menopause Flashcards
Menopause
Final menstrual period - defined once followed by 12 months of amenorrhoea.
Retrospective clinical diagnosis.
Given many women may not be naturally menstruation (contraception, hysterectomy/ablation) pragmatic definition is permanent cessation of ovarian function.
Early menoapuse <45years.
POI <40 years. (cessation of ovarian funciton before age of 40yrs)
Average age 51years in caucasians - varies across ethnicities.
AFC, AMH, early follicular FSH, inhibin B more useful in a fertility context and are not essential in diagnosis of menopause.
STRAW+10
Stages of Reproductive Aging Workshop.
Three broad stages.
Reproductive
Menopausal transition
Postmenopause
These three further categorised into -
early, peak (repro stage only) and late.
Can’t be used in POI, PCOS, those with hormonal suppresion of menstrual, endometrial ablation, removal of a single ovary or hysterectomy. In these woman supportive criteria should be used to determine reproductive stage.
POI
Primary hypogonadism prior to age 40 in women who previously had normal menstrual cycles.
Diagnosed:
- 2 x elevated FSH results (>40iu/l) 4-6 weeks apart.
- Characterised by menopausal symptoms and oligomenorrhoea or amenorrhoea.
1% <40
0.1% <30
POI risks
Premature morbidity and mortality
Impaired endothelial function, IHD, ischemic stroke, osteoporotic fractures, impaired cognition, diminished sexual well being.
POI etiology
Can be primary or secondary.
Primary:
Idiopathic (30% of these will have FHx suggestive genetic etiology)
Turner Syndrome (monosomy X, mosaicism, X chromosome rearrangements, X-autosome transloactaions, isochromosomes)
FMR1 premutation
Others genes (BMP15, INHA, GDF9, NOBOX, FSHRmutation)
Enzyme deficiencies
Autoimmune - polyendocrinopathy, polyglandular autoimmune diseases can occur. (AIRE)
Secondary:
Chemo
RT
Surgical - oophorectomy
Hyst/salpingectomy if blood supply to ovary comprimised
Infections
Inappropriate luteinisation of graafian follicles can occur (due to very high LH levels), prevents ovulation and pregnancy.
Investigations for POI
FSH, LH, E2, Testosterone, DHEAS, cortisol (morning), ACTH, TSH, T4, AMH
Karyotype and FMR1 gene mutation. (guidelines say in <30 yos)
Adrenal antibodies, thyroid antibodies, HbA1c.
Pelvic USS.
DEXA (dual xray absorptiometry) if concerns for BMD.
MHT for POI
Need higher doses than older women.
MHT may reduce symptoms and preserve bone density and should be advised until at least average age of menopause.
estradiol valerate - 2mg daily
CEE (conjugated equine estrogen) 1.25mg
Transdermal oestradiol 75-100mcg/24hour patch, twice weekly.
Ethinyoestradiol 10mcg daily
Or COCP (though may be suboptimal for bone and cardiovascular health, data lacking, small RCTs suggest MHT better for these)
Progesterone component.
Mirena - 20mcg/day - 52mg levonorgestrel.
Micronized progesterone - 200mg nocte 12 days per month or if continuous 100mg nocte.
Consideration of testosterone if hypoactive sexual desire dysfunction.
10mg/ml gel, apply 5 mg (0.5 mL) once daily to the upper thigh or buttock
Follow up of POI
Reviewed at least annually.
Assessment of symptom control. Adherence to tx. CVD assessment.
BMD ideally assessed every 2 years however availability of DEXA scans is limited.
Breast cancer screeninge every 2 years from 45-69 with a mammogram
Fertility options
- Oocyte freezing (if known risk whilst still fertile)
- Embryo freezing (as above)
- ovarian tissue cryopreservation and subsequent transposition (OTC) +/- IVF.
- Ovarian PRP (very experimental still)
- Donor oocyte.
- Donor embryo.
- Adoption.
- Childlessness.
Life style interventions for menopause.
Diet, nutrition
Exercise cardiovascular + weight bearing x2/week
Decrease caffeine
Decrease alcohol
Avoid smoking
Loose and cool clothing + layering
Environment
Weight management (obesity associated with more hot flushes)
Urogenital symptoms
female genital tract and lower urinary tracts both arise from urogenital sinus. Both are sensitive to effects of female sex steroid hormones throughout life. ER and PR found in vagina, urethra, bladder, pelvic floor.
Urinary incontinence - cochrane review (2012) showed systemic worsened incontinence.
Topical oestrogen - appears to be of benefit.
Recurrent UTIs
- Decrease vaginal pH and reverse the microbiological changes that occur in the vagina following the menopause (Cochrane review 2008)
SUI
Pelvic floor muscle training
Surgery
Overactive bladder
Lifestyle changes and bladder retraining
Antimuscarinics (oxybutynin)
Local e2 may have a role
Urogenital atrophy
Improves dryness, pruritis, dyspareunia
Cochrane 2016 low-quality evidence showing improvement in symptoms.
Osteoporosis - diagnosis/definition
Systemic skeletal disease characterised by diminished bone strength, with the risk of sustaining a fragility fracture (own body height fall)
Can occur from - failure to attain peak bone density, accelerated bone loss after menopause (induced by E2 deprivation), age related bone loss.
Definition - T-score <-2.5 (compared to healthy young persons bones) on DEXA or fragility fracture.
FRAX model used to determine risk of fracture over 10 years.
Appropriate assessment of fracture risk and secondary causes of osteoporosis should precede any therapeutic decisions
cardiovascular disease
Principal cause of morbidity and mortality in PM women.
Primary prevention measures.
Aspirin and statin use do not improve mortality in women (as they do in men).
- MHT likely cardioprotective if started around the time of menopause, and may be harmful if started more than 10 years after menopause.
- Cochrane showed reduction in all cause mortality in 50-59yos and cardiovascular mortality (Non SS)
Stroke
Risk may increase is MHT started >60
<60yo no increased risk (cochrane and WHI)
Risk related to oral therapy, no sig risk with transdermal.
VTE
Orally administered estrogen (estradiol or CEE) may exert a prothrombotic effect through the hepatic impact of these molecules. The prothrombotic effect is possibly related to high concentrations of estrogen in the liver due to the ’first-pass’ effect.
Most prevalent adverse effect of oral oestrogens.
Risk increases with age, weight and thrombophilias.
Epidemiological studies don’t show a link with transdermal E2 only oral.
Oral 6/10 000 women-years oral E+P (MPA and continuous higher risk
4/10 000 women-years oral E)
Neurological
MHT should not be used to enhance cognitive function.
MHT after onset of Alzeihmer’s does not benefit cognitive function or slow disease progression.
MHT initiation >60 increases risk of dementia
MHT initiation <60 decreases risk of dementia
Finding are inconsistent as to whether MHT improves depressive symptoms. Short term use for depression which commences during menopause transition may help.
Breast cancer
In low risk women the benefits of HRT for up to 5 years probably outweigh the harms.
Combined E+P increases risk of BC. Likely duration dependent.
- avoidance of synthetic progesterone may help
- it is not dose dependent.
E2 alone - no inc risk. Vaginal e2 - no inc risk.
Inc risk of BC with combined MHT assoc with addition of synthetic progestogen to oestrogen therapy (CEE + MPA continous combined therapy) and related to duration of use.
Risk may be lower with micronized progestogen or dydrogesterone.
Increased risk is small (extra 8 women per 10 000), risk decreases progressively after treatment stops.
Lack of safety data to support the use of MHT in breast cancer survivors.
Breast cancer risk should be evaluated before MHT prescription.
Estrogen alone decreases risk.
Androgens and menopause
Ovary - produces testosterone and androstenedione.
Adrenal cortex zona reticularis - produces androstenedione, DHEA and DHEAS.
Androgen precursors are converted to testosterone peripherally.
Androgen levels decline with age in women with no acute change associated with natural menopause.
Surgical menopause causes a significant drop in testosterone production.
Management in perimenopause- MHT options
COCP - eliminate pill free week if VMS breakthrough
Should switch to Combined sequential once contraception not required.
E+con P - The 52 mg LNG-IUD can be combined with oral/transdermal estrogen and can be left in situ for up to 8 years for contraception and provides endometrial protection for up to 5 years.
POP that suppress ovulation (cerazette - desogestrel 75mg) could be used off label with transdermal oestrogen for those with CI to COCP.
High dose progestogen only regimes can reduce VMS and tx endometrial hyperplasia. Can have side effects too (weight gain, mastalgias, fluid retention)
Cyclical MHT - not contraceptive as don’t suppress ovulation. Often get sx of e2 excess (mastalgia and erratic bleeding) due to exogenous variable estrogen production.
Management of PM - MHT options
ospemifene - SERM oral, used for urogenital symptoms 60mg/day
Non-hormonal options
Fezolinetant is a neurokinin 3B receptor antagonist acts centrally in the brain to reduce VMS. 45mg/day. No concern for endometrial effects. Ok for those with BC.
Just been TGA approved for use in Aus.
CBT and hypnosis both shown to significant reduce VMS.
Clonidine less effective. Gabapentin often has intolerable side effects - somnolence, headache, dizziness.
BRCA1 BRCA2
The use of estrogen therapy after RRBSO does not increase the risk of breast cancer among women with a BRCA 1 mutation and should reassure BRCA1 mutation carriers considering preventive surgery that HT is safe. RRBSO usually performed 35-40 once family complete for BRCA1 carriers.
BRCA2 breast cancers more likely to be ER+. Still ok to use HRT until natural age of menopause according to most guidelines but evidence is scarce.
As above for risk reducing strategies.
