Menopause

Question 1

What is menopause?

Answer 1

The permanent (>12 months) cessation of menstruation due to loss of ovarian follicular function

Question 2

What is perimenopause?

Answer 2

• 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

Question 3

What is the average age of menopause?

Answer 3

51

Question 4

When is premature ovarian failure diagnosed?

Answer 4

Diagnosed when menopausal below or at age of 40

Question 5

What factors influence the age onset of menopause?

Answer 5

• smoking (2 year reduction in age at menopause + shorter transitions)
• hysterectomy
• endometriosis
• chemotherapy
• radiotherapy
• genetic determinants
• ethnicity

Question 6

What are the symptoms of menopause?

Answer 6

• 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

Question 7

What 4 pathological observations underly menopause?

Answer 7

• reduced follicle count - none/few at menopause
• reduced granulosa cell number
• reduced granulosa cell function
• increased chromosomal abnormality of oocyte

Question 8

How do the number of primordial follicles change over time in a woman, from fetus to post-menopause?

Answer 8

• 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

Question 9

Why does follicular depletion occur?

Answer 9

• 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

Question 10

There is a 30% decrease in granulosa cells in older women c/w younger. Why is there a decline in granulosa cell number & function?

Answer 10

• 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

Question 11

Why is there a shortened cycle in early menstrual transition?

Answer 11

• decline in inhibin B production (granulosa cells)
• leads to elevated FSH in follicular phase
• earlier elevated levels of oestrogen production + earlier LH surge

Question 12

Why is there delayed/absent ovulation in late menstrual transition?

Answer 12

• 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

Question 13

Why do menopausal women have heavier periods?

Answer 13

• longer oestrogen stimulation of endometrium
• thicker lining
• oestrogen levels may be higher than in women aged under 35

Question 14

Why do perimenopausal women have breast tenderness?

Answer 14

Transitory increases oestrogen

Question 15

Hot flushes happen very close to menopause. Why do they occur?

Answer 15

• reduced oestrogen levels
• disturbance of serotonin levels
• resets thermoregulatory nucleus + leads to heat loss

Question 16

What is the hormonal profile (changes) that occur in someone leading up to menopause?

Answer 16

• 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

Question 17

Why is there a decline in oocyte function and development?

Answer 17

• 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

Question 18

What are the markers for declining fertility?

Answer 18

• 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

Question 19

What are management principles surrounding the prescription of HRT?

Answer 19

• 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

Question 20

How can oestrogen induced endometrial hyperplasia be avoided?

Answer 20

• 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

Question 21

How are oestrogen and progesterone administered?

Answer 21

• 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

Question 22

Which of the following is the best treatment for hot flushes in a 53 year old woman who has had a thrombotic stroke?

Answer 22

• 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

Question 23

A 39 year old woman has a premature menopause. She is fit and well. What is the best form of HRT for her?

Answer 23

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

Question 24

What are alternatives to oestrogen for osteoporosis?

Answer 24

• bisphosphonates
• ? raloxifene (SERM)
• calcium + vit D
• strontium