What is menopause?
The permanent (>12 months) cessation of menstruation due to loss of ovarian follicular function
What is perimenopause?
- aka menopausal transition
- period from approx 2-8years prior to final menstrual period (FMP) to up to 1 year after the FMP
- the menstrual transition begins with cycle irregularity
What is the average age of menopause?
51
When is premature ovarian failure diagnosed?
Diagnosed when menopausal below or at age of 40
What factors influence the age onset of menopause?
- smoking (2 year reduction in age at menopause + shorter transitions)
- hysterectomy
- endometriosis
- chemotherapy
- radiotherapy
- genetic determinants
- ethnicity
What are the symptoms of menopause?
- initially reduced cycle length due to reduced follicular phase
- mean 4 years prior to final menstrual period: some women exp irregular periods, w/ episodes of amenorrhoea
- around year before menopause or later, hot flushes + disturbed sleep due to declining oestrogen levels
- dry vagina
- some women have no menstrual irregularity prior to the menopause
- impaired fertility
What 4 pathological observations underly menopause?
- reduced follicle count - none/few at menopause
- reduced granulosa cell number
- reduced granulosa cell function
- increased chromosomal abnormality of oocyte
How do the number of primordial follicles change over time in a woman, from fetus to post-menopause?
- fetus (20-24 weeks): 6-7million
- birth: 700K-1million
- puberty: 300-400K
- menstrual transition (no irregularities): 25K
- menstrual transition (irregularities): 140
- post-menopause: hardly any
Why does follicular depletion occur?
- increased follicular death (apoptosis)
- ovarian env eg. smoking reduces age at menopause by mean of 2 yrs + shorter transition
- accelerated follicular loss
- granulosa cells produce AMH, AMH inhibits FSH
- AMH decline -> high FSH -> early follicular depletion
There is a 30% decrease in granulosa cells in older women c/w younger. Why is there a decline in granulosa cell number & function?
- reduced inhibin B production from granulosa cells in follicular phase (allows higher FSH levels)
- anovulatory cycles lead to decreased inhibin A normally prod in lutealphase (allows higher FSH)
- reduced FSH receptors + sensitivity impairs recruitment of dominant follicle
- impaired secretion of growth factors + other signalling pathways, survival factors, oestrogen and progesterone
Why is there a shortened cycle in early menstrual transition?
- decline in inhibin B production (granulosa cells)
- leads to elevated FSH in follicular phase
- earlier elevated levels of oestrogen production + earlier LH surge
Why is there delayed/absent ovulation in late menstrual transition?
- oestrogen production is stimulated earlier in cycle by elevated FSH
- but may not reach high enough levels to induce GnRH surge
- due to impaired granulosa cell function
- consequently, ovulation delayed or doesn’t occur
Why do menopausal women have heavier periods?
- longer oestrogen stimulation of endometrium
- thicker lining
- oestrogen levels may be higher than in women aged under 35
Why do perimenopausal women have breast tenderness?
Transitory increases oestrogen
Hot flushes happen very close to menopause. Why do they occur?
- reduced oestrogen levels
- disturbance of serotonin levels
- resets thermoregulatory nucleus + leads to heat loss
What is the hormonal profile (changes) that occur in someone leading up to menopause?
- AMH levels first sign of declining ovarian function
- inhibin B declines around 2 years before FMP
- FSH levels variable each cycle but increase towards menopause
- LH increases but later in menopause
- oestrogen levels fall close to the menopause
- adrenal + ovarian levels decline w age (from 20s) - not related to menopause
- no progesterone production after menopause
Why is there a decline in oocyte function and development?
- consequence of impaired prod of growth factors/survival factors from granulosa cells
- increased aneuploidy (chromosomal disorder)
- increased oocyte abnormality impairs follicle recruitment, even with clomiphene
- resultant: anovulatory cycles + inc miscarriage rate
What are the markers for declining fertility?
- ovarian volume as proxy for # of follicles (or antral follicle count)
- response to ovarian stimulation - antral follicle count
- anti-mullerian hormone
useful for planning family/or including older women in IVF
What are management principles surrounding the prescription of HRT?
- start with low dose (60% efficacy) to minimise unwanted effects, such as mastalgia + nausea
- patient centred - woman should be clear about indication, risks, benefits + plan for review
- consider baseline individual risks: eg. slim non smoking woman diff from obese smoking woman w/ fhx of breast cancer
- always use progesterone for 13 days for women with a uterus (protect from endometrial cancer)
- need contraception if less than 1 yr amenorrhoea (could still be ovulating)
- risks are low for short term usage
How can oestrogen induced endometrial hyperplasia be avoided?
- hyperplasia is found in 56% women who use unopposed oestrogens, ~3% develop carcinoma
- protection obtained by 10-13 days of progesterone
- best protection obtained by continuous combined oestrogen and progesterone, though may get break through bleeding and not good for women whose periods have stopped
How are oestrogen and progesterone administered?
- oestrogen tablets, transdermal patches, subcutaneous implants + gel
- progesterone tablets, intrauterine device, patches (combined w/ oestrogen), gel
- combined oestrogen + progesterone HRT - continous combined or cyclical progesterone
- oestrogen alone - continuous oestrogen for women w/out uterus
- vaginal oestrogen creams or rings for vaginal dryness
Which of the following is the best treatment for hot flushes in a 53 year old woman who has had a thrombotic stroke?
- give sertraline (SSRI) - don’t normally use for hot flushes, but this is an exceptional situ
- reluctant to give any oestrogen at all
- oral increase risk of thrombosis, transdermal don’t
A 39 year old woman has a premature menopause. She is fit and well. What is the best form of HRT for her?
any of the following:
- Oestrogen and progesterone tablets with monthly break
- Continuous oestrogen and progesterone tablets
- Oestrogen patches and intrauterine progesterone secreting coil
- Oestrogen patches and progesterone tablets
- Tibolone tablets
ask her what is easiest for her
What are alternatives to oestrogen for osteoporosis?
- bisphosphonates
- ? raloxifene (SERM)
- calcium + vit D
- strontium
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Intro to Reproduction and Sexual Differentiation28
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Hypothalamic / pituitary / gonadal axis27
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Puberty and Its Disorders41
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Folliculogenesis22
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Social construction of gender14
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The Menstrual Cycle39
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Uterus, uterine tubes and cervix28
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Contraception40
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Psychosexual development43
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Pharmacology of androgens and anti-androgens41
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Spermatogenesis24
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Fertilisation and the Luteal Phase21
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Maternal changes in pregnancy26
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Implantation, placentation and hormone changes in pregnancy25
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Labour29
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Complications of Pregnancy31
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Pharmacology of the Uterus36
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Menopause24
