Key Facts

POI (previously termed premature menopause or premature ovarian failure) describes cessation of ovarian function before age 40. It differs from natural menopause as intermittent ovarian activity may occur.

Epidemiology

• Prevalence: 1% of women <40, 0.1% <30
• Accounts for 10-28% of primary amenorrhoea and 4-18% of secondary amenorrhoea
• Increasing iatrogenic cases due to cancer treatment survival improvements

Aetiology

• Idiopathic: >50% of cases
• Autoimmune (20%): associated with Addison disease, thyroiditis, type 1 diabetes, SLE
• Genetic: Turner syndrome (45,X), fragile X premutation (FMR1), galactosaemia
• Iatrogenic: chemotherapy (especially alkylating agents), pelvic radiotherapy, bilateral oophorectomy
• Infections: mumps oophoritis, TB (rare)
• Environmental: smoking accelerates ovarian ageing

Pathophysiology

• Accelerated follicular atresia or reduced initial follicle pool
• Ovarian follicle depletion → reduced oestradiol and inhibin B production
• Loss of negative feedback → elevated FSH and LH
• Intermittent follicular development may occur (unlike true menopause) → unpredictable ovulation

Menstrual Disturbance

• Secondary amenorrhoea or oligomenorrhoea (most common presentation)
• Primary amenorrhoea (if onset before menarche, e.g., Turner syndrome)
• Irregular periods preceding cessation

Oestrogen Deficiency Symptoms

• Hot flushes and night sweats
• Vaginal dryness, dyspareunia
• Mood changes: anxiety, depression, irritability
• Reduced libido
• Sleep disturbance

Long-term Consequences (if untreated)

• Osteoporosis: significant bone loss without oestrogen replacement
• Cardiovascular disease: increased risk compared to age-matched women
• Cognitive decline: possible increased dementia risk
• Subfertility: primary concern for many patients

Red Flags

• POI + adrenal crisis symptoms → screen for Addison disease
• POI with learning difficulties → consider fragile X premutation
• Short stature + POI → karyotype for Turner syndrome

Bedside

• Pregnancy test (exclude first)
• BMI assessment
• Assessment of oestrogen deficiency symptoms

Bloods

• FSH: >25 IU/L on two occasions 4-6 weeks apart (diagnostic)
• LH: elevated
• Oestradiol: low
• Anti-Müllerian hormone (AMH): very low or undetectable (reflects ovarian reserve)
• TFTs: screen for autoimmune thyroid disease
• Adrenal antibodies (21-hydroxylase): screen for Addison disease (present in 3-4% of POI)
• Coeliac screen: tTG antibodies
• Fasting glucose/HbA1c: metabolic screening
• Lipid profile: cardiovascular risk

Imaging

• Pelvic ultrasound: assess ovarian size and follicle count (small ovaries with few/no follicles)
• DEXA scan: baseline bone density assessment

Special Tests

• Karyotype: especially if POI <30 years (exclude Turner syndrome, Y chromosome material)
• FMR1 premutation testing: fragile X carrier screening (especially with family history of learning difficulties or early menopause)
• Short Synacthen test: if adrenal antibodies positive

Non-pharmacological

• Emotional support and counselling: diagnosis can be devastating, particularly regarding fertility
• Support groups (Daisy Network UK – POI support charity)
• Lifestyle advice: regular weight-bearing exercise, adequate calcium and vitamin D intake, smoking cessation
• Discuss fertility options early

Pharmacological

HRT (essential – not optional for women with POI):

• Continue until at least age 51 (average natural menopause age)
• No increased breast cancer risk with HRT in POI (replacing physiological oestrogen)
• Options:
  • Combined HRT: oestradiol + progestogen (if uterus present)
  • Transdermal oestradiol patches (50-100 mcg) + micronised progesterone 200mg for 12 days/cycle
  • COCP (e.g., ethinylestradiol 30mcg preparations) – provides contraception + oestrogen replacement
  • Oestrogen-only HRT if post-hysterectomy
• Testosterone supplementation for persistent low libido despite adequate oestrogen replacement
• Calcium 1000mg/day + vitamin D 800 IU/day
• Vaginal oestrogen (estriol cream) for persistent vaginal symptoms

Fertility:

• Egg donation + IVF is the most successful option (success rate ~30-40% per cycle)
• Spontaneous pregnancy occurs in ~5% (unpredictable)
• Oocyte/embryo cryopreservation before treatment if iatrogenic cause anticipated
• Ovarian tissue cryopreservation: experimental in the UK

Referral Criteria

• All women with suspected POI → endocrinology/gynaecology
• Fertility concerns → reproductive medicine
• Under 30 → genetic counselling
• Positive adrenal antibodies → endocrinology for Addison disease monitoring

• POI is generally a permanent condition, though 5-10% may have intermittent ovarian function
• Spontaneous conception rate: ~5% (unpredictable)
• Without HRT: accelerated bone loss, 50% increased cardiovascular mortality, potential cognitive decline
• With appropriate HRT: bone density maintained, cardiovascular risk normalised, symptoms well controlled
• No increased breast cancer risk with HRT use in POI up to age 51
• Quality of life significantly improved with appropriate support and hormone replacement

Key Differences: POI vs Natural Menopause

Autoimmune Screening in POI