lecture 9: menopause

Question 1

What is the menopause?

Answer 1

• 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

Question 2

What is perimenopause?

Answer 2

• 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

Question 3

What is post menopause?

Answer 3

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

Question 4

What is early menopause?

Answer 4

• 40 - 45 years
• 5%

Question 5

What is premature ovarian insufficiency?

Answer 5

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

Question 6

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

Answer 6

• postmenopause

Question 7

How many women can expect to reach the menopause?

Answer 7

• 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

Question 8

What is the aetiology of menopause?

Answer 8

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

Question 9

How many eggs are in the ovary?

Answer 9

• 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

Question 10

What is the age related decline in follicle numbers?

Answer 10

Question 11

What are factors regulating the age at natural menopause?

Answer 11

• 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

Question 12

What is the aetiology of premature menopause (POI)?

Answer 12

• 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

Question 13

What chromosomal abnormalities can affect ovarian function?

Answer 13

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

Question 14

What are physiologic changes associated with reproduction?

Answer 14

• 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

Question 15

What is the ovarian follicle?

Answer 15

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

produce oestrogen, activin, inhibin, follistatin, AMH

Question 16

What are varying stages of follicular development?

Answer 16

• 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

Question 17

What are the phases of menstruation?

Answer 17

• 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

Question 18

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

Answer 18

• 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

Question 19

What is seen at the menopause?

Answer 19

• 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

Question 20

What is the aetiology of perimenopause?

Answer 20

• 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

Question 21

What are perimenopausal hormonal changes?

Answer 21

• 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

Question 22

What are hormone changes after the menopause?

Answer 22

• 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

Question 23

What are hormonal transitions?

Answer 23

• FSH less than 10 is normal for younger

Question 24

What are the investigations and treatment in POI?

Answer 24

• 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’

Question 25

What are the consequences of menopause?

Answer 25

* 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

Question 26

What are hot flushes?

Answer 26

* 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

Question 27

What are urogenital symptoms?

Answer 27

* 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)

Question 28

What affects emotional health during menopause?

Answer 28

* 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

Question 29

What are bone symptoms and osteoporosis?

Answer 29

* 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)

Question 30

What is the cardiovascular risk?

Answer 30

* 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)

Question 31

What is the risk of HRT?

Answer 31

* 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

Question 32

What are the benefits of HRT?

Answer 32

* 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

Question 33

What is HRT?

Answer 33

* 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

Question 34

What are clinical practice guidelines for HRT?

Answer 34

* 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

Question 35

What are conclusions about menopause?

Answer 35

* 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