Gonadal system - menopause
Description
- Final menstrual period, diagnosed retrospectively after 12 months of amenorrhoea with no other cause
| Term | Definition |
|---|---|
| Perimenopause | Cycle variability >=7 days -> to 12 months after FMP. Fertility is reduced but not zero - contraception still needed |
| Menopause | 12 months amenorrhoea; median age 51-52 in Australia |
| Early menopause | 40-45 years |
| Premature ovarian insufficiency (POI) | <40 years - a different disease with a different treatment imperative |
| Surgical/iatrogenic | Bilateral oophorectomy, chemotherapy, pelvic radiotherapy - abrupt, more severe symptoms |
Symptom domains
- Vasomotor - hot flushes, night sweats; ~80% of women, median duration ~7-10 years (longer if onset in early perimenopause, and in Black and Hispanic cohorts)
- Genitourinary syndrome of menopause (GSM) - vaginal dryness, dyspareunia, urinary urgency, recurrent UTI
- *Progressive and does not remit* - unlike flushes
- Sleep disturbance, mood (new or recurrent depression, especially perimenopause), brain fog
- Musculoskeletal - arthralgia, frozen shoulder
- Accelerated bone loss - fastest in the 1-2 years around the FMP
Epidemiology
- ~80% experience vasomotor symptoms; ~20-25% severe enough to seek treatment
- POI ~1% of women under 40; ~0.1% under 30
- Smoking brings menopause forward by ~1-2 years
- MHT use fell ~80% after the 2002 WHI publication and has only partially recovered
- The WHI cohort had a mean age of 63 - a decade past the typical treatment window, which is why its risk estimates do not apply to a symptomatic 51-year-old
Aetiopathogenesis
- Follicular depletion -> dec inhibin B and AMH -> loss of negative feedback -> inc FSH first
- Then dec oestradiol -> inc LH
- Perimenopause is characterised by erratic, sometimes supraphysiological oestradiol - not a smooth decline
Why the flush happens
- Oestrogen withdrawal -> hypertrophy and hyperactivity of hypothalamic KNDy neurons (kisspeptin/neurokinin B/dynorphin) in the arcuate nucleus
- -> neurokinin B signalling at the NK3 receptor destabilises the thermoregulatory set-point in the median preoptic nucleus
- *This is the mechanism the NK3 antagonists block* - the first non-hormonal drugs designed for the actual pathophysiology
Consequences of oestrogen deficiency
- Bone: inc RANKL, dec OPG -> inc osteoclast activity -> rapid trabecular bone loss
- Urogenital: thin epithelium, dec glycogen -> dec lactobacilli -> inc pH -> GSM and recurrent UTI
- Metabolic: central fat redistribution, dec HDL, inc LDL, inc insulin resistance
Diagnosis
Over 45 - clinical diagnosis
- *Do not measure FSH or oestradiol in a woman over 45 with typical symptoms* - they fluctuate wildly and cannot exclude perimenopause
- Amenorrhoea 12 months = menopause; changing cycles + symptoms = perimenopause
When to test
- Age <45 - FSH x2, at least 4-6 weeks apart
- Age <40 (suspected POI) - FSH >25-40 IU/L on two occasions >=4 weeks apart with amenorrhoea/oligomenorrhoea
- Then: karyotype (Turner mosaic), FMR1 premutation (fragile X), adrenal (21-hydroxylase) and thyroid antibodies, pelvic ultrasound
- A woman with POI has an ~5% chance of spontaneous conception - she still needs contraception if not seeking pregnancy
- Hysterectomised or on hormonal contraception/LNG-IUD - FSH is uninterpretable on combined contraception
Exclude before attributing to menopause
- Pregnancy, thyroid disease, hyperprolactinaemia
- *Any postmenopausal bleeding, or new heavy/irregular perimenopausal bleeding, needs endometrial assessment* - transvaginal ultrasound +/- pipelle/hysteroscopy
- Depression, sleep apnoea (often new after menopause), anaemia, phaeochromocytoma or carcinoid if flushing is atypical
- AMH does not diagnose menopause and should not be used for it
Baseline before starting MHT
- BP, weight, personal and family history of breast cancer and VTE, migraine with aura
- Up-to-date BreastScreen and cervical screening
- Absolute CVD risk; lipids, glucose
Management
Organise by what she has presented with - not everyone needs everything
A. Vasomotor symptoms
### MHT - the most effective treatment
- Oestrogen
- Transdermal (patch or gel) preferred - *no increase in VTE or stroke risk*, and preferred in obesity, migraine, hypertriglyceridaemia, gallbladder disease, and anyone with VTE risk
- Oral oestradiol acceptable in low-risk women
- Progestogen - mandatory with an intact uterus
- *Unopposed oestrogen -> endometrial hyperplasia and carcinoma*
- Continuous combined if >12 months postmenopausal (no bleed)
- Cyclical/sequential in perimenopause or <12 months postmenopausal (withdrawal bleed)
- Micronised progesterone is the preferred progestogen (best breast and cardiovascular profile); LNG-IUD is an accepted alternative and also gives contraception
- Tibolone is an alternative single agent; conjugated oestrogen + bazedoxifene where available
- Start with the lowest effective dose, titrate to symptoms - there is no blood test to titrate to
### The timing hypothesis - the single most important prescribing rule
- Benefit exceeds risk when MHT is started before age 60, or within 10 years of the final menstrual period
- Outside that window the cardiovascular risk-benefit shifts unfavourably
- *No arbitrary duration limit or stopping age* - review annually, individualise
### Non-hormonal
- NK3 receptor antagonists - fezolinetant, elinzanetant; effective for moderate-severe flushes without hormones
- Fezolinetant needs scheduled liver function monitoring (hepatotoxicity); elinzanetant requires less intensive monitoring
- Particularly relevant after breast cancer
- SSRI/SNRI - venlafaxine, desvenlafaxine, escitalopram, paroxetine
- *Never paroxetine or fluoxetine with tamoxifen* - CYP2D6 inhibition blocks conversion to endoxifen
- Gabapentin (good for night sweats), oxybutynin, clonidine (weak)
- CBT and hypnotherapy have genuine evidence; cooling strategies, weight loss, reduce alcohol and smoking
- Phytoestrogens, black cohosh and evening primrose oil: not supported
B. Genitourinary syndrome of menopause
- Vaginal oestrogen (pessary/cream) - low systemic absorption, NO progestogen needed, no washout, safe long-term
- Usually safe even after breast cancer in discussion with the oncologist; avoid or discuss carefully with aromatase inhibitors
- Non-hormonal moisturisers and lubricants; vaginal DHEA (prasterone); ospemifene
- Treat indefinitely - symptoms return within weeks of stopping
- Reduces recurrent UTI
C. Low sexual desire
- Treat GSM, mood, sleep and relationship factors first
- Testosterone for hypoactive sexual desire disorder in postmenopausal women - the only evidence-based indication
- Australia has a TGA-approved female testosterone cream (AndroFeme 1%); monitor levels to keep in the female physiological range
D. Bone protection
- MHT prevents fracture at all sites and is first-line in early menopause and POI
- Calcium 1300 mg/day (diet preferred), vitamin D, weight-bearing and resistance exercise
- Bisphosphonate/denosumab per fracture risk in older postmenopausal women
E. Premature ovarian insufficiency - a different calculation entirely
- *MHT (or the combined oral contraceptive) until at least the average age of menopause (~51) is standard of care, not optional*
- Doses are higher than for a 55-year-old - she is replacing, not supplementing
- Untreated POI -> osteoporosis, cardiovascular disease, cognitive decline, and reduced life expectancy
- Fertility counselling, psychological support, cardiovascular and bone surveillance
Contraindications to systemic MHT
- Oestrogen-dependent cancer (breast, endometrial), undiagnosed vaginal bleeding
- Active or recent VTE, arterial thromboembolic disease (MI, stroke, angina)
- Active liver disease
- Relative: migraine with aura (use transdermal), gallbladder disease, hypertriglyceridaemia (use transdermal)
Contraception
- Continue until 12 months of amenorrhoea if >50, or 24 months if <50
- MHT is not contraception
Associations
- Osteoporosis and fragility fracture
- Cardiovascular disease - risk rises after menopause, steeply in POI and early menopause
- Genitourinary syndrome of menopause, recurrent UTI, pelvic floor dysfunction
- Metabolic syndrome, central obesity, dyslipidaemia
- Depression and anxiety (perimenopause is a window of vulnerability)
- Obstructive sleep apnoea
- POI associations: Turner syndrome/mosaicism, FMR1 premutation, autoimmune (APS-2, Addison's, thyroid), galactosaemia, chemotherapy (alkylating agents - highest gonadotoxicity) and pelvic radiotherapy
Natural history & complications
- Vasomotor symptoms: median ~7-10 years, ~10% persist beyond 15 years
- GSM is progressive and does not resolve spontaneously - it needs indefinite treatment
- Bone loss ~2%/year around the FMP, then ~1%/year
- MHT risks in absolute terms, for a woman starting in the standard window:
- Combined MHT and breast cancer: small excess emerging after ~5 years, roughly 1 extra case per 1,000 women per year; oestrogen-only carries little or no excess; risk declines after stopping
- VTE: oral oestrogen roughly doubles a low baseline risk; transdermal does not raise it
- Stroke: small excess with oral oestrogen, none demonstrated with transdermal
- Endometrial cancer: prevented by adequate progestogen; caused by inadequate progestogen
- Weigh these against the untreated burden: sleep loss, mood, function, sexual health, and bone
- Review annually - efficacy, dose, bleeding pattern, risk profile, and whether she still wants it
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