Menopause Flashcards
What is the menopausal transition?
period of time from changes in menstrual pattern to menopause
What is menopause?
permanent cessation of menstruation due to loss of ovarian follicular function
must have amenorrhoea for 12 months - retrospective Dx
What is perimenopause?
no consistent definition
period of changing ovarian function which preceded the menopause by 2-8 yrs
What is premature ovarian failure?
menopause < 40
What are the Sx of the menopause?
VARIABLE
- initially reduced menstrual cycle (reduced follicular phase)
- mean = 4yrs before final menstrual period
- irregular periods, with amenorrhea episodes
- hot flushes, disturbed sleep (occurs 1year before menopause, due to reducing E2 levels)
- dry vagina
- no menstrual irregularity
- impaired fertility
Why does menopause occur?
- number of granulosa cells in pre-antral follicles reduces with age
- ability to synthesise E2 also decreases
What is the mechanism behind menopause?
- active follicles become inefficient in E2, Inhibin B and AMH synthesis
- high levels of serum FSH
- GnRH secretion impaired -> impaired LH surge -> anovulation
What pathophysiogical observations are noted with menopause?
- reduced follicle count - none or few at menopause
- reduced granulosa cell number
- reduced granulosa cell function
- increased aneuploidy in oocyte
(higher miscarriage rate, increased T21 risk)
What is the ‘critical threshold’ of ova numbers?
point at which there is an accelerated decline in the number of ova (due to follicular atresia)
occurs at ~37yr
Why is there an acceleration in follicular loss?
- follicular depeletion
- decline in granulosa cell/function
What are the main mechanisms in follicular depletion?
- increased follicular atresia (pro-apoptotic environment e.g. smoking)
- accelerated follicular loss (AMH declines, FSH increases, increased follicular recruitment)
What are the mechanisms underlying decreased granulosa cells/function?
- 30% decrease in granulosa cells in oder women
- reduced Inhibin B production leads to high FSH levels [follicular phase]
- anovulatory cycle: reduced inhibin A [no luteal phase] so higher FSH
- reduced FSH receptors so impaired follicle recruitment
- impaired GF secretion, E and P
What are the main consequences of granuolosa cell dysfunction?
SHORTENED CYCLE
- decline in inhibin B production (from granulosa cells)
- elevated FSH in follicular phase
- earlier E2 production and earlier LH surge
DELAYED/ABSENT OVULATION
- E2 production stimulates earlier in cycle (elevated FSH)
- however not high enough [E2] to induce GnRH-mediated LH surge (dysfunctional granulosa cells)
- ovulation is delayed or doesn’t occur
- FSH insensitivity
How does FSH insensitivity result in heavier periods in peri-menopause ?
Fewer FSH-R in granulosa cells -> FSH insensitivity
fewer follicles recruited, no inhibin A -> FSH rises
longer E2 stimulation with higher [E2] -> rich, thick endometrium
sloughs off due to weight of lining -> menorrhagia
What causes breast tenderness in peri-menopause?
transitory increases in E2
What causes hot flushes in peri-menopause?
reduced E2 levels -> disturbed serotonin levels
resets thermoregulatory nucleus -> excessive heat loss
N.B. SSRIs can be an effective Rx (in place of HRT)
What are the hormonal consequences of menopause?
- AMH levels: first sign of declining ovarian function
- declining inhibin B: ~2yr before final menstrual period
- FSH levels generally variable, but will increase towards menopause
- LH increases later in menopause
- E2 levels fall near the menopause
- Androgen levels decline (ovarian and adrenal) NOT RELATED TO MENOPAUSE
- no progesterone production post-menopause
Why is there a decline in oocyte function and development during menopause?
- consequence of impaired production of GFs from granulosa cells
- increased aneuploidy
- increased oocyte abnormality -> impaired follicle recruitment (even with clomiphene)
= anovulatory cycles
= increased miscarriage rate
What is clomiphene?
used to treat infertility for women who do not ovulate
it is selectively modulate the ER by acting like an oestrogen analogue
What is the variation in age of menopause attributed to?
- smoking status
- geographical location
- maternal age at menopause
- (polygenic) risk loci
surgery/chemo
What markers can be used to indicate declining fertility?
- ovarian volume = antral follicle count
- ovarian stimulation = antral follicle count
- AMH
not very reliable for menopause prediction
Why considerations should be taken when prescribing HRT?
- oestrogen has 80% efficacy at reducing hot flushes (lower doses also effective)
- patient centred
- consider baseline risks
- always use P for women with uterus
- need contraception if <1yr amenorrhea
- minimise side effects: mastalgia, nausea
- risks are lower for short term use: transdermal oestrogen (patch) = low VTE risk
What is oestrogen-induced endometrial hyperplasia?
found in 56% of women who use unopposed oestrogen
~3% develop carcinoma
protection obtained by 10-13 days of P
cyclical P: pre-menopausal with periods
continuous P: menopausal women with amenorrhoea
Which kinds of oestrogen preparations have VTE risk?
transdermal and gel: no increased risk
oral oestrogen: increased VTE risk
How is HRT usually given?
COCP: continuous E2, cyclical P
oestrogen alone: continuous E2 for women w/o uterus
topical oestrogen: vaginal creams or rings for dryness (reduced endometrial risk as no systemic absorption)
What alternatives to HRT can be used to treat osteoporosis in menopausal women?
- bisphosponates
- ? raloxifene (Selective ER modulator - SERM)
- calcium and vitamin D
- Strontium
Other (currently under Ix)
- teriparatide (PTH peptide fragment)
- simvastatin
- leptin
- photo-oestrogens
- manipulation of RANK-L gene
- anti-oxidants
What techniques have modern medicine come up with for premature ovarian failure?
- ovaries removed (earlier in disease)
- re-implanted ovarian fragments near fallopian tube
- stimulated follicular development
- removed eggs
results: 27 women, 1 live birth
