Case 24.2 – Secondary Amenorrhoea

Definition: Secondary amenorrhoea = absence of menstruation for >3 months in a woman with previously regular cycles, OR >6 months in woman with previously irregular cycles.

Causes of Secondary Amenorrhoea (4-tier classification):

1. Hypothalamic causes (35%):

• Functional hypothalamic amenorrhoea:
  • Stress - psychological, illness
  • Weight loss/low BMI (\<18.5) - anorexia nervosa, excessive exercise
  • Excessive exercise - athletes, gymnasts (female athlete triad: amenorrhoea + osteoporosis + eating disorder)
• Mechanism: ↓ GnRH pulsatility → ↓ FSH/LH → ↓ oestrogen → amenorrhoea
• Bloods: Low FSH, Low LH, Low oestradiol

2. Pituitary causes (20%):

• Hyperprolactinaemia (prolactinoma or other causes):
  • Prolactin inhibits GnRH → ↓ FSH/LH → amenorrhoea + galactorrhoea
  • Causes: Prolactinoma (pituitary adenoma), medications (antipsychotics, metoclopramide, domperidone), hypothyroidism
  • Bloods: High prolactin (\>1000 suggests prolactinoma), low FSH/LH
• Sheehan syndrome: Postpartum pituitary necrosis (following massive PPH)
• Other pituitary tumours: Non-functioning adenomas, craniopharyngioma

3. Ovarian causes (40%):

• Polycystic ovary syndrome (PCOS): Most common cause overall
  • Hyperandrogenism (acne, hirsutism), insulin resistance, polycystic ovaries on USS
  • Bloods: High LH:FSH ratio (\>2:1), high testosterone, high insulin
• Premature ovarian insufficiency (POI): Menopause <40 years
  • Symptoms: Hot flushes, night sweats, vaginal dryness
  • Bloods: High FSH (\>25 IU/L on 2 occasions), low oestradiol
  • Causes: Idiopathic, autoimmune, Turner syndrome (45,XO), chemotherapy/radiotherapy

4. Uterine/outflow tract causes (5%):

• Asherman syndrome: Intrauterine adhesions (synechiae)
  • Following D&C, endometritis, surgery
  • Diagnosis: Hysteroscopy (gold standard)
• Cervical stenosis: Following LLETZ, cone biopsy, cervical surgery

Always exclude FIRST:

• PREGNANCY - most common cause! Always do urine βhCG first

Investigations for Secondary Amenorrhoea:

First-line (all patients):

• Urine βhCG - Exclude pregnancy (mandatory!)
• Serum prolactin - Hyperprolactinaemia (prolactinoma, medications, hypothyroidism)
• TFTs (TSH, free T4) - Hypothyroidism (can cause ↑ prolactin and amenorrhoea)
• FSH and LH - Determine level of dysfunction:
  • Low FSH/LH → hypothalamic/pituitary cause
  • High FSH → ovarian failure (POI)
  • High LH:FSH ratio (\>2:1) → PCOS
• Testosterone - Hyperandrogenism (PCOS, androgen-secreting tumour if very high)

Second-line (guided by first-line results):

• Pelvic ultrasound: Assess ovaries (polycystic morphology), uterus, endometrial thickness
• MRI pituitary: If prolactin >1000 mU/L or visual field defects/headaches
• Karyotype: If POI suspected (especially if <30 years) - exclude Turner syndrome
• Hysteroscopy: If Asherman syndrome suspected (history of D&C/endometritis)

This patient's investigations reveal:

• Negative βhCG → pregnancy excluded
• Very high prolactin (4200 mU/L) → hyperprolactinaemia
• Normal TFTs → hypothyroidism excluded
• Low FSH/LH → pituitary/hypothalamic cause (as expected with high prolactin)
• MRI: 12mm prolactinoma (pituitary macroadenoma)
• Galactorrhoea + headaches + visual field defect consistent with prolactinoma with mass effect

Hyperprolactinaemia: Elevated serum prolactin >500 mU/L (normal <500 in women, <450 in men).

Causes of Hyperprolactinaemia:

• Physiological: Pregnancy, breastfeeding, stress, exercise, sexual intercourse
• Prolactinoma (pituitary adenoma secreting prolactin):
  • Microadenoma: <10mm (prolactin usually 1000-5000 mU/L)
  • Macroadenoma: >10mm (prolactin usually >5000 mU/L)
  • More common in women (microprolactinomas), men present later with macroprolactinomas
• Medications: Antipsychotics (risperidone, haloperidol), metoclopramide, domperidone, SSRIs, verapamil
• Hypothyroidism: ↑ TRH → ↑ prolactin
• Pituitary stalk compression: Non-functioning pituitary tumours (↓ dopamine delivery → ↑ prolactin)
• Chronic renal failure: Reduced prolactin clearance
• PCOS: Mild elevation (500-1000)

Clinical Features of Hyperprolactinaemia:

• Women:
  • Oligomenorrhoea/amenorrhoea (prolactin inhibits GnRH)
  • Galactorrhoea (40-80% of cases)
  • Infertility
  • Reduced libido
  • Vaginal dryness (due to low oestrogen)
• Men:
  • Erectile dysfunction
  • Reduced libido
  • Infertility
  • Galactorrhoea (rare)
  • Gynaecomastia
• Mass effect (if macroadenoma):
  • Headaches - frontal, worse in mornings
  • Visual field defects: Bitemporal hemianopia (compression of optic chiasm)
  • Cranial nerve palsies (if cavernous sinus invasion)
  • Pituitary apoplexy (sudden hemorrhage into adenoma - neurosurgical emergency)

Diagnosis:

• Serum prolactin:
  • >1000 mU/L → prolactinoma likely
  • >5000 mU/L → macroprolactinoma likely
  • 500-1000 mU/L → consider other causes (medications, stress, PCOS)
• Check macroprolactin: If borderline elevation - some assays detect inactive prolactin (macroprolactin) which is not clinically significant
• MRI pituitary: If prolactin >1000 or any visual symptoms/headaches
• Visual field testing (perimetry): If macroadenoma or visual symptoms
• Other pituitary hormones: Check for hypopituitarism if large tumour (cortisol, TFTs, IGF-1)

Management of Prolactinoma:

Medical Treatment (First-line):

• Dopamine agonists:
  • Cabergoline - First-line (long-acting, taken 1-2x/week)
    • Starting dose: 250-500mcg once weekly, titrate up to 0.5-3mg/week
    • 80-90% normalise prolactin, 70-80% shrink tumour
    • Fewer side effects than bromocriptine
  • Bromocriptine - Alternative (shorter-acting, taken daily)
    • Starting dose: 1.25mg at night, titrate to 2.5-15mg/day
    • More side effects (nausea, dizziness, postural hypotension)
    • Preferred in pregnancy (more safety data)
• Mechanism: Dopamine agonists suppress prolactin secretion and shrink tumour
• Monitoring:
  • Serum prolactin at 4-6 weeks, then 3-6 monthly
  • MRI pituitary at 6-12 months to assess tumour shrinkage
  • Visual fields if macroadenoma
• Duration: Usually long-term (years). Can attempt withdrawal after 2-3 years if prolactin normalized and tumour shrunk

Surgical Treatment (Trans-sphenoidal adenomectomy):

• Indications:
  • Intolerance/resistance to dopamine agonists
  • Visual field defects not improving with medication
  • Pituitary apoplexy
  • Patient preference (rare)
• Cure rate: 70-90% for microadenomas, 30-50% for macroadenomas
• Complications: Hypopituitarism, diabetes insipidus, CSF leak

Radiotherapy:

• Third-line - only if medication and surgery fail
• Slow effect (years), high risk of hypopituitarism

Fertility and Pregnancy:

• Dopamine agonists restore fertility in 80-90%
• During pregnancy:
  • Usually stop cabergoline once pregnant (switch to bromocriptine if needed)
  • Microprolactinomas rarely enlarge in pregnancy (\<5%)
  • Macroprolactinomas may enlarge (20-30%) - monitor visual fields

This patient's management:

1. Diagnosis: 12mm prolactinoma (macroadenoma) with suprasellar extension and optic chiasm compression
2. Urgent referral to endocrinology
3. Start cabergoline: 250mcg once weekly, titrate up based on prolactin levels
   • Goal: Normalize prolactin, shrink tumour, restore menstrual function, improve visual fields
4. Ophthalmology review: Formal visual field testing (perimetry)
5. Monitoring:
   • Prolactin levels every 4-6 weeks
   • MRI pituitary at 6 months (expect tumour shrinkage)
   • Repeat visual fields in 3-6 months
6. Prognosis: Excellent response expected to cabergoline - prolactin normalization, tumour shrinkage, restoration of menses and fertility