W3L1 Mon menopause Flashcards
What is menopause
- The menopause is the final menstrual period
- Average age of menopause around 51-52 years (age range 48-55 years)
- Defined retrospectively after 12 months of absent periods
Stages of manopause
Peri-menopause, menopause transition, Climacteric
* The period when ovarian function declines, cycles are irregular and menopausal symptoms appear
* Begins mid to late 40s, ends one year after menopause
Post menopause
* The whole lifetime after menopause
* No periods, no ovulations, steroid hormones low, cannot conceive
Early menopause
* 40-45 years, 5-8% of women
Premature ovarian insufficiency (POI), premature menopause
* Menopause prior to 40 years old, 2% of women (Mishra et al., 2017 Human Reprod)
* May have intermittent ovarian activity, pregnancy rate 5-50% in lifetime
Changes in age of menopause
-Increased life expectancy from ~42 to ~85 in 100 yrs, with 95% women now reaching menopause
* Factors regulating the age at natural menopause are poorly understood/controversial
* Genetic factors – are important
* Cigarette smoking - Menopause is 1-2 yrs earlier
* Surgical history - Hysterectomy may reduce the age at menopause by around 3-4 yrs
* Ethnicity
* High BMI
* Age at Menarche (<12yrs old)?
* Nulliparity
* Not influenced by Oral contraceptive pill
Age related decline in ovarian follicle numbers
Term 1-2 million follicles
Puberty 300 000-400 000
37 years 100 000, then rapid loss
Peri-menopausal threshold <1000 follicles?
Also decline in quality
Peri-menopause Aetiology
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- erratic/short cycle (follicular phase)
* Decrease in oestrogen (and progesterone), follicular –ve feedback reduced – multiple ovulation – twinning risk
* Irregular anovulatory cycles lead to prolonged unopposed oestrogen
* May lead to endometrial hyperplasia and cancer risk
Peri-menopause endocrine 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
Menopause characteristics
- Decline in oocyte quantity and quality in the years preceding
- Loss of ovarian follicular activity at menopause
- Very low oestrogen (and progesterone)
- Increased FSH/LH levels
- Cessation of menstruation
- Cessation/reduction of sexual drive
Menopause ovarian and endocrine changes
- Ovarian primordial follicle stores are exhausted by atresia and ovulation
- Ovulation will not occur after menopause, but this is retrospective
- Therefore use contraception until no periods for one year, as ovulation may occur right up until last period, though less frequently
- Oestradiol declines following menopause- lack of negative feedback
FSH >40 u/l
LH >30-40 u/l - Androstenedione is still produced by the ovary and adrenal gland and is converted in peripheral tissues to oestrone (E1) = low levels
- Androgens gradually decline during reproductive life but no dramatic change after menopause
Aetiology of Premature Menopause/ Premature Ovarian Insufficiency (POI) <40yrs
Idiopathic (> 70% of cases) Spontaneous POI
Rare causes: Galactosaemia
Auto-immune Addison’s disease, thyroid abnormalities
Genetic: Turner’s syndrome, Fragile X syndrome
Iatrogenic: Surgery/chemo/radiotherapy (8-19% of women under 40)
Premature Menopause/
Premature Ovarian Insufficiency (POI) Diagnosis
- No periods for 4 months before age 40
- FSH levels greater than 40mIU/ml 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
Management of POI
- NO CURE
- Actually still need contraception: lifetime chance of ever conceiving 5-10%
- HRT/contraception until around 50 years- because ↑ mortality due to osteoporosis and cardiovascular issues
- For young women/girls- monitoring key is susceptible
- If chemo/surgical – move ovary out of the way (experimental)
- Ovarian cryopreservation
- Superovulation- egg freezing or IVF
- Egg Donation
Oestrogen-related consequences of Menopause incidence
20-40% of women have menopausal symptoms requiring treatment
Oestrogen-related consequences of Menopause short-term problem
- vasomotor symptoms (hot flushes, night sweats, formication- skin thin and dry)
- urogenital symptoms (vaginal dryness, atrophic vaginitis, dyspareunia, dysuria, frequency)
- sleep disturbance
- reduced libido
- depression, anxiety, labile mood
- memory loss, fatigue (may be due to other not sleeping etc)
Oestrogen-related consequences of Menopause medium and long-term problem
- Bone loss and osteoporosis
- Weight gain - change in body form (pear to apple), ↓sensitivity of tissues to insulin (hyperglycaemia)
- Cardiovascular disease – increase blood cholesterol, renin (angiotensin II) linked to hypertension
Hot Flushes: oestrogen related consequences
- Most common symptom- occurs in ~ 80% of women
- Mechanisms not known- hypothalamus thermoregulation
- Last 4 min on average (1 to > 10 times a day)
- Up to 30-50% resolve after 3 to 12mths
- Up to 40% may continue to have significant symptoms up to 10 years after menopause
- Increased with smoking, alcohol, surgical menopause, caffeine, weight
- Main reason why women request treatment
- Oestrogen: most effective treatment, 80% reduction
- Meditation, relaxation to reduce anxiety
Urogenital symptoms
- Start at late peri-menopasuse
- Affects ~ 40% of post menopausal women
- Persist or worsen over time- atrophy of E2 sensitive tissues
- Vaginal dryness, discomfort, pruritis, dyspareunia, UTI (change to alkaine pH) and urgency- epithelium thinning
- Pallor dryness, redness, decreased rugosity
- Endometrial atrophy- thin, exposed vessels- can cause bleeding
- First line is intra-vaginal oestrogen (not systemic HRT)
- For most patients
Other symptoms of oestrogen related consequences of menopause
- Musculoskeletal aches and pain
- Skin thinning, dryness and itchiness (formication)
- Hair thinning and loss, male pattern baldness in some women- due to androgen:E2 ratio
- Facial hair growth
- CNS, decrease memory – especially after surgical induced menopause, slower cognitive function
Menopause: emotional health
- Psychological symptoms affect 25-50% of women
- No direct evidence for increased depression
- Decreased serotonin levels
Bones and Osteoporosis
- Oestrogen deficiency increases bone reabsorption- osteoclast activity
- Directly impairs gut calcium absorption
- Directly increases renal calcium excretion
- Sharp acceleration of bone loss during the initial 5 years following menopause (35%/year)
- Rate of loss then falls back to the age related loss of 1%/year –ethnicity a factor
- Low bone mass increases fracture risk- ↑ mortality
- Prevalence 4% around 50-59 yrs old, >50 % by 80 yrs old
- Early PREVENTION is key!!
- Calcium intake (diet- 1200mg/day), Vitamin D (800-1000U/day)
- Weight-bearing exercise
- Good nutrition – avoid toxins alcohol, caffeine, smoking
- HRT- only helpful before 60 yrs old – prevent fractures, can’t reverse damage
Body weight, shape and lipid metabolism
- As age increase natural tendency for weight gain
- Decrease lean mass, increase body and trunk fat
- Absence of oestrogen at menopause:
- increased lipoprotein lipase enzyme:
- increased cholesterol and LDL and decreased HDL
- plus lower lipolysis in gluteal and abdominal regions:
- slower fat metabolism
- body shape changes from female ‘pear’ to male ‘apple’ pattern
Cardiovascular risk
Major killer of women- contributes to ~50% of deaths
* Lack of E2- increases risk of coronary heart disease (CHD) similar to men
* After menopause, increasing central adiposity, decreased resting energy expenditure, worsening CVS, lipid and metabolic profiles
* Hypertension (HT)- Lack of oestrogen affects on the renin angiotensin system
* Potentially mediated by low oestrogens and loss of inhibition of metabolic neuropeptides
* Together with insulin-resistance (diabetic women) further increases the CHD risk post menopausal
* HRT does not prevent Cardiovascular Disease (CVD), may exacerbate in some women
Menopause: Management and treatment
Hormone Replacement Therapy
- Safe and effective if used in peri-menopausal or early postmenopausal women (≤ 5 years of menopause) with vasomotor symptoms
- If given using these guidelines- no contraindications (breast/endometrial cancer/cardiovascular issues), if so case by case
- HRT contains oestrogen to treat symptoms and progestin (if needed) to protect the endometrium
Risk of HRT
- Combined oestrogen and progestin, given to post menopausal women 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 >5 years use (0.8/1000/year)
- Increased incidence of coronary heart disease
- BUT new data from 2017 (Manson et al., JAMA) - follow up of these cohorts (27,000 women, found NO change in mortality rates between women who did or didn’t take HRT.
However, for women who did take a E2 and P4 combined treatment, the risk of breast cancer was still elevated. - Also new data 2019 (Lancet article)- meta-analysis using 108,647 postmenopausal women showed HRT > 1 yr after 50 yrs old lead to ↑ breast cancer by the age of 65 yrs old, worst is the combined E2 and P4 HRT.
- Very different to treating POI, in which women are expecting to see E2 and P4 at that age (before 51 years old)
Benefits of HRT
- Most effective treatment for menopausal symptoms
- Reduces frequency and severity vasomotor symptoms by 75-85%
- Improves vaginal dryness and vaginal/endometrial atrophy
- Maintains bone density and reduces fracture risk (1/1000 women/year), but not first line for treatment for bone
- May improve QOL, sleep, muscle aches and pains
- Lowers incidence of Alzheimer’s disease
- Reduced colorectal cancer risk 0.8/1000/year (combined long term)
Clinical practice guidelines (ACEC, FDA)
- Maybe a time of significant physiological, emotional and physical change during mid-life
- Lifestyle advice remains the main focus for the mid-life woman. Important to understand these changes so we may best address the needs of women
- 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 peri-menopausal or early post menopausal women not >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
