000 follicles?
  • also decline in quality
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5
Q

What is premature ovarian insufficiency (POI)?

A
  • incidence and cause
    • POI or premature ovarian failure (POF)
    • affects ~1% of population
    • genetic - Turner and Fragile X syndrome, inhibin alpha gene
    • unknown - autoimmune?
    • side effect of cancer/fertility issues and treatment
  • symptoms
    • no periods for 4 months before age 40
    • FSH levels greater than 40mlU/ml on 2 occasions at least 1 month apart (never rely on one off level); day 2-6 if cycling
    • abnormally low AMH and oestrogen level
    • exclusion of all other causes of absent periods, chromosome test
  • treatment
    • no known treatment
    • sometimes responsive to ovarian stimulation, donor eggs to conceive
    • at risk pre-pubertal girls option of ovarian cryopreservation
    • still need contraception: lifetime chance of ever conceiving 5-10%
    • HRT/contraception until around 50 years
    • major problem is decreased oestrogen on related health issues
  • related health issues
    • osteoporosis
    • heart disease
    • hypothyroidism
    • auto-immune diseases
    • support networks
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6
Q

What are problems with ovulation?

A
  • no ovulation = no egg = no pregnancy
  • 40% of all infertile women
  • symptoms
    • oligomenorrhoea (infrequent period)
    • amenorrhoea (absent period), more than 6 months
  • causes
    • hormone deficiency
    • very low body weight (less than 20%) - eating disorders
    • obesity (10-15%) and weight fluctuations
    • diet and stress
    • over exercise
    • hormone resistance (insulin)
    • damaged or diseases ovaries, pituitary tumour
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7
Q

What is anovulation?

A
  • diagnosis
    • ultrasound
      • abnormalities - ovarian (cysts), uterine growths, endometriosis
    • blood tests
      • steroids, gonadotrophins, prolactin, thyroid, AMH
  • treatment
    • lifestyle changes?
    • hormonal ovulation induction (OI)
      • clomiphene citrate (Clomid/Serophene)
        • pill for 5 days, side-effects
        • stimulates ovulation (80%), twinning (10%)
      • gonadotrophins (FSH, LH, hCG)
        • injections, side-effects
        • promoting follicle growth
        • risk of multiples
    • IVF treatment
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8
Q

What is polycystic ovary syndrome (PCOS)?

A
  • affects 5-10% of women - most common endocrine disorder
  • indigenous Australian women up to 21%
  • issues with diagnosis, could be more?
  • syndrome - multifaceted symptoms, several diseases
  • symptoms
    • weight gain (centralised)
    • increased acne and bad skin
    • hirsutism - face (male patterns)
    • anovulation, irregular menstrual cycles
    • subfertility - lack of pregnancy and higher miscarriage
    • mood swings, decreased libido, ovulation kit useless
  • variation in symptoms and how many are evident
  • effects on embryo/foetus - programming?
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9
Q

How is PCOS diagnosed?

A
  • strict but changing criteria
    • increased androgens - hirsutism (70%), increased acne
    • anovulation, irregular menstrual cycles
    • presence of cystic follicles – enlarged ovaries, increased small surface cysts
  • must have 2 of 3 - can have PCOS and NOT have cystic ovaries (40%)!
  • blood tests
    • increased LH, decreased FSH, decreased SHBG, increased androgens, increased oestrogens (oestrone)
  • ultrasound
    • greater than 12 follicles 2-9mm (small), increased ovary size
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10
Q

What is the interaction between theca and granulosa cells?

A
  • interact to make oestrogens
  • theca: cholesterol → androgens
  • granulosa: androgens → oestrogens
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11
Q

What happens to theca and granulosa in PCOS?

A
  • over production of LH and androgens
  • theca: cholesterol → androgens
  • granulosa: androgens X oestrogens
  • testosterone goes into blood → fat cell → production of oestrone → anterior pituitary
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12
Q

What are causes and risk factors for PCOS?

A
  • genetic factors??
  • weight
    • change, over/under, hard to lose (metabolic)
    • loss of just 5% BW can resolve anovulation
    • half of all PCOS women are NOT overweight
  • insulin resistant (increased circulating insulin) 80% of women
    • insulin → increased androgens
    • insulin → decreased SHBG (liver)
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13
Q

What is follicular development in PCOS?

A
  • insulin acts on developing follicle
  • responds to LH
  • → final step in development
  • follicular development stopped
  • death of granulosa cells
  • death of theca cells prevented by insulin
  • cyst
  • testosterone secreted
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14
Q

What are factors associated with PCOS?

A
  • obesity and metabolic sequelae
  • type II diabetes
  • cardiovascular disease
  • uterine/ovarian carcinomas (increased oestrone)
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15
Q

What are treatments for PCOS?

A
  • OCP (+ androgen inhibitors)
  • clomiphene - to boost FSH
  • blockers of androgen synthesis (e.g. flutamide)
  • metformin - insulin sensitiser
  • need to treat underlying causes !!
    • weight loss
    • exercise
    • dietary interventions
      • low GI diet (glucose)
      • vegetables and pulses
      • vitamin D (deficiency - insulin resistance)
  • combinations
  • patient specific BUT don’t address all symptoms
  • sources of advice
    • diagnosis, treatments etc
    • Jean Hailes
    • POSAA
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16
Q

What is a definition of ovarian tumours?

A
  • ovarian tumours may arise at any age but are most common between 30 and 60 years old
  • ovarian tumours are particularly liable to be or to become malignant
  • in their early stages they are asymptomatic and painless
  • they may grow to a large size and tend to undergo mechanical complications such as torsion and perforation
17
Q

What is diagnosis and incidence of ovarian tumours?

A
  • difficult to diagnose - lack of specific symptoms
  • approximately 25% of all tumours are malignant
    • 80% primary and 20% secondary growths
  • in developed countries, the lifetime risk of developing ovarian cancer is ~2%
  • slightly greater than the risk of cervical or endometrial cancers (but well below the 7% risk of breast cancer)
  • in 2010 USA< ~22,000 new cases and ~14,000 women died of ovarian cancer (greater than 50% deaths in women 55-74 years old)
  • difficult to understand if increase due to better detection methods and/or increased incidence
  • poor prognosis as when identified 60% of women have stage III or IV
18
Q

What are suggestive features of tumour malignancy?

A
  • age - over 50 years old, chance greater than 50%, under 50 less than 15%
  • rapid growth
  • ascites
  • solid tumour or multilocular cysts
  • referred pain suggests nerve involvement
  • identification of blood markers (CA125)
19
Q

What are primary and secondary tumours?

A
  • primary - epithelial carcinomas (90%), stromal, germ cell
  • secondary
    • krukenberg tumour - from a stomach carcinoma
    • breast
    • other parts of genital tract
20
Q

What are risk factors and reducers of ovarian tumours?

A
  • risk factors
    • age is the strongest risk factor, especially postemenopausal and after HRT
    • genetic factors can account for 10% of ovarian tumours, as in the Lynch Syndrome of familial breast, colorectal and ovarian cancer (BRAC1, BRAC2 gene). Epigenetics??
    • obesity increases the risk and the heaviest women have the greatest risk
    • ovulation induction with Clomiphene over more than a year carries a 10-fold increased risk of ovarian cancer
  • risk reducers
    • long term oral contraceptive - greater than 5 years use reduces by half the risk, reduced ovulation the key?
    • child bearing women are less likely to develop ovarian cancer. risk decreases with every pregnancy, breastfeeding may offer added protection
    • tubal ligation/hysterectomy (Ovaries intact) believed to help
    • removing ovaries for women with genetic mutations and also other high risk factors
    • healthy diet reduced fat and increased vegetables for more than 4 years - still further evidence needed
21
Q

What is screening, treatment and survival rates for ovarian cancer?

A
  • screening methods
    • blood test for CA-125 protein (germ cell - hCG, AFP, LDH)
    • ultrasound /CT scans
  • surgery
    • remove ovary (S1) and other tissues (S2-4)
  • chemotherapy
    • post-surgery (all stages) - oral, i.v., i.p. administration of drugs
  • targeted therapies
    • inhibitors of angiogenesis e.g. Avastin
    • new area of research, side effects?
  • subsequent treatment
    • trigger for increased risk of other medical conditions, fatigue (exercise)
  • dependent on stage at diagnosis
    • epithelial 18-89% after 5 years, LMP 77-99% after 5 years
22
Q

What are possible ovarian fertility treatments?

A
  • ovarian freezing and grafting
    • developed in 1999, first human birth 2004 (belgium)
    • application POI, cancer, or beyond natural reproduction
    • risks, inefficiency, and side-effects?
    • sherman silber (St Louis, MO), greater than 30 babies born
  • in vitro follicle culture
    • novel 3D follicle culture in alginate hydrogel (teresa woodruff)
    • fresh and cryopreserved tissue
    • primary to mature → healthy offspring
    • mouse, primate, human (pre-ovulation)
  • in vitro activation
    • POI and PCOS patients
    • brand new, combination of multiple techniques
    • key transcription factors
23
Q

What is in vitro activation?

A

Hippo signalling disruption and Akt stimulation of ovarian follicles for infertility treatment

grafted ovaries lead to succesful pregnancy

  • POI patients
  • remove ovaries
  • preparation of ovarian strips for vitrification and histology
  • cryo-preservation
  • (Hippo Siganlling Disruption )
  • fragmentation of ovarian strips to cubes
  • (Akt stimulators)
  • culture of ovarian cubes
  • return of activated ovarian cubes beneath serosa of fallopian tubes
  • retrieve mature eggs
  • IVF with husbands’ sperm
  • embryos
  • embryo transfer
  • baby