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Flashcards in lecture 9: menopause Deck (35):

What is the menopause?

  • The menopause is the final menstrual period
  • the average age of menopause is around 51-52 years (age range 48 - 55 years) 
  • defined retrospectively after 12 months of absent periods 


What is perimenopause?

  • climacteric, menopause transition 
  • the period when ovarian function declines, cycles are irregular and menopausal symptoms appear
  • begins mid to late forties, ends one year after menopause 
  • lasts for years  


What is post menopause?

  • is the whole of women's life after menopause 
  • no periods, no ovulation, hormones low, cannot conceive 


What is early menopause?

  • 40 - 45 years
  • 5% 


What is premature ovarian insufficiency? 

  • premature menopause
  • menopause prior to 40 years 
  • 1%


In what 'state' does a woman spend a lot of her life?

  • postmenopause


How many women can expect to reach the menopause?

  • 95% of women 
  • female life expectancy has increased while age of menopause has remained constant 
  • around a third of our life is spent beyond the menopause 


What is the aetiology of menopause?

  • loss of ovarian follicular activity at menopause 
  • decline in quantity and quality in the years preceding 


How many eggs are in the ovary?

  • atresia (degeneration) of ovarian follicles (eggs) during the lifespan 
  • foetus at 20 weeks' gestation 
    • each ovary contains about 5 million follicles 
  • term
    • 1-2 million follicles 
  • puberty 
    • 300 000 - 400 000 
  • 37 years 
    • 100 000, then rapid loss 
  • perimenopausal threshold
    • <1000 follicles? 
  • also a decline in quality of the follicles 
  • the follicles are not lost just through ovulation 
  • the vast majority of follicles are lost through atresia and apoptosis 


What is the age related decline in follicle numbers?


What are factors regulating the age at natural menopause?

  • poorly understood 
  • not influenced by race, age of menarche, parity, OCP
  • genetic factors – are important 
  • cigarette smoking 
  • menopause is 1 - 2 years earlier 
  • surgical history 
    • hysterectomy may reduce the age at menopause by around 3 - 4 years 
    • may be due to impairment of the ovarian blood supply 


What is the aetiology of premature menopause (POI)?

  • idiopathic 
    • karyotypically normal 
    • spontaneous POI (1%) 
  • iatrogenic 
    • surgery/chemo/radiotherapy (8 - 19% of women under 40) 
  • rare causes: 
    • galactosaemia (excess milk products, galactose is stored in the ovaries and is toxic to oocytes)
  • auto-immune 
    • auto-immune 
  • genetic 
    • turner's syndrome
    • fragile x syndrome 


What chromosomal abnormalities can affect ovarian function?

  • deletion in X chromosome between positions 13 and 26 can affect ovarian function 


What are physiologic changes associated with reproduction?

  • hypothalamus becomes activated around puberty with  pulsatile release of GnRH
  • causes release of LH and FSH in a pulsatile manner from the anterior pituitary 
  • FSH affects the ovaries 
    • binds to granulosa cells and grows follicles 
    • follicles produce oestrogen 
    • results in secondary sexual development (eventually menstruation) 
  • LH binds to theca cells (stroma around the follicles)
    • results in androgen production 


What is the ovarian follicle?

  • secondary oocyte 
  • corona radiata
  • cumulus oophorus 
  • antrum 
  • granulosa cells
  • theca interna 
  • theca externa 


produce oestrogen, activin, inhibin, follistatin, AMH


What are varying stages of follicular development?

  • in the cortex 
  • primary follicles as they are stimulated by FSH get larger, secondary
  • produce oestrogen which thickens the lining of the uterus, and increasing oestrogen causes a surge of LH → stimulates ovulation 


What are the phases of menstruation?

  • proliferative/follicular and secretory 
  • follicular phase 
    • FSH grows follicles
    • follicles grow the lining of the uterus 
    • the glands are being developed 
    • increased growth and height 
    • as the follicles get larger and larger more oestrogen is produced 
    • this results in an LH surge 
    • produces a dominant follicle
    • this dominant follicle produces progesterone
    • important event because it stabilises this lining 
  • secretory phase
    • further development of the glands 
    • they become secretory 
    • progesterone maintains the lining
  • women who are anovulatory and don't produce progesterone
    • lining keeps growing and growing
    • very long and irregular cycles 
    • at risk of endometrial hyperplasia and cancer 


Why is the dominant follicle able to continue growing for a while?

  • follicles as well as producing oestrogen produce inhibin 
  • inhibin inhibits FSH
  • FSH peak but then starts to come down 
  • yet one of the follicles continues to grow (dominant follicle) while the rest start to undergo atresia 
  • the dominant follicle essentially self-selects 
  • has more FSH receptors so can mop up more 


What is seen at the menopause?

  • ovarian primoridal follicle stores are exhausted by atresia and ovulation 
  • ovulation will not occur after menopause, by this is retrospective 
  • therefore use contraception until no periods for one year, as ovulation may occur right up until last period, though less frequently 


What is the aetiology of perimenopause?

  • ovarian primordial follicles decrease with age with an accelerated rate of loss from 37 years 
  • follicles become progressively more resistant to stimulation by gonadotrophins 
  • follicles that do develop may not secrete sufficient oestradiol (E2) and progesterone (P4) to produce regular menstruation 
  • during perimenopause, irregular anovulatory cycles lead to prolonged unopposed E2 
    • may lead to endometrial hyperplasia and cancer risk 


What are perimenopausal hormonal changes?

  • decreased ovarian inhibin B, AMH from the ovarian granulosa cells 
  • gradual rise in FSH 
  • fluctuations in oestradiol and progesterone 
  • no substantial changes in androgen levels 
  • sex steroid levels fluctuate markedly on a daily basis 
  • measuring sex steroids is not useful when a woman of normal menopausal age develops symptoms 


What are hormone changes after the menopause?

  • oestradiol declines following menopause 
  • FSH > 40 u/l 
  • LH > 30-40 u/l 
  • FSH starts to change before LH does 
  • androstenedione is still produced by the ovary and adrenal gland and is converted in peripheral tissues to oestrone (E1) 
  • androgens gradually decline during reproductive life but no dramatic change after menopause 


What are hormonal transitions?

  • FSH less than 10 is normal for younger 


What are the investigations and treatment in POI?

  • no periods for 4 months before age 40
  • FSH levels greater than 40mlU/nl on 2 occasions at least 1 month apart (never rely on one of level); day 2- 6 if cycling 
  • exclusion of all other causes of absent periods, chromosome test 
  • acutally still need contraception: lifetime chance of ever conceiving 5 - 10% 
  • HRT/Contraception until around 50 years 
  • important to test for fertility reasons, depression, the effect on bones and even cardiovascular risk 
  • mortality increases by about 2% per year for the years of 'periods lost' 


What are the consequences of menopause?

  • 20 - 40% of women have menopausal symptoms requiring treatment 
  • short-term:
    • vasomotor symptoms (hot flushes, night sweats, formication) 
    • urogenital symptoms: vaginal dryness, atrophic vaginitis, dyspareunia, dysuria, frequency of urine 
    • sleep disturbance 
    • reduced libido 
    • depression, anxiety, labile mood
    • memory loss, fatigue (may be due to other not sleeping etc) 
  • medium to long-term:
    • bone loss and osteoporosis 


What are hot flushes?

  • occur in ~80% of women 
  • mechanisms not known 
    • maybe due to abnormal hyperthalamic regulation, thermoregulation 
  • last 4 min on average 
  • can last up to hours 
  • up to 30-50% resolve in 3/12 months
  • up to 40% may continue to have significant symptoms up to 10 years after menopause 
  • increased with smoking, ETOH, surgical menopause, caffeine 
  • main reason why women request treatment 
  • oestrogen: most effective, 80% reduction 
  • meditation, relaxation, CBT to reduce anxiety 
  • think it is because of abnormal hype 


What are urogenital symptoms?

  • affects ~40% of postmenopausal women 
  • persist or worsen over time 
  • vaginal dryness
  • discomfort 
  • dyspareunia 
  • UTI 
  • urgency
  • pallor dryness
  • redness
  • decreased rugosity 
  • endometrial atrophy
  • first line is intravaginal oestrogen (not systemic) 


What affects emotional health during menopause?

  • empty nest
  • changing roles 
  • frail or ill parents 
  • loss of parents 
  • loss of fertility, identity as a woman 
  • sensual difficulties → marital difficulties 
  • loss of partner 
  • change in physical image/attractiveness 
  • retirement of self or husband 
  • adolescent children 


What are bone symptoms and osteoporosis?

  • oestrogen deficiency increases bone reabsorption 
  • directly impairs gut calcium absorption 
  • directly increases renal calcium excretion 
  • sharp acceleration of bone loss during the initial 5 years following menopause (3 - 5%/year) 
  • rate of loss then falls back to the age related loss of 1%/year 
  • low bone mass increases fracture risk 
  • prevalence 4% around 50 - 59 yo, greater than 50% by 80 yo
  • mortality is increased by 25% in the first year after a fracture 
  • 25% of women, if they survive, need long term care 
  • can be treated/prevented/managed by increasing weight bearing exercise, vitamin D, calcium intake (1200mg/day) 


What is the cardiovascular risk?

  • after menopause, increasing central adiposity, decreased resting energy expenditure, worsening CVS, lipid and metabolic profiles 
  • hypertension (HT) 
  • potentially mediated by low oestrogens and loss of inhibition of metabolic neuropeptides 
  • HRT does not prevent Cardiovascular Disease (CVD) 


What is the risk of HRT?

  • combined oestrogen and progestogen, 50-79 years 
  • increased risk of stroke (0.8/1000/year)
  • increased risk of clots (0.8/1000/year) 
  • increased risk of breast cancer with greater than 5 years use (0.8/1000/year) 
  • increased incidence of coronary heart disease
  • WHI JAMA 2002, 2004 


What are the benefits of HRT?

  • most effective treatment for menopausal symptoms 
    • reduces frequency and severity of vasomotor symptoms by 75 - 85% 
  • improves vaginal dryness 
  • maintains or improves bone density and reduces fracture risk (1/1000 women/year) 
  • may improve quality of life, sleep, muscle aches and pains 
  • reduced colorectal cancer risk 0.8/1000/year (combined long term)
  • however because of the risks of HRT it is not the firstline treatment for osteoporosis  


What is HRT?

  • hormone replacement therapy 
  • HRT contains oestrogen to treat symptoms and progestogen (if needed) to protect the endometrium 
  • would generally never prescribe to someone over 60 years of age 
  • usually prescribed for short-term gain
    • lowest dose possible
    • less than 5 years 
    • individualised risk 
  • contraindications
    • history of breast cancer
      • individualised 
    • endometrial cancer
    • known clots and CVD
  • do use it in the short term to treat menopausal symptoms 
    • mainly flushes, if required 
  • if someone has a uterus and is given oestrogen alone they are at risk of endometrial cancer, so also give progestagen 
  • can be administered in various ways:
    • pills
    • implant under the skin (under anterior abdominal skin) 
    • patches (replaced every three days) 
    • vaginal oestrogen 
    • oestrogen gels 
    • can be administered cyclically or continuously 
    • cyclically:
      • oestrogen every day
      • progestagen two weeks on two weeks off 
    • whenever you give a hormone and withdraw it, that will induce a period 


What are clinical practice guidelines for HRT?

  • ACEC, FDA 
  • limited efficacy/safety data on complementary medicines 
  • HRT indicated only for moderate to severe menopausal symptoms (flushes, urogenital), women should consider the risks and benefits 
  • use HRT at the lowest dose and for the shortest duration possible, in perimenopausal or early postmenopausal women not older than 60 years 
  • healthy women with no contraindications 
  • do not use HRT for the prevention of CVD or dementia 
  • HRT is not a first line treatment for osteoporosis 


What are conclusions about menopause?

  • menopause may be associated with significant physiological, physical emotional changes in mid-life 
  • important to understand these changes so we may best address the needs of women 
  • lifestyle evaluation and advice remain the cornerstone of advice for the mid-life woman