EndocrinologyTier 2Disease (DEADMAN)

Hypothalamic–pituitary axis disorders - prolactin excess – prolactinoma and stalk effect

Description

Prolactin is tonically inhibited by hypothalamic dopamine via the stalk
- -> anything that severs the stalk raises prolactin. The only anterior pituitary hormone under net inhibitory control
Excess prolactin -> suppression of GnRH pulsatility -> hypogonadotropic hypogonadism

Two distinct mechanisms

	Prolactinoma	Stalk effect
Source	Autonomous lactotroph tumour	Any lesion compressing stalk/hypothalamus
Prolactin	Scales with tumour size; macroadenoma usually >5000 mIU/L	Usually <2000-3000 mIU/L regardless of mass size
Response to dopamine agonist	Shrinks and normalises	Prolactin falls, mass does not shrink

*Large sellar mass + only modestly raised prolactin = non-functioning adenoma with stalk effect, not a prolactinoma - it needs surgery, not cabergoline*
Micro <10 mm, macro >=10 mm; giant >=40 mm

Presentation by sex

Women - usually microadenoma: oligo/amenorrhoea, infertility, galactorrhoea, dyspareunia
- Menstrual disturbance brings them in early, while the tumour is small
Men - usually macroadenoma: dec libido, ED, infertility, gynaecomastia, low BMD, anaemia; galactorrhoea rare
- Presents late with mass effect - headache, bitemporal field loss

Commonest functioning pituitary adenoma (~40-50% of all pituitary tumours)
Prevalence ~50/100,000; F:M ~10:1 in the reproductive years, equalising after 50
Peak 20-50y in women
Micro:macro ratio reverses by sex - women micro, men macro

Physiological

Pregnancy (rises to ~10x term), lactation, nipple stimulation, stress, sleep, exercise, chest wall injury/herpes zoster
Post-partum: normalises within a few weeks if not breastfeeding, ~6 months if breastfeeding

Pharmacological - the commonest cause overall

Antipsychotics - risperidone, paliperidone, amisulpride, haloperidol, phenothiazines (aripiprazole is a partial agonist and lowers prolactin)
Metoclopramide, domperidone, prochlorperazine
Oestrogen, opioids, verapamil, methyldopa, SSRIs, H2 antagonists, cocaine

Pathological

Prolactinoma
Stalk effect - non-functioning adenoma, craniopharyngioma, meningioma, germinoma, sarcoid, hypophysitis, trauma
Primary hypothyroidism - inc TRH stimulates lactotrophs, and can cause pituitary hyperplasia mimicking an adenoma. Both reverse with thyroxine - do not operate
CKD (dec clearance), cirrhosis, PCOS, seizures
Acromegaly - ~25% of GH adenomas co-secrete prolactin
MEN1, AIP mutation (young, aggressive, macro)

Confirm it is real

Repeat the level - a single stressed/venepuncture-related sample is not enough
Macroprolactin - prolactin-IgG complex, biologically inert; asymptomatic hyperprolactinaemia -> ask the lab to screen for it before imaging
Hook effect - very high prolactin saturates the immunoassay -> falsely low or normal result
- Suspect with any large tumour and unimpressive prolactin - request a 1:100 dilution

Exclude the reversible causes before imaging

beta-hCG, TSH and fT4, UEC, LFT, drug history
Then FSH/LH + oestradiol (women) or testosterone (men), IGF-1, full pituitary panel

Imaging and staging

Interpreting the level

When to treat

Macroadenoma - always (growth and mass-effect risk)
Microadenoma only if symptomatic: infertility, bothersome galactorrhoea, oligo/amenorrhoea, hypogonadism/low BMD, gynaecomastia, hirsutism/acne, or documented growth
*Asymptomatic microprolactinoma with normal menses can simply be observed* - most never grow

Drug-induced

Stop or switch the drug if clinically possible (aripiprazole if antipsychotic needed)
If not - do not start a dopamine agonist in a psychotic patient; treat the hypogonadism with sex steroid replacement instead

Prolactinoma - medical first line

Cabergoline is the agent of choice - longer half-life, twice-weekly, more effective and better tolerated than bromocriptine
- Normalises prolactin in ~85-90% and shrinks macroadenomas in ~80%
- Start 0.25-0.5 mg weekly, titrate to prolactin
Bromocriptine - retained where fertility/pregnancy is the goal (longest safety record)
Side effects: nausea, postural hypotension, headache, nasal congestion, impulse control disorders (gambling, hypersexuality) - ask directly, and warn the partner
- Rare: psychosis, CSF rhinorrhoea as a large invasive tumour shrinks away from the skull base
Cardiac valvulopathy: echocardiography not required below 2 mg/week; if above 2 mg/week, echo every 2-3 years
Withdrawal after >=2 years if prolactin normal, no residual tumour or marked shrinkage - ~30-50% sustain remission; monitor prolactin for years

Surgery - a legitimate alternative, not only a rescue

2023 Pituitary Society consensus: selective trans-sphenoidal surgery is a reasonable primary option for a microprolactinoma or well-circumscribed macroadenoma in expert hands, particularly in young women who wish to avoid decades of therapy
Established indications
- Dopamine-agonist resistance (no normalisation at maximal tolerated dose) or intolerance
- Tumour growth on treatment; apoplexy
- Persistent chiasmal compression despite medical therapy; cystic tumour unresponsive to drug
- CSF leak on dopamine agonist
- Pre-pregnancy debulking of a macroadenoma abutting the chiasm

Refractory disease

Higher-dose cabergoline -> surgery -> radiotherapy -> temozolomide for aggressive/malignant prolactinoma

Pregnancy

Stop the dopamine agonist once pregnancy confirmed for a microadenoma
Do not monitor prolactin in pregnancy - physiologically raised, uninterpretable
Macroadenoma: visual fields each trimester; restart bromocriptine if symptomatic growth
Symptomatic enlargement in pregnancy: ~2-3% of micro, ~20-30% of untreated macroadenomas

MEN1 - prolactinoma + primary hyperparathyroidism + pancreatic NET
AIP mutation - familial isolated pituitary adenoma, young and aggressive
Acromegaly (co-secretion), Cushing disease
Primary hypothyroidism, PCOS, CKD
Antipsychotic therapy - a major cause of osteoporosis and sexual dysfunction in that population
Chest wall trauma, herpes zoster, spinal cord lesions

Most microprolactinomas never progress to macroadenoma
Untreated: infertility, and in amenorrhoeic women oestrogen deficiency -> low BMD and fracture
- Bone density is preserved in hyperprolactinaemic women who keep menstruating - the oestrogen loss, not the prolactin, is what damages bone
Macroadenoma untreated -> progressive field loss, hypopituitarism from mass effect alone
Response to cabergoline is usually rapid: fields improve within days-weeks, menses return within months
Malignant prolactinoma (CSF/systemic metastases) is exceedingly rare
Excess mortality is low with treatment; morbidity is fertility, bone and vision

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