Hyperprolactinaemia is the excessive secretion of prolactin from the anterior pituitary, commonly caused by prolactinomas, medications, or hypothalamic-pituitary stalk disruption, leading to galactorrhoea, menstrual irregularities, and hypogonadism.

Exam domain	One-glance essentials
Definition / diagnosis	Sustained serum prolactin elevation; local teaching uses > 500 mU/L ^[1]^[2] Prolactin is uniquely under *tonic hypothalamic dopamine inhibition via D2 receptors* ^[1]
Epidemiology / risks	Physiological: pregnancy/lactation; drugs: antipsychotics, metoclopramide and domperidone ^[2]^[3] Pituitary prolactinoma or stalk compression; systemic causes include primary hypothyroidism and CKD ^[2]
Core mechanism	Reduced dopamine delivery or D2 blockade disinhibits lactotrophs → raised prolactin ^[1]^[3] Raised prolactin suppresses GnRH → hypogonadotrophic hypogonadism
Clinical picture	Amenorrhoea/oligomenorrhoea, infertility, galactorrhoea, reduced libido or erectile dysfunction ^[2] Macroadenoma: headache, bitemporal hemianopia and other pituitary deficits ^[1]
Investigations	*Exclude pregnancy first*; repeat a mild elevation under rested conditions and check macroprolactin ^[2]^[4] Review drugs; check TFT, renal/liver function and all pituitary axes; then contrast MRI ^[2]^[4] Correlate prolactin level with tumour size ^[1]
Management	Treat the cause; cabergoline is first-line for prolactinoma and usually lowers prolactin and shrinks tumour ^[2] Surgery for dopamine-agonist resistance/intolerance, apoplexy or failure of tumour shrinkage ^[2]^[5]
Complications	Chronic hypogonadism → infertility, sexual dysfunction and osteoporosis ^[2] Mass effect, hypopituitarism and pituitary apoplexy are tumour complications ^[5]
Prevention / follow-up	Monitor prolactin, tumour response, visual fields and other pituitary axes ^[1]^[2] Counsel that fertility may return rapidly with dopamine-agonist therapy; protect bone health in prolonged hypogonadism ^[2]
Exam traps	Large mass + modest prolactin → stalk effect, not necessarily prolactinoma ^[1] Giant mass + unexpectedly low prolactin → request dilution for the hook effect ^[2] *Sheehan syndrome causes prolactin deficiency, not hyperprolactinaemia* ^[6]

References

^[1] Lecture slides: GC 067. I keep on bumping into people on my side.pdf ^[2] Senior notes: Maksim Medicine Notes.pdf, p107–108 ^[3] Senior notes: Ryan Ho Psychiatry.pdf, p46 ^[4] Senior notes: Block A - Introduction to Endocrine investigations.pdf, p1, p3–4, p9 ^[5] Senior notes: Ryan Ho Neurology.pdf, p166 ^[6] Past papers: 2023 Fourth Summative MCQ.pdf, p15, Question 38

Hyperprolactinaemia

Hyperprolactinaemia refers to a sustained elevation of serum prolactin above the upper limit of normal (typically > 500 mU/L by most Hong Kong laboratory assays, or roughly > 25 µg/L in international units) ^[1]^[2]. It is the most common hypothalamic-pituitary hormonal disorder encountered in clinical endocrinology.

Breaking the word down:

"Hyper" = excess
"Prolactin" = the anterior pituitary hormone whose primary function is to promote lactation (Latin pro- = for, lac = milk)
"-aemia" = in the blood

So the name literally tells you: too much prolactin in the blood.

Prevalence: Hyperprolactinaemia is common — found in up to ~0.4% of the general population, but much higher in selected groups:
- ~9–17% of women with reproductive disorders (amenorrhoea, infertility)
- ~25–30% of patients on typical antipsychotics
Sex distribution: Clinical presentation is far more common in women of reproductive age because menstrual disturbance and galactorrhoea prompt earlier investigation; men often present late with macroadenomas or hypogonadal symptoms.
Age: Prolactinomas peak in women aged 20–50 years; in men, presentation is typically later (40–60 years) because symptoms are more insidious.

Risk factors for hyperprolactinaemia:

Female sex (oestrogen stimulates lactotroph proliferation — this is why the pituitary doubles in size during pregnancy)
Use of dopamine-antagonist drugs (antipsychotics, anti-emetics)
Pregnancy and lactation (physiological)
Hypothyroidism, CKD, liver cirrhosis
Pituitary/hypothalamic pathology

3. Anatomy & Physiology of Prolactin Regulation

Understanding the pathophysiology of hyperprolactinaemia requires a solid grasp of how prolactin secretion is controlled. This is unique among anterior pituitary hormones because prolactin is predominantly under tonic inhibitory control by dopamine.

Key Points:

Dopamine is the predominant inhibitor of prolactin secretion ^[1]^[2]^[3].
- Dopamine is produced by tuberoinfundibular neurons in the arcuate nucleus of the hypothalamus.
- It travels down the pituitary stalk (infundibulum) via the hypothalamic-hypophyseal portal system to reach lactotroph cells.
- Dopamine binds D2 receptors on lactotrophs → inhibits prolactin gene transcription + inhibits prolactin release + inhibits lactotroph cell proliferation.
Stimulatory factors:
- TRH (thyrotropin-releasing hormone) — this is why primary hypothyroidism causes hyperprolactinaemia: the compensatory rise in TRH stimulates both TSH and prolactin ^[1]^[2]^[3].
- VIP (vasoactive intestinal peptide)
- Oestrogen — stimulates lactotroph proliferation and prolactin gene transcription (explains physiological hyperprolactinaemia in pregnancy and why prolactinomas are more common in women)
- Suckling reflex — afferent nerve impulses from the nipple travel via intercostal nerves → spinal cord → hypothalamus → suppress dopamine → increase prolactin (this is the "suckling pathway")
Short-loop negative feedback: Prolactin itself feeds back to the hypothalamus to stimulate dopamine release, thus creating an auto-regulatory loop.

Why Dopamine is King

Unlike other anterior pituitary hormones that require hypothalamic releasing hormones to be secreted, prolactin will be constitutively secreted if the pituitary stalk is severed or if the hypothalamic signal is interrupted. This is because the predominant hypothalamic signal is inhibitory (dopamine). Stalk damage → loss of dopamine delivery → hyperprolactinaemia. This concept is called "disconnection hyperprolactinaemia" or "stalk effect" ^[1]^[2]^[3].

Target	Action	Clinical Relevance
Breast	Stimulates milk production (lactogenesis)	Galactorrhoea when excess
GnRH neurons	Inhibits GnRH pulsatile secretion	Hypogonadotrophic hypogonadism
Gonads	Directly inhibits gonadal steroidogenesis	Contributes to hypogonadism
Immune system	Immunomodulatory	Less clinically relevant
Bone	Indirectly via hypogonadism → ↓BMD	Osteoporosis risk

High Yield: The most important clinical consequence of hyperprolactinaemia is hypogonadotrophic hypogonadism due to inhibition of GnRH secretion ^[2]^[3]. This drives the majority of symptoms in both sexes.

4. Aetiology

This is a favourite SAQ topic ^[2]. A systematic approach divides causes into physiological, pharmacological, pathological, and others.

Cause	Mechanism
Pregnancy	High oestrogen → lactotroph hyperplasia → ↑prolactin (levels can reach 6,000–10,000 mU/L at term)
Lactation / nipple stimulation	Suckling reflex → suppression of dopamine via neural pathway
Stress (physical, emotional, exercise, seizures)	Stress → ↑serotonin, ↑VIP → ↑prolactin
Sleep	Prolactin has diurnal variation; peaks during sleep
Coitus	Transient rise
Chest wall stimulation / irritation (including herpes zoster of chest wall) ^[2]^[3]	Irritation of intercostal nerves mimics the suckling pathway afferents → ↓dopamine → ↑prolactin

Chest Wall Stimulation

Herpes zoster (shingles) affecting the chest wall can cause hyperprolactinaemia by stimulating intercostal nerve afferents that are part of the suckling reflex arc ^[2]^[3]. This is a classic exam favourite!

Drug-induced hyperprolactinaemia is the most common cause of non-physiological hyperprolactinaemia ^[1]^[2]^[3].

Drug Class	Examples	Mechanism
Dopamine (D2) receptor antagonists	Antipsychotics (haloperidol, risperidone, olanzapine); Antiemetics (metoclopramide, domperidone)	Block D2 receptors on lactotrophs → loss of dopamine inhibition
Dopamine-depleting drugs	Methyldopa, reserpine	Deplete presynaptic dopamine stores
Oestrogen-containing preparations	OCP, HRT	Mimic pregnancy state → stimulate lactotrophs
H2 receptor blockers	Cimetidine, ranitidine	Uncertain; may alter dopamine turnover
Verapamil	—	Mechanism unknown ^[3]; possibly inhibits dopamine release
Opioids	Morphine, methadone	Stimulate prolactin release via µ-opioid receptors
SSRIs / TCAs	Fluoxetine, amitriptyline	Serotonin stimulates prolactin release

Drug-Induced Hyperprolactinaemia — Exam Pearls

Risperidone is the antipsychotic most commonly associated with hyperprolactinaemia (it is a potent D2 blocker).
Metoclopramide and domperidone are very commonly tested as causes ^[2]. Domperidone does not cross the blood-brain barrier well, so it has fewer central side effects, but it does cause peripheral hyperprolactinaemia because the pituitary is outside the blood-brain barrier (it is a circumventricular organ).
Drug-induced prolactin levels are typically 500–5,000 mU/L (rarely > 5,000) ^[2]^[3].

4.3 Pathological Causes

Cause	Detail
Prolactinoma (prolactin-secreting pituitary adenoma)	Most common pituitary adenoma (~40%). Classified as microprolactinoma (< 10 mm) or macroprolactinoma (≥ 10 mm). Prolactin level generally correlates with tumour size ^[1]^[2]^[3].
Non-functioning pituitary adenoma (causing stalk effect)	Large adenoma compresses the pituitary stalk → interrupts dopamine delivery → "disconnection hyperprolactinaemia." Prolactin typically < 5,000 mU/L (unlike true macroprolactinoma where PRL is > 5,000) ^[1]^[2]^[3].
Mixed GH + prolactin-secreting adenoma	GH and prolactin share a common cell lineage (somatotrophs and lactotrophs both derive from Pit-1 lineage); a single adenoma can co-secrete both → concomitant acromegaly ^[2].
Other pituitary tumours	Craniopharyngioma, meningioma, germinoma — cause stalk compression

Stalk Effect vs. Prolactinoma — The Critical Distinction

This is one of the most important clinical distinctions:

A large non-functioning pituitary adenoma compressing the stalk causes hyperprolactinaemia by interrupting dopamine delivery (stalk effect / disconnection hyperprolactinaemia). The prolactin is typically < 5,000 mU/L ^[1]^[2]^[3].
A macroprolactinoma directly secretes prolactin. The prolactin is typically > 5,000 mU/L and often > 10,000 mU/L ^[2]^[3].
Why does this matter? Treatment is completely different. A prolactinoma responds to dopamine agonists; a non-functioning adenoma with stalk effect usually needs surgery.
If you see a large pituitary mass with a mildly elevated prolactin (1,000–4,000 mU/L), do NOT assume it is a prolactinoma — it is likely stalk effect from a non-functioning adenoma ^[1].

Cause	Mechanism
Hypothalamic tumours (craniopharyngioma, glioma, germinoma)	Interrupt dopamine delivery (stalk effect)
Infiltrative disease (sarcoidosis, histiocytosis, haemochromatosis) ^[3]	Damage hypothalamic dopaminergic neurons or stalk
Pituitary stalk damage (radiotherapy, trauma, surgery) ^[2]	Physical disruption of dopamine pathway

Cause	Mechanism
Primary hypothyroidism	↑TRH → stimulates prolactin secretion (TRH is a prolactin-releasing factor) ^[1]^[2]^[3]
Chronic kidney disease (CKD)	↓Dopamine secretion + ↓Prolactin renal clearance ^[3]
Liver cirrhosis	↓Oestrogen metabolism → ↑oestrogen → stimulates lactotrophs ^[2]
PCOS (polycystic ovarian syndrome)	High oestrogen state → stimulates prolactin ^[3]
Idiopathic or familial hyperprolactinaemia	PRLR (prolactin receptor) mutation described in some families ^[3]

High Yield Mnemonic for Causes of Hyperprolactinaemia — "HYPERPROL":

H — Hypothyroidism (primary)

Y — "Y" not physiological? (Pregnancy, lactation, stress, chest wall stimulation)

P — Pituitary tumour (prolactinoma, non-functioning with stalk effect)

E — oEstrogen (OCP, pregnancy)

R — Renal failure (CKD)

P — Pharmacological (antipsychotics, antiemetics, methyldopa)

R — Radiotherapy / stalk damage

O — Other hypothalamic lesions (sarcoidosis, craniopharyngioma)

L — Liver cirrhosis

5. Pathophysiology — How Elevated Prolactin Causes Disease

The pathophysiology of clinical features stems from two main mechanisms:

Excess prolactin stimulates the mammary glands to produce milk → galactorrhoea ^[2]^[3]
Note: Breast development (duct growth) is oestrogen-dependent, NOT prolactin-dependent. Prolactin only drives milk production. This is why galactorrhoea in males is rare unless gynaecomastia (oestrogen-mediated) is already present ^[3].

This is the dominant clinical effect:

Hyperprolactinaemia causes hypogonadotrophic hypogonadism because prolactin inhibits GnRH pulsatile secretion ^[2]^[3]. Additionally, prolactin may directly inhibit gonadal steroidogenesis at the ovary/testis level.

If the hyperprolactinaemia is due to a pituitary tumour, the mass itself can cause:

Bitemporal hemianopia (compression of the optic chiasm — "I keep on bumping into people on my side" ^[1])
Headache (stretching of the dura)
Hypopituitarism (compression of other anterior pituitary cell types)
Cranial nerve palsies (CN III, IV, V1, V2, VI — if tumour extends into the cavernous sinus)
CSF rhinorrhoea (if tumour erodes through the floor of the sella into the sphenoid sinus)

6. Classification

The degree of prolactin elevation helps localise the cause ^[2]^[3]:

Prolactin Level (mU/L)	Likely Cause
< 500	Normal
500 – 1,000	Stress, drugs (mild elevation)
1,000 – 5,000	Drugs, microprolactinoma, disconnection hyperprolactinaemia (stalk effect)
> 5,000	Highly suggestive of macroprolactinoma
> 100,000	Potential for high-dose hook effect → false negative

The High-Dose Hook Effect

When prolactin levels are extremely high (> 100,000 mU/L), the assay can paradoxically report a falsely low/normal result ^[2]^[3]. This is a laboratory artefact:

In a standard two-site immunometric ("sandwich") assay, extremely high analyte saturates both the capture and detection antibodies separately rather than forming the proper "sandwich" → signal is paradoxically low.
Clinical consequence: A patient with a massive macroprolactinoma may have a "mildly elevated" prolactin on standard assay, leading the clinician to wrongly diagnose stalk effect and proceed to surgery (which would be wrong — it's a prolactinoma that should be treated medically).
Solution: If a large pituitary mass is found, always request serial dilution of the sample to unmask the hook effect ^[2]. PWH (Prince of Wales Hospital) assay automatically rules out macroPRL ^[2].

Macroprolactin is a distinct concept from macroprolactinoma ^[3]:

Macroprolactin = prolactin bound to IgG antibody → forms a large molecular weight complex
Cannot cross blood vessel walls → NOT physiologically active ^[3]
May cause interference in prolactin assays → falsely elevated measured prolactin
Clinical significance: A patient with "macroprolactinaemia" (high measured prolactin due to macroprolactin) is asymptomatic and requires no treatment
Solution: Use assays that are known not to cross-react ^[3], or request PEG (polyethylene glycol) precipitation to remove macroprolactin before measurement

Type	Size	Notes
Microprolactinoma	< 10 mm	More common in women; PRL usually 1,000–5,000 mU/L
Macroprolactinoma	≥ 10 mm	More common in men (late presentation); PRL usually > 5,000 mU/L
Giant prolactinoma	> 40 mm	Rare; PRL can be > 100,000 mU/L

7. Clinical Features

7.1 Symptoms

In Females ^[2]^[3]:

Symptom	Pathophysiological Basis
Amenorrhoea (secondary)	↑Prolactin → ↓GnRH → ↓LH/FSH → ↓oestrogen → no endometrial cycling
Oligomenorrhoea	Partial suppression of GnRH pulsatility
Infertility	Anovulation due to hypogonadotrophic hypogonadism
Galactorrhoea	Direct prolactin effect on mammary glands → stimulates milk production in a primed breast
Climacteric symptoms (hot flushes, vaginal dryness, night sweats)	Oestrogen deficiency from hypogonadism mimics menopause ^[2]^[3]
↓ Bone mineral density (BMD) / risk of osteoporosis	Oestrogen deficiency → ↑osteoclast activity → bone resorption ^[2]
Decreased libido	Oestrogen deficiency

In Males ^[2]^[3]:

Symptom	Pathophysiological Basis
↓ Libido	↓Testosterone from hypogonadotrophic hypogonadism
Erectile dysfunction	↓Testosterone + possible direct prolactin effect on erectile physiology
↓ Shaving frequency	↓Testosterone → ↓androgen-dependent hair growth ^[2]^[3]
Infertility	↓FSH → impaired spermatogenesis; ↓LH → ↓testosterone
Lethargy	↓Testosterone; generalised hypogonadal state ^[3]
Galactorrhoea	Rarely occurs in males unless gynaecomastia is already present (because breast tissue must be primed by oestrogen first before prolactin can stimulate milk production) ^[3]
Gynaecomastia	Not directly due to prolactin; may occur if oestrogen:androgen ratio changes
↓ BMD	Same mechanism — testosterone deficiency → bone loss

Sex Differences in Presentation

Women present early with menstrual disturbance and galactorrhoea → more likely to have microprolactinomas at diagnosis. Men present late with mass effects (visual field defects, headache) + hypogonadal symptoms → more likely to have macroprolactinomas at diagnosis. This is not because men get bigger tumours biologically — it's because their symptoms are more insidious and tolerated for longer.

Symptom	Pathophysiological Basis
"I keep on bumping into people on my side" — peripheral vision loss ^[1]	Suprasellar extension compresses the optic chiasm → bitemporal hemianopia (nasal retinal fibres cross at the chiasm; these carry temporal visual field information)
Headache	Dural stretching by expanding tumour within the sella turcica
Diplopia	Lateral extension into cavernous sinus → CN III, IV, VI compression
Facial numbness/pain	CN V1, V2 compression in cavernous sinus
Symptoms of hypopituitarism	Compression of normal pituitary tissue → ↓other hormones (ACTH → adrenal insufficiency; TSH → hypothyroidism; GH → GH deficiency; LH/FSH → further hypogonadism)
CSF rhinorrhoea	Erosion of sella floor into sphenoid sinus
Concomitant acromegaly symptoms (coarsening of features, enlarged hands/feet, sweating) ^[2]	GH and prolactin share common cell lineage (Pit-1 lineage) → mixed GH/PRL-secreting adenoma

Hypothyroid symptoms (if primary hypothyroidism → ↑TRH)
Drug history (psychiatric medications, antiemetics)
Uraemic symptoms (if CKD)
Stigmata of chronic liver disease (if cirrhosis)

7.2 Signs

Sign	Pathophysiological Basis
Galactorrhoea (expressible milky nipple discharge on examination)	Direct prolactin stimulation of mammary glands
Signs of hypogonadism in males: testicular atrophy, sparse body/facial hair, soft testes, gynaecomastia	↓Testosterone from hypogonadotrophic hypogonadism
Signs of hypogonadism in females: vaginal atrophy, ↓breast fullness	↓Oestrogen
↓BMD on DEXA scan (if chronic)	Chronic oestrogen/testosterone deficiency → accelerated bone loss ^[2]

Sign	Pathophysiological Basis
Bitemporal hemianopia on visual field testing (confrontation or formal perimetry)	Optic chiasm compression by suprasellar tumour extension ^[1]
↓Visual acuity	Direct optic nerve compression
Optic disc pallor/atrophy (on fundoscopy)	Chronic optic nerve compression
CN III palsy (ptosis, "down and out" eye, dilated pupil)	Cavernous sinus invasion
Other CN palsies (IV, VI → diplopia; V → facial sensory loss)	Cavernous sinus invasion

Sign	Hormone Affected
Pale, smooth skin; loss of axillary/pubic hair	ACTH deficiency (secondary adrenal insufficiency) — note: no hyperpigmentation unlike primary (Addison's)
Postural hypotension	Cortisol deficiency
Myxoedematous features (dry skin, bradycardia)	TSH deficiency → secondary hypothyroidism
Short stature (children)	GH deficiency
Features of acromegaly (prognathism, frontal bossing, spade-like hands, macroglossia)	Co-secretion of GH from a mixed adenoma ^[2]

Sign	Condition
Goitre, bradycardia, dry skin, delayed relaxation of ankle jerks	Primary hypothyroidism
Cushingoid features (if on steroids for another condition)	—
Stigmata of chronic liver disease (spider naevi, palmar erythema, jaundice)	Liver cirrhosis
Arteriovenous fistula, uraemic frost	CKD
Vesicular rash in dermatomal distribution on chest wall	Herpes zoster

8. Important Concepts & Special Situations

Any process that interrupts the hypothalamic-pituitary stalk will remove dopaminergic inhibition and cause hyperprolactinaemia ^[1]^[2]^[3]. Causes include:

Non-functioning pituitary macroadenoma (most common cause of stalk effect)
Craniopharyngioma
Radiotherapy ^[2]
Trauma, surgery ^[2]
Infiltrative disease (sarcoidosis, Langerhans cell histiocytosis)

Key distinguishing feature: Prolactin in stalk effect is usually < 5,000 mU/L (often 1,000–3,000 mU/L) ^[1]^[2]^[3].

Oestrogen during pregnancy stimulates lactotroph hyperplasia → a microprolactinoma may enlarge
Macroprolactinomas have a higher risk of significant enlargement during pregnancy (up to 30%) vs. microprolactinomas (< 5%)
Bromocriptine is the preferred dopamine agonist in pregnancy (longer safety track record) ^[2]
Cabergoline has increasing safety data but bromocriptine remains the standard recommendation for pregnancy planning in HK practice

A brief but important clinical pearl from rheumatology teaching: hyperprolactinaemia treated with bromocriptine is "not good for Raynaud's" ^[4] — bromocriptine (an ergot derivative) can cause vasoconstriction and worsen Raynaud's phenomenon. Cabergoline (also an ergot derivative but with different receptor profile) may be better tolerated, though all ergot-derived dopamine agonists carry some risk.

Lithium (used in bipolar disorder) has multiple endocrine side effects ^[5]:

Hypothyroidism (most common)
Hyperthyroidism
Hyperparathyroidism / Hypercalcaemia
Nephrogenic diabetes insipidus

While lithium itself is not a classic cause of hyperprolactinaemia, the hypothyroidism it induces can cause secondary hyperprolactinaemia via ↑TRH.

Pathophysiological Mechanism	Clinical Features
↑Prolactin → direct mammary stimulation	Galactorrhoea
↑Prolactin → ↓GnRH → ↓LH/FSH → ↓oestrogen/testosterone	Amenorrhoea, oligomenorrhoea, infertility, ↓libido, ED, ↓shaving frequency, climacteric symptoms, ↓BMD
Tumour mass → optic chiasm compression	Bitemporal hemianopia
Tumour mass → dural stretching	Headache
Tumour mass → cavernous sinus invasion	CN palsies (III, IV, V, VI)
Tumour mass → compression of normal pituitary	Hypopituitarism (secondary adrenal insufficiency, hypothyroidism, GH deficiency)
Pit-1 lineage shared → co-secreting adenoma	Concomitant acromegaly
↑TRH (primary hypothyroidism)	↑Prolactin (secondary cause)
Stalk damage → loss of dopaminergic inhibition	Disconnection hyperprolactinaemia
Drugs blocking D2 receptor	Drug-induced hyperprolactinaemia

High Yield Summary

Definition: Sustained elevation of serum prolactin (> 500 mU/L).

Key Physiology: Prolactin is uniquely under tonic dopaminergic inhibition via D2 receptors on lactotrophs. TRH and oestrogen are stimulatory.

Aetiology (SAQ favourite):

Physiological: Pregnancy, lactation, stress, chest wall stimulation (herpes zoster!), sleep
Pharmacological: D2 antagonists (antipsychotics, metoclopramide, domperidone), dopamine-depleting (methyldopa), oestrogens, verapamil, H2 blockers
Pituitary: Prolactinoma (micro < 10 mm, macro ≥ 10 mm), non-functioning adenoma (stalk effect), mixed GH/PRL adenoma
Hypothalamic/Stalk: Craniopharyngioma, radiotherapy, trauma, infiltrative disease (sarcoidosis)
Systemic: Primary hypothyroidism (↑TRH), CKD (↓dopamine, ↓clearance), liver cirrhosis, PCOS

Prolactin Levels and Causes:

< 500: Normal
500–1,000: Stress, drugs
1,000–5,000: Drugs, microprolactinoma, stalk effect
5,000: Macroprolactinoma
100,000: Hook effect risk (false negative!)

Clinical Features:

Hypogonadotrophic hypogonadism (amenorrhoea, ↓libido, ED, infertility, ↓BMD, climacteric symptoms)
Galactorrhoea (more common in females)
Mass effects (bitemporal hemianopia, headache, CN palsies, hypopituitarism)
Concomitant acromegaly (shared Pit-1 lineage)

Critical Distinction: Stalk effect (PRL < 5,000, large non-functioning adenoma) vs. macroprolactinoma (PRL > 5,000) → completely different management!

Macroprolactin: PRL-IgG complex, NOT physiologically active, can cause assay interference → PEG precipitation to exclude.

Active Recall - Hyperprolactinaemia (Definition, Aetiology, Pathophysiology, Clinical Features)

^[1] Lecture slides: GC 067. I keep on bumping into people on my side.pdf ^[2] Senior notes: Maksim Medicine Notes.pdf (Endocrinology section, p107) ^[3] Senior notes: Ryan Ho Endocrine.pdf (Section 5.2.2, p110) ^[4] Senior notes: Block A - Syncope and irregular heartbeat_ Cardiac arrhythmia; Heart blocks, Bradycardia.pdf (p29 — lupus/Raynaud's pearl) ^[5] Senior notes: Block A - Drugs and the Kidney.pdf (p11 — Lithium endocrine side effects)

Differential Diagnosis of Hyperprolactinaemia

Hyperprolactinaemia is a biochemical finding, not a diagnosis in itself. The clinical challenge is to determine why prolactin is elevated, because management differs radically depending on the cause. A prolactinoma is treated medically with dopamine agonists; a non-functioning adenoma causing stalk effect requires surgery; drug-induced hyperprolactinaemia may simply need drug substitution; and primary hypothyroidism just needs thyroxine replacement. Getting the DDx wrong can lead to the wrong treatment — potentially catastrophic.

The differential is best organised by first asking: Is this physiological, pharmacological, or pathological? Then within pathological causes, subdivide by anatomical site (hypothalamic, pituitary stalk, pituitary, systemic).

The serum prolactin level itself is a powerful discriminator ^[1]^[2]^[3]:

Prolactin Level (mU/L)	Differential Considerations
< 500	Normal
500 – 1,000	Stress, drugs, macroprolactinaemia (macroprolactin artefact)
1,000 – 5,000	Drugs, microprolactinoma, stalk effect / disconnection hyperprolactinaemia, primary hypothyroidism, CKD
> 5,000	Highly suggestive of macroprolactinoma
> 100,000	Giant prolactinoma (beware high-dose hook effect giving falsely low result)

GC 067 Case — The Stalk Effect Trap

The GC lecture slide presents a classic case ^[6]: A 40-year-old woman with oligomenorrhoea, PRL 1,923 mU/L, a 2.1 cm pituitary tumour with left suprasellar extension encroaching on the optic chiasm. Despite starting bromocriptine (which normalised PRL to 145 mU/L and restored menstruation), MRI showed no tumour shrinkage after 4 months. The final diagnosis was hyperprolactinaemia due to stalk compression by a non-functioning pituitary macroadenoma — NOT a prolactinoma.

Why? The prolactin was only ~1,900 mU/L with a 2.1 cm mass. A true macroprolactinoma of that size would produce PRL > 5,000 mU/L. The lack of tumour shrinkage on dopamine agonist further confirmed it was a non-functioning tumour — dopamine agonists shrink prolactinomas (by inhibiting lactotroph proliferation) but have no effect on non-functioning adenoma tissue. The tumour stained negative for all pituitary hormones on immunohistochemistry after transsphenoidal surgery.

This case is extremely high-yield for in-house exams: always correlate the degree of prolactin elevation with the tumour size.

Cause	Key Distinguishing Features	Mechanism
Pregnancy	Always the first thing to exclude in any woman of reproductive age ^[7]. Positive urine βhCG. PRL can reach 6,000–10,000 mU/L at term.	High oestrogen → lactotroph hyperplasia → ↑PRL
Lactation	History of breastfeeding. PRL elevated but falls over weeks-months if not breastfeeding.	Suckling reflex → ↓dopamine → ↑PRL
Stress (physical, emotional, exercise, seizure, venepuncture)	Always repeat the test if PRL is only mildly elevated ^[7] — a single mildly elevated result could be stress-related.	Stress → ↑serotonin/VIP → ↑PRL
Chest wall stimulation / injury	History of herpes zoster on thoracic dermatomes, chest wall surgery, burns ^[2]^[3]^[6]	Intercostal nerve afferent irritation → mimics suckling pathway → ↓dopamine → ↑PRL
Sleep	Diurnal variation; PRL peaks 2–5 AM. Timing of blood draw matters.	Physiological nocturnal PRL surge
Coitus	Transient. Not clinically significant.	Neuroendocrine reflex

Rule #1: Always Exclude Pregnancy First

A urine pregnancy test must ALWAYS be done to exclude pregnancy as a physiological cause of hyperprolactinaemia in any woman of reproductive age ^[7]. This is emphasised in every guideline and lecture — missing a pregnancy while investigating hyperprolactinaemia is a classic mistake.

Drug-induced hyperprolactinaemia is the most common non-physiological cause ^[2]^[3]^[6]. A thorough drug history is essential before any invasive investigation.

Drug Class	Examples	Mechanism	Typical PRL Level
Dopamine D2 receptor antagonists	Antipsychotics (risperidone, haloperidol, olanzapine, chlorpromazine); Antiemetics (metoclopramide, domperidone) ^[2]^[6]	Block D2 receptors on lactotrophs → removes tonic dopaminergic inhibition	500 – 5,000 mU/L (risperidone can occasionally cause higher)
Dopamine-depleting drugs	Methyldopa, reserpine ^[2]^[6]	Deplete presynaptic dopamine stores → less dopamine available to inhibit PRL	500 – 3,000 mU/L
H2 receptor antagonists	Cimetidine, ranitidine ^[6]	Uncertain; may alter hypothalamic dopamine turnover	Mild elevation
Oestrogen-containing preparations	OCP, HRT ^[6]	Mimic pregnancy → stimulate lactotroph proliferation and PRL gene expression	Mild–moderate
Verapamil	— ^[3]	Mechanism unknown ^[3]; possibly inhibits dopamine release from hypothalamus	Mild–moderate
Opioids	Morphine, methadone	µ-opioid receptor stimulation → ↑PRL via disinhibition of dopaminergic neurons	Mild
SSRIs / TCAs	Fluoxetine, amitriptyline	Serotonin stimulates PRL-releasing pathways	Mild

High Yield: Drug-induced PRL is typically < 5,000 mU/L ^[2]^[3]. If PRL is > 5,000 in a patient on antipsychotics, you cannot simply blame the drug — you must image the pituitary to exclude a macroprolactinoma.

How to distinguish drug-induced from pathological hyperprolactinaemia:

Review timing: did PRL elevation appear after starting the drug?
If safe to do so, withdraw the offending drug for 72 hours (with psychiatric supervision for antipsychotics) and recheck PRL. If PRL normalises → drug-induced.
If withdrawal is unsafe (e.g. unstable schizophrenia), proceed directly to MRI pituitary to exclude a tumour ^[7].

3. Pathological Causes — Pituitary

Feature	Detail
Prevalence	Most common functioning pituitary adenoma (~40% of all pituitary adenomas) ^[1]^[3]
Classification	Microprolactinoma (< 10 mm) vs Macroprolactinoma (≥ 10 mm)
Key principle	PRL level generally correlates with tumour size ^[1]^[2]^[3]
Micro	PRL usually 1,000–5,000 mU/L. More common in premenopausal women (early detection due to amenorrhoea).
Macro	PRL usually > 5,000 mU/L, often > 10,000 mU/L. More common in men (late presentation with mass effects).
Giant	> 40 mm; PRL can exceed 100,000 mU/L (beware hook effect).
Distinguishing from stalk effect	A large mass (> 10 mm) with PRL < 5,000 mU/L is more likely stalk effect from a non-functioning adenoma ^[1]^[2]^[6]. A true macroprolactinoma of that size would produce much higher PRL.
Response to DA	Prolactinomas shrink on dopamine agonists (because DA inhibits lactotroph proliferation); non-functioning adenomas do not shrink ^[6].

Feature	Detail
Mechanism	Large tumour compresses the pituitary stalk → interrupts dopamine delivery from hypothalamus → lactotrophs released from tonic inhibition → modest PRL rise ^[1]^[2]^[3]^[6]
PRL level	Typically < 5,000 mU/L (usually 1,000–3,000) ^[1]^[2]^[6]
Immunohistochemistry	Tumour stains negative for all pituitary hormones (as in the GC case ^[6])
Response to DA	PRL normalises (because DA acts directly on normal lactotrophs), but tumour does NOT shrink ^[6] — this is the key differentiator
Management	Transsphenoidal surgery (not medical therapy) ^[6]

The PRL Level : Tumour Size Mismatch

Always ask yourself: "Does the PRL level match the tumour size?"

A 2 cm tumour with PRL 2,000 → stalk effect (PRL too low for that tumour size)
A 2 cm tumour with PRL 20,000 → macroprolactinoma (PRL matches size)
A 4 cm tumour with PRL 3,000 → either stalk effect OR giant prolactinoma with hook effect → request serial dilution!

GH and prolactin share a common cell lineage (Pit-1 transcription factor lineage) ^[2] — somatotrophs and lactotrophs both derive from Pit-1-expressing progenitors.
A single adenoma can co-secrete both hormones → patient presents with features of both hyperprolactinaemia AND acromegaly ^[2].
Look for: coarsening of facial features, enlarged hands/feet, sweating, prognathism + amenorrhoea/galactorrhoea.
Check IGF-1 as a screen for co-existing GH excess.

Craniopharyngioma, meningioma, germinoma, metastases — any mass in the sellar/suprasellar region can compress the stalk.
PRL elevation is modest (< 5,000 mU/L).

Cause	Mechanism	How to Distinguish
Hypothalamic tumours (craniopharyngioma, glioma, hamartoma) ^[6]	Disrupt dopaminergic neurons or compress stalk	MRI shows hypothalamic/suprasellar mass distinct from pituitary
Infiltrative disease (sarcoidosis, Langerhans cell histiocytosis, haemochromatosis) ^[3]	Granulomatous/infiltrative destruction of hypothalamic DA neurons or stalk	Systemic features (e.g. bilateral hilar lymphadenopathy in sarcoidosis, skin lesions in histiocytosis); biopsy may be needed
Pituitary stalk damage (radiotherapy, trauma, surgery) ^[2]^[6]	Physical disruption of dopamine pathway	History of cranial irradiation, head injury, or prior neurosurgery

Cause	Mechanism	How to Distinguish
Primary hypothyroidism	↑TRH → stimulates PRL secretion ^[2]^[3]^[6]^[7]. TRH acts on lactotrophs via TRH receptors.	TFT shows high TSH, low fT4 ^[7]. PRL normalises with thyroxine replacement — no need for DA agonist. Must exclude hypothyroidism in every case of hyperprolactinaemia ^[7].
Chronic kidney disease (CKD)	↓Dopamine production + ↓renal clearance of PRL ^[3]^[5]^[6]	Elevated creatinine, known CKD history. PRL usually mildly elevated (< 3,000 mU/L).
Liver cirrhosis	↓Hepatic oestrogen metabolism → ↑oestrogen → stimulates lactotrophs ^[2]	Clinical stigmata of CLD, deranged LFT, imaging
PCOS	High oestrogen state → stimulates PRL ^[3]	Hyperandrogenism, oligo-/anovulation, polycystic ovaries on USS

Feature	Detail
What is it?	Macroprolactin = prolactin-IgG immune complex ^[3]^[7]
Physiological activity	Cannot cross blood vessel walls → NOT physiologically active ^[3]
Clinical significance	Patient is asymptomatic despite elevated measured PRL. No treatment required.
How it causes confusion	Many standard immunoassays detect macroprolactin alongside monomeric prolactin → falsely elevated total PRL
How to exclude	PEG (polyethylene glycol) precipitation removes macroprolactin; re-measure PRL in supernatant. PWH assay automatically rules out macroprolactin ^[2]. Use assays known not to cross-react ^[3].
When to suspect	Elevated measured PRL in an asymptomatic patient with no identifiable cause and normal MRI

After excluding all the above, some patients have mildly elevated PRL with no identifiable cause → idiopathic ^[6].
Familial hyperprolactinaemia due to PRLR (prolactin receptor) mutation has been described ^[3] — reduced receptor-mediated clearance.
These patients typically have mild, stable PRL elevation and are asymptomatic or minimally symptomatic.

The GC 067 lecture case ^[6] perfectly illustrates steps 5 → 6 → MRI → PRL:tumour-size mismatch → stalk effect diagnosis → surgery. The patient had normal fT4/TSH, normal short Synacthen test, a 2.1 cm tumour but PRL only 1,923 mU/L → classic stalk compression by a non-functioning adenoma.

Cause	Typical PRL (mU/L)	MRI Pituitary	Response to DA Agonist	Other Clues
Microprolactinoma	1,000–5,000	< 10 mm intrasellar lesion	PRL ↓ + tumour shrinks	Young woman with amenorrhoea
Macroprolactinoma	> 5,000	≥ 10 mm ± suprasellar extension	PRL ↓ + tumour shrinks	Male with visual field defect
Non-functioning adenoma (stalk effect)	< 5,000 (disproportionately low for size)	Large mass (often > 10 mm)	PRL ↓ but tumour does NOT shrink ^[6]	Tumour stains negative for all hormones ^[6]
Drug-induced	500–5,000 (rarely > 5,000)	Normal	PRL ↓ on drug withdrawal	Temporal correlation with drug start
Primary hypothyroidism	500–3,000	Normal	PRL normalises with T4 replacement	High TSH, low fT4
CKD	500–3,000	Normal	Partial response	Elevated creatinine
Macroprolactinaemia	Variable (artefactually elevated)	Normal	Not needed	Asymptomatic; PEG precipitation diagnostic
Giant prolactinoma (hook effect)	Falsely low / normal on standard assay	Very large mass (> 40 mm)	—	Serial dilution unmasks true PRL > 100,000

Galactorrhoea (milky nipple discharge) can occur with or without hyperprolactinaemia:

With hyperprolactinaemia: all the causes above
Without hyperprolactinaemia (normoprolactinaemic galactorrhoea): idiopathic, excessive breast stimulation, chest wall nerve irritation, post-lactation persistence
Non-milky nipple discharge: must consider intraductal papilloma (bloody), breast carcinoma, duct ectasia (greenish) — these are NOT galactorrhoea ^[8]

Since amenorrhoea is a common presenting complaint of hyperprolactinaemia, the DDx of secondary amenorrhoea is relevant:

Pregnancy (always first!)
Hyperprolactinaemia (any cause above)
Hypothalamic amenorrhoea (stress, weight loss, excessive exercise)
PCOS
Premature ovarian insufficiency
Thyroid disease (hypo- or hyperthyroidism)
Asherman syndrome (intrauterine adhesions)
Sheehan syndrome (postpartum pituitary necrosis → hypopituitarism)

High Yield Summary — DDx of Hyperprolactinaemia

Always exclude pregnancy first (urine βhCG) ^[7]
Always repeat the test if mildly elevated (exclude stress) ^[7]
Always exclude macroprolactin (PEG precipitation)
Drug history — most common non-physiological cause ^[2]^[3]^[6]
TFT — must exclude primary hypothyroidism ^[7]
RFT, LFT — exclude CKD, cirrhosis
MRI pituitary if PRL remains elevated after above exclusions
Correlate PRL level with tumour size — the critical step:
- PRL matches size → prolactinoma → DA agonist
- PRL disproportionately low for size → stalk effect → surgery ^[6]
- Very large mass + unexpectedly low PRL → request serial dilution for hook effect
Non-functioning adenoma with stalk effect: PRL normalises on DA agonist but tumour does NOT shrink ^[6]; tumour stains negative for all pituitary hormones ^[6]
Check IGF-1 to exclude co-existing GH excess (mixed adenoma, Pit-1 lineage) ^[2]

Active Recall — Differential Diagnosis of Hyperprolactinaemia

References

^[1] Lecture slides: GC 067. I keep on bumping into people on my side.pdf ^[2] Senior notes: Maksim Medicine Notes.pdf (Endocrinology section, p107) ^[3] Senior notes: Ryan Ho Endocrine.pdf (Section 5.2.2, p110) ^[5] Senior notes: Block A - Chronic Kidney Disease and its Complications.pdf (p13) ^[6] Lecture slides: GC 067. I keep on bumping into people on my side.pdf (p24 — clinical case) ^[7] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p1553 — diagnosis of hyperprolactinaemia) ^[8] Senior notes: Maksim Surgery Notes.pdf (p188–189 — breast tumours, nipple discharge DDx)

Diagnostic Criteria, Algorithm & Investigations for Hyperprolactinaemia

Unlike conditions such as diabetes mellitus or rheumatoid arthritis, hyperprolactinaemia does not have a set of formal consensus diagnostic criteria with point-scoring systems. Instead, the diagnosis is biochemical (elevated serum prolactin above the laboratory upper limit of normal) combined with a systematic investigative algorithm to identify the underlying cause. The real diagnostic challenge is not confirming hyperprolactinaemia itself — it is determining why prolactin is elevated and whether the elevation is clinically significant.

Prolactin levels and their interpretation ^[2]^[3]^[9]:

Serum Prolactin (mU/L)	Interpretation
< 500	Normal
500 – 1,000	Mildly elevated — stress, drugs, macroprolactinaemia (artefact)
> 1,000	Clinically significant — consider prolactinoma, drugs, stalk effect
> 5,000	Highly suggestive of macroprolactinoma
> 100,000	Giant prolactinoma — beware high-dose hook effect (false negative)

Note on units: Hong Kong Hospital Authority (HA) laboratories typically report prolactin in mU/L. Internationally, some centres use µg/L (ng/mL). Approximate conversion: 1 µg/L ≈ 21–25 mU/L (assay-dependent). Normal is roughly < 20–25 µg/L or < 500 mU/L ^[2]^[7].

GC Lecture Slide Key Point

The GC 067 lecture case ^[6] demonstrates the practical interpretation: PRL of 1,923 mU/L with a 2.1 cm pituitary mass. Because a true macroprolactinoma of that size would produce PRL > 5,000 mU/L, this level is disproportionately low → stalk compression by a non-functioning adenoma, NOT a prolactinoma. Always correlate PRL level with tumour size ^[6]^[9].

Principle 1: Sequence of investigations ^[9]:

History and physical examination
Baseline blood tests (CBC, LRFT)
Screening biochemistry tests (serum prolactin, TFT, RFT)
Confirmatory / dynamic tests (if needed — though in hyperprolactinaemia, dynamic tests are rarely needed)
Imaging with MRI (contrast MRI for pituitary — soft tissue differentiation ^[9])
Invasive tests (venous sampling — rarely needed for prolactin)

General principle: less invasive before more invasive ^[9].

Endocrine is unique: biochemistry before imaging ^[9]:

"Resolution is too high with our imaging nowadays — so we might find benign lesions (incidentalomas) which are not related to the condition" ^[9]. This is critical: you must establish biochemical hyperprolactinaemia and exclude common causes (drugs, hypothyroidism, CKD) BEFORE ordering an MRI. Otherwise, you may find an incidental pituitary microadenoma that is completely unrelated to the patient's symptoms.

Principle 2: Timing of blood sampling matters ^[9]:

"Many hormones are released in a diurnal rhythm — crucial to know when to take blood" ^[9]. Prolactin has a diurnal variation (peaks during sleep). Take samples in the morning, fasting, and at rest to avoid false elevations from stress, sleep, or food.

3. Investigation Modalities — Detailed Breakdown

Aspect	Detail
Sample conditions	Fasting, morning, at rest, non-stressed ^[9]. Ideally cannulate 20 minutes before sampling to allow stress of venepuncture to settle.
Normal range	< 500 mU/L (or < 20–25 µg/L) ^[2]
Interpretation	See threshold table above
Pitfalls	(1) Stress of venepuncture can mildly elevate PRL → always repeat if mildly elevated ^[7]. (2) Hook effect in giant prolactinomas → request serial dilution ^[2]^[7]. (3) Macroprolactin interference → request PEG precipitation ^[3]^[7].

High Yield: PWH (Prince of Wales Hospital) assay automatically rules out macroprolactin ^[2]. This is a local HK exam point.

When to Repeat PRL

ALWAYS REPEAT the test if serum prolactin is only mildly elevated since it can increase slightly during sleep, after strenuous exercise, or with physical or emotional stress (e.g. during venepuncture) ^[7]. A single mildly elevated result is NOT diagnostic. Two elevated readings on separate occasions are needed for confidence.

Aspect	Detail
Why	ALWAYS exclude pregnancy as a physiological cause of hyperprolactinaemia in any woman of reproductive age ^[7]
Test	Urine βhCG (rapid dipstick)
Rationale	Pregnancy causes prolactin levels up to 6,000–10,000 mU/L at term due to oestrogen-driven lactotroph hyperplasia. Missing this is a classic and dangerous error.

Aspect	Detail
Why	MUST exclude hypothyroidism as a cause of hyperprolactinaemia ^[7]
Expected findings	High TSH + low fT4 = primary hypothyroidism → ↑TRH stimulates prolactin release
Clinical significance	Treating with thyroxine normalises both TSH and prolactin — no dopamine agonist or pituitary imaging needed
GC case correlation	In the GC 067 case ^[6], fT4 and TSH were normal — hypothyroidism was correctly excluded before proceeding to imaging

From CFB OG04 Menstrual Disorders lecture ^[10]: When investigating secondary amenorrhoea, the hormonal profile should include assessment for hyperprolactinaemia → proceed with MRI pituitary to exclude adenoma and thyroid function.

Test	Why	Expected Finding if Causative
RFT (Creatinine, eGFR)	CKD causes hyperprolactinaemia via ↓dopamine secretion + ↓prolactin clearance ^[3]	Elevated creatinine, low eGFR
LFT	Liver cirrhosis → ↓oestrogen metabolism → ↑oestrogen → lactotroph stimulation	Deranged transaminases, low albumin, prolonged INR

Aspect	Detail
What is macroprolactin?	Prolactin-IgG antibody complex — large molecular weight, cannot cross blood vessel walls → NOT physiologically active ^[3]^[7]
Why it matters	Standard immunoassays may detect macroprolactin → falsely elevated total PRL in an asymptomatic patient → unnecessary investigation and treatment
How to test	PEG (polyethylene glycol) precipitation: PEG precipitates macroprolactin; monomeric prolactin remains in supernatant. Remeasure PRL in supernatant — if now normal, the original elevation was due to macroprolactin.
Local practice	PWH assay automatically rules out macroprolactin ^[2]. At other HA centres, PEG precipitation should be specifically requested if clinical suspicion arises.
When to suspect	Elevated measured PRL in an asymptomatic patient with no identifiable cause and normal MRI

Aspect	Detail
Modality	Contrast MRI is the imaging modality of choice for pituitary lesions ^[9] — superior soft tissue differentiation compared to CT
Indications for MRI ^[2]	Symptomatic hyperprolactinaemia / PRL > 1,000 mU/L / Evidence of pituitary insufficiency (e.g. low fT4)
Protocol	Dedicated pituitary protocol: thin-cut (2–3 mm) coronal and sagittal T1-weighted images, pre- and post-gadolinium contrast ^[9]. Dynamic contrast sequences help identify microadenomas (they enhance later than normal pituitary tissue).
Key findings
— Microadenoma	< 10 mm hypointense lesion within pituitary on post-contrast T1 (delayed enhancement relative to normal gland)
— Macroadenoma	≥ 10 mm mass ± suprasellar extension (encroaching on optic chiasm) ± cavernous sinus invasion ± infrasellar erosion
— Stalk deviation	The pituitary stalk may deviate away from a microadenoma, or be compressed by a macroadenoma
— Loss of posterior pituitary bright spot	Normal posterior pituitary appears as a "bright spot" on T1 (stored vasopressin in neurosecretory granules). Loss of bright spot suggests posterior pituitary dysfunction (e.g. stalk damage, infiltrative disease) ^[11]
— "Empty sella"	If the sella is partially empty with flattened pituitary tissue — may indicate previous pituitary apoplexy or idiopathic intracranial hypertension

Biochemistry Before Imaging

In endocrine investigation, always establish the biochemical diagnosis before imaging ^[9]. Pituitary incidentalomas are found in up to 10–20% of MRI scans performed for other reasons. If you image before confirming biochemical hyperprolactinaemia and excluding drug/systemic causes, you may attribute symptoms to an irrelevant incidental finding.

Once a pituitary mass is identified, or if there is any evidence of pituitary insufficiency, all anterior pituitary axes must be evaluated ^[2]^[11]:

Axis	Screening Test	What You Are Looking For
GH axis	Serum IGF-1 ^[2]	Elevated IGF-1 → co-secreting GH/PRL adenoma (Pit-1 lineage) ^[2]. Low IGF-1 → GH deficiency from mass compression.
ACTH/Cortisol axis	9 AM cortisol ^[2]; Short Synacthen test (SST) if cortisol equivocal ^[6]	Low morning cortisol or subnormal SST response → secondary adrenal insufficiency. The GC case ^[6] performed a 1g Short Synacthen test.
TSH/Thyroid axis	TSH and fT4 ^[2]	Low fT4 with low/normal TSH → secondary hypothyroidism (pituitary cause). High TSH + low fT4 → primary hypothyroidism (systemic cause of hyperprolactinaemia).
LH/FSH/Sex hormones	LH, FSH, oestradiol (F) or testosterone (M) ^[2]	Low LH/FSH with low E2/T → hypogonadotrophic hypogonadism (confirms prolactin is suppressing GnRH). High FSH/LH with low E2 → ovarian insufficiency (different mechanism) ^[10].
Posterior pituitary	Serum and urine osmolality; water deprivation test if DI suspected	Post-operative diabetes insipidus is a recognised complication of TSS ^[6] — the GC case required oral DDAVP post-operatively.

GC 067 Case Post-Operative Findings ^[6]: After transsphenoidal surgery, the patient developed diabetes insipidus and insulin tolerance test (ITT) showed subnormal peak cortisol and GH → required oral DDAVP and hydrocortisone 10 mg OM. This demonstrates the importance of post-operative pituitary axis reassessment.

Aspect	Detail
What is it?	The gold standard dynamic test for assessing the GH and ACTH/cortisol axes simultaneously
How it works	IV insulin → hypoglycaemia (glucose < 2.2 mmol/L) → physiological stress → should stimulate ACTH → cortisol release AND GH release. If peak cortisol or GH are subnormal, the axis is deficient.
When used	Post-operatively after pituitary surgery to assess residual pituitary function ^[6]; pre-operatively if hypopituitarism suspected
Contraindications	Epilepsy, ischaemic heart disease, adrenal insufficiency (dangerous hypoglycaemia)
GC case ^[6]	ITT showed subnormal peak cortisol and GH → confirmed secondary adrenal insufficiency and GH deficiency post-surgery

Aspect	Detail
Why	Any macroadenoma with suprasellar extension risks compressing the optic chiasm → bitemporal hemianopia
Method	Formal automated perimetry (e.g. Humphrey visual field test) — more sensitive than bedside confrontation testing
When	All patients with pituitary macroadenoma or any tumour with suprasellar extension. Also as baseline before starting treatment and for monitoring response (visual fields should improve if tumour shrinks on DA agonist or after surgery).
GC case	Visual field was normal in the GC 067 case ^[6], despite left suprasellar extension encroaching on the optic chiasm — this means the chiasm was not yet significantly compressed (early detection).

Aspect	Detail
Why	Chronic hypogonadism from hyperprolactinaemia → oestrogen/testosterone deficiency → ↓BMD → osteoporosis risk ^[2]
When	Consider in patients with prolonged hyperprolactinaemia, especially if hypogonadal for > 1 year
Sites	Lumbar spine (L1–L4) and femoral neck

4. Diagnosing the Underlying Cause — Specific Patterns

The diagnosis of a prolactinoma is essentially clinical and biochemical, NOT histological ^[9]:

Step	Finding
Screening	Serum prolactin usually > 10× upper limit of normal ^[9] (i.e. > 5,000 mU/L for macroprolactinoma)
MRI	Pituitary adenoma visible
Confirmation	Tumour shrinkage by > 50% when treated with dopamine agonists — seen in ~90% of prolactinomas ^[9]. "The diagnosis is effectively by treating it and seeing a response" ^[9].
PRL 3–10× ULN with mass	Could be prolactin-producing tumour OR stalk compression → need to trial DA agonist and monitor for tumour shrinkage ^[9]

Diagnosing Prolactinoma — A Therapeutic Diagnosis

A prolactinoma is one of the few tumours where the diagnosis is confirmed by response to treatment ^[9]. If PRL normalises AND the tumour shrinks on DA agonist, it is a prolactinoma. If PRL normalises but the tumour does NOT shrink (as in the GC 067 case ^[6]), it is stalk effect from a non-functioning adenoma.

Feature	Finding
PRL	< 5,000 mU/L (disproportionately low for tumour size) ^[6]
MRI	Large pituitary mass
DA agonist trial	PRL normalises but tumour does NOT shrink ^[6]
Immunohistochemistry (post-surgery)	Tumour stains negative for all pituitary hormones ^[6]

Feature	Finding
PRL	500–5,000 mU/L (rarely exceeds 5,000)
Drug history	Temporal correlation with drug initiation
Drug withdrawal test	PRL normalises within 72 hours of stopping offending drug (if safe)
MRI	Normal (if performed)

Feature	Finding
TFT	High TSH + low fT4
PRL	Mildly elevated (500–3,000 mU/L)
Response to thyroxine	PRL normalises with adequate T4 replacement

Investigation	Purpose	Key Findings / Interpretation
Serum prolactin	Confirm diagnosis + guide aetiology	< 500 normal; 500–1000 stress/drugs; > 1000 investigate; > 5000 macroprolactinoma; > 100,000 hook effect risk
Urine βhCG	Exclude pregnancy	Positive → physiological cause
PEG precipitation	Exclude macroprolactinaemia	If post-PEG PRL normal → macroprolactin artefact
TFT	Exclude primary hypothyroidism	High TSH + low fT4 → treat with thyroxine
RFT	Exclude CKD	Elevated creatinine / low eGFR
LFT	Exclude liver cirrhosis	Deranged LFT pattern
Serial dilution	Unmask hook effect	If diluted sample shows much higher PRL → giant prolactinoma
MRI pituitary (contrast)	Identify pituitary/hypothalamic mass	Micro vs macro adenoma; suprasellar extension; stalk compression
IGF-1	Screen for GH co-secretion	Elevated → mixed GH/PRL adenoma
9 AM cortisol / SST / ITT	Assess ACTH-cortisol axis	Low → secondary adrenal insufficiency
LH, FSH, E2/testosterone	Confirm hypogonadotrophic hypogonadism	Low LH/FSH + low sex hormones → PRL-mediated GnRH suppression
Visual field perimetry	Detect optic chiasm compression	Bitemporal hemianopia
DEXA scan	Assess bone mineral density	Low BMD / osteoporosis from chronic hypogonadism

High Yield Summary — Diagnostics of Hyperprolactinaemia

Diagnostic Approach — The 7 Steps:

Urine pregnancy test — always first in reproductive-age women ^[7]
Serum prolactin — fasting, morning, rested; repeat if mildly elevated ^[7]^[9]
Exclude macroprolactin — PEG precipitation (PWH auto-excludes) ^[2]
Drug history — most common non-physiological cause
TFT, RFT, LFT — exclude hypothyroidism, CKD, cirrhosis ^[7]
MRI pituitary (contrast) — only after biochemical workup ^[9]; indicated if PRL > 1,000, symptomatic, or evidence of pituitary insufficiency ^[2]
Screen all pituitary axes — IGF-1, ACTH/cortisol, TSH/fT4, LH/FSH/sex hormones ^[2]

Key Principles:

Biochemistry before imaging ^[9]
Correlate PRL level with tumour size ^[6]^[9]
Prolactinoma diagnosis is a therapeutic diagnosis — confirmed by tumour shrinkage on DA agonist ^[9]
Stalk effect: PRL < 5,000 with large mass; PRL normalises on DA but tumour does NOT shrink ^[6]
Hook effect: Very large mass + unexpectedly low PRL → serial dilution ^[2]^[7]
Post-surgical assessment: Re-evaluate all axes; watch for DI and cortisol/GH deficiency ^[6]

Active Recall — Diagnosis and Investigation of Hyperprolactinaemia

References

^[2] Senior notes: Maksim Medicine Notes.pdf (Endocrinology section, p107) ^[3] Senior notes: Ryan Ho Endocrine.pdf (Section 5.2.2, p110) ^[6] Lecture slides: GC 067. I keep on bumping into people on my side.pdf (p24 — clinical case) ^[7] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p1553 — diagnosis of hyperprolactinaemia) ^[9] Senior notes: Block A - Introduction to Endocrine investigations.pdf (p1, p3–4 — principles of endocrine investigation, sequence, imaging) ^[10] Lecture slides: CFB (OG04) Menstrual Disorders.pdf (p70 — investigation of amenorrhoea) ^[11] Senior notes: Block A - Two cases of polyuria and polydipsia.pdf (p2 — posterior pituitary bright spot, pituitary axis assessment)

Management of Hyperprolactinaemia

The management of hyperprolactinaemia is entirely dependent on the underlying cause. There is no "one-size-fits-all" approach. The key management decision tree revolves around three questions:

Is the cause reversible without specific treatment? (e.g. drug-induced, pregnancy, primary hypothyroidism)
Is this a prolactinoma? → Medical therapy with dopamine agonists is first-line
Is this a non-functioning adenoma causing stalk effect? → Surgery is first-line

The aim of treatment is to avoid the long-term consequences of hypogonadism ^[2] — namely infertility, osteoporosis, and symptoms of sex hormone deficiency — as well as to control any mass effect from a pituitary tumour.

1. Management by Cause

Aspect	Detail
Principle	Remove the cause if possible
Approach	Withdraw or substitute the offending drug — but always with specialist input (especially for antipsychotics, where abrupt withdrawal risks psychotic relapse)
Antipsychotics	Switch to a prolactin-sparing antipsychotic (e.g. aripiprazole — a partial D2 agonist that does not block tuberoinfundibular D2 as strongly, or quetiapine which has low D2 affinity) ^[12]. Discuss with psychiatry.
Antiemetics	Substitute metoclopramide/domperidone with a non-dopaminergic antiemetic (e.g. ondansetron — a 5-HT3 antagonist)
If drug cannot be changed	Proceed to MRI pituitary to exclude coexistent prolactinoma. If no tumour, options include: (1) add-back oestrogen/testosterone for hypogonadal symptoms and bone protection, or (2) low-dose dopamine agonist (though this can theoretically antagonise the psychiatric benefit of antipsychotics — use with extreme caution)

Antipsychotics and Hyperprolactinaemia — Why It Happens

FGA (first-generation/typical antipsychotics) cause hyperprolactinaemia via global D2 blockade of the tuberoinfundibular pathway — blocking dopamine inhibition on lactotrophs → ↑prolactin ^[12]. SGA (second-generation/atypical antipsychotics) have a 5-HT2A-blocking effect at lactotrophs that partially counteracts this ^[12], which is why SGAs generally cause less hyperprolactinaemia than FGAs. However, risperidone is the notable exception — despite being an SGA, it is a very potent D2 blocker and causes hyperprolactinaemia as frequently as FGAs.

Clinical consequences of antipsychotic-induced hyperprolactinaemia include galactorrhoea, amenorrhoea, infertility, and demineralisation of bone ^[12].

Thyroxine replacement normalises both TSH and prolactin — the elevated TRH that was stimulating prolactin secretion falls as T4 replaces the deficiency.
No dopamine agonist or pituitary imaging is needed if TFT clearly confirms primary hypothyroidism and PRL normalises with thyroxine.

Treat the underlying systemic disease.
Hyperprolactinaemia in CKD partially improves with dialysis (improved clearance) or renal transplantation.
Dopamine agonists can be used if symptomatic and the underlying condition cannot be fully corrected.

Pregnancy/lactation: No treatment needed. Prolactin physiologically elevated.
Stress: Reassurance. Repeat PRL under non-stressed conditions.

2. Management of Prolactinoma — The Core Topic

Dopamine agonist therapy is the first-line treatment for prolactinomas ^[2]^[6] — this is one of the few brain tumours treated primarily with medication rather than surgery.

Why do dopamine agonists work?

They are D2 receptor agonists that mimic dopamine's action on lactotrophs
Two effects: (1) ↓ prolactin secretion (immediate) and (2) ↓ size of prolactinoma (over weeks to months, by inhibiting lactotroph cell proliferation and inducing cell shrinkage/apoptosis) ^[2]
~90% of prolactinomas show tumour shrinkage ^[9]

Drug Choices:

Feature	Cabergoline	Bromocriptine
Receptor	D2 agonist (ergot-derived)	D2 agonist (ergot-derived)
Dosing	1–2× per week (long half-life ~65 hours)	2–3× daily (short half-life ~6 hours)
Efficacy	Higher efficacy (normalises PRL in ~85% vs ~70%) ^[2]	Lower efficacy
Side effects	Less frequent side effects ^[2]	More S/E
Pregnancy	Increasing safety data, but…	Bromocriptine is preferred in pregnancy (longer safety track record with > 6,000 documented pregnancies) ^[2]
First-line	Cabergoline is generally preferred outside pregnancy ^[2]	First-line in pregnancy planning

Side effects of dopamine agonists ^[2]:

Nausea and vomiting (dopamine stimulation of chemoreceptor trigger zone — start at low dose and titrate up)
Postural hypotension (dopamine-mediated vasodilation)
Constipation
Psychosis (dopamine stimulation of mesolimbic pathway — important to be aware of in psychiatric patients)
Retroperitoneal fibrosis (rare, more with ergot derivatives)
Cardiac valve fibrosis (especially tricuspid regurgitation) ^[2] — this is a concern primarily with cabergoline at high doses (as used in Parkinson's disease; the doses used for prolactinoma are generally much lower and the risk is small, but echocardiographic monitoring is recommended if on high doses or long-term therapy)

Indications for Dopamine Agonist Therapy

Indications for starting a dopamine agonist ^[2]:

Symptomatic hyperprolactinaemia (regardless of serum prolactin level)
Serum prolactin > 10,000 mU/L
MRI pituitary showing macroadenoma
MRI pituitary showing microadenoma + hyperprolactinaemia

The goal is to prevent the long-term consequences of hypogonadism (infertility, osteoporosis, climacteric symptoms) and to reduce tumour mass if applicable.

Duration of therapy ^[2]:

Microprolactinoma: taper off after 2 years of sustained normal prolactin levels ^[2]. Why only microprolactinomas? Because they have a lower risk of regrowth, and many microprolactinomas may undergo fibrosis/involution on prolonged DA therapy.
Macroprolactinoma: continue indefinitely (or until menopause in women) ^[2] — higher risk of tumour regrowth if stopped.

Practical points:

Advise contraception as needed — fertility may return rapidly once prolactin normalises (even before menses return) ^[2]. Patients who do not wish to become pregnant must be counselled.
Start at low dose and titrate up gradually to minimise nausea/postural hypotension.
Monitor: serum prolactin (6–8 weekly initially, then 6-monthly once stable), MRI pituitary (repeat at 3–6 months, then annually if macroadenoma), visual fields (if macroadenoma with suprasellar extension).

Transsphenoidal surgery is second-line for prolactinomas ^[2]. "Trans-sphenoidal" = through the sphenoid bone (via the nose/upper lip → sphenoid sinus → sella turcica).

Indications for surgery in prolactinoma ^[2]:

Remains symptomatic / high PRL despite medical treatment (DA agonist resistance — defined as failure to normalise PRL or achieve ≥ 50% tumour shrinkage on maximally tolerated DA dose)
DA agonist fails to shrink the tumour significantly (macroadenoma) ^[2]
Pituitary apoplexy ^[2] — haemorrhagic infarction of the tumour; a neurosurgical emergency (see below)
Planning pregnancy ^[2] — some women (especially with macroprolactinoma) prefer definitive surgical cure before pregnancy to avoid the risks of tumour enlargement during pregnancy (although most can be managed with bromocriptine during pregnancy)
Intolerance of dopamine agonists (severe side effects)
CSF leak from tumour erosion

Surgical approaches ^[13]:

Transsphenoidal (transnasal endoscopic or sublabial microscopic) — the standard approach
Transcranial — reserved for very large tumours with significant suprasellar extension not accessible transsphenoidally

Cure rates:

Microprolactinoma: ~70–90% surgical cure
Macroprolactinoma: ~30–50% surgical cure (lower because complete resection is harder with larger tumours, especially if invading cavernous sinus)

Adjuvant RT (external beam radiotherapy / stereotactic radiosurgery) ^[2]:

Indicated if residual mass after resection and histology shows radiosensitive tumour ^[2]
Options include conventional fractionated EBRT or stereotactic radiosurgery (e.g. Gamma Knife — single high-dose focused radiation)
Radiotherapy takes months to years to achieve full effect
Risk: delayed hypopituitarism (progressive damage to normal pituitary cells) — patients require lifelong follow-up of all pituitary axes

This is fundamentally different from managing a prolactinoma:

Aspect	Detail
Key distinction	DA agonist normalises PRL but does NOT shrink the tumour ^[6] — because the tumour is not made of lactotrophs
First-line	Transsphenoidal surgery ^[6] — to debulk the mass, relieve stalk compression, and prevent/reverse visual field defects
Indications for surgery	Symptomatic mass effect (visual field defect, headache, hypopituitarism), enlarging tumour on surveillance, or diagnostic uncertainty
Post-operative management	Reassess all pituitary axes: watch for diabetes insipidus, secondary adrenal insufficiency, GH deficiency ^[6]
Observation	Small, incidental, non-functioning microadenomas with normal visual fields and no hormonal deficiency → can be observed with serial MRI and PRL monitoring

GC 067 Case Management Sequence ^[6]: Bromocriptine → PRL normalised + menses returned, BUT no tumour shrinkage after 4 months → proceeded to transsphenoidal surgery → tumour stained negative for all pituitary hormones → post-op DI + subnormal cortisol and GH on ITT → required oral DDAVP and hydrocortisone 10 mg OM.

Understanding these is essential both for pre-operative counselling and post-operative management ^[2]^[13]:

Complication	Mechanism	Management
Hypopituitarism	Damage to residual normal pituitary tissue during resection	High-dose IV hydrocortisone from the day of surgery ^[2] (steroid cover); lifelong hormone replacement as needed
Diabetes insipidus → SIADH → DI ("triphasic response") ^[2]	Phase 1: stalk damage → ↓vasopressin → DI. Phase 2: damaged posterior pituitary releases stored vasopressin → transient SIADH. Phase 3: permanent DI if severe damage.	Monitor I/O, serum Na, urine osmolality daily ^[2]. DDAVP for DI. Fluid restrict for SIADH.
CSF rhinorrhoea	Breach of the sellar floor dura during surgery → CSF leaks through nose	Test fluid for beta-2 transferrin ^[2] (specific marker for CSF). May require surgical repair.
Diplopia / Vision loss	Damage to optic chiasm or cranial nerves ^[2]^[13]	Urgent assessment; may be permanent
Meningitis	CSF leak → ascending infection	Antibiotics; surgical repair of CSF leak
Vascular injury / CVA	Damage to internal carotid artery (runs adjacent to sphenoid sinus)	Rare but catastrophic
Intracranial haemorrhage	Intraoperative or postoperative bleed	Neurosurgical management
ENT symptoms	Nasal congestion, sinusitis (from transnasal approach)	Conservative

The Triphasic Response Post-TSS

DI → SIADH → DI ^[2] is a classic post-operative pattern:

Day 1–3: Surgical damage to the posterior pituitary/stalk → acute vasopressin deficiency → diabetes insipidus (polyuria, polydipsia, dilute urine, rising serum Na)
Day 4–10: Uncontrolled release of stored vasopressin from damaged neurons → transient SIADH (hyponatraemia, concentrated urine)
Day 10+: If damage is permanent, vasopressin stores exhausted → permanent DI

Monitor I/O, serum Na, and urine osmolality daily post-operatively ^[2]. Not all patients go through all three phases; some recover after the first phase.

5. Special Management Situations

Aspect	Detail
Pre-conception	Bromocriptine is the preferred DA agonist for women planning pregnancy ^[2] (longest safety record). Cabergoline is increasingly used but bromocriptine remains standard HK practice.
During pregnancy	Microprolactinoma: Stop DA agonist once pregnancy confirmed (risk of tumour enlargement < 5%). Monitor clinically. Restart if symptoms of tumour growth (headache, visual field change).
	Macroprolactinoma: Higher risk of enlargement (~30%). Options: (1) continue bromocriptine through pregnancy if high-risk, or (2) stop and monitor closely with visual field testing each trimester. Restart urgently if visual deterioration.
Monitoring	Do NOT monitor PRL during pregnancy — it is physiologically elevated and uninterpretable. Monitor by symptoms and visual fields.
Post-partum	Breastfeeding is generally safe with microprolactinoma (PRL is already elevated from suckling). Recheck PRL after weaning.
Advise contraception	Fertility may return rapidly once PRL normalises on DA agonist ^[2] — patients not wishing to conceive must use contraception.

Defined as failure to normalise PRL or achieve ≥ 50% tumour shrinkage on maximally tolerated DA agonist
Occurs in ~10–15% of prolactinomas (more common with macroprolactinomas)
Management: Transsphenoidal surgery ^[2] ± adjuvant radiotherapy ^[2]
Temozolomide (alkylating chemotherapy) can be considered for aggressive/malignant prolactinomas refractory to surgery and RT

Aspect	Detail
Definition	Haemorrhagic infarction of a pituitary tumour ^[13] — a neurosurgical emergency
Presentation	Sudden excruciating headache, diplopia (CN III compression), hypopituitarism (especially adrenal crisis), visual field defects, altered consciousness ^[13]
Imaging	Hyperdensity (acute blood) in pituitary region on CT ^[13]
Management	Immediate IV hydrocortisone (life-saving — prevents adrenal crisis). Urgent surgical decompression under steroid cover if signs of ↑ICP, change in conscious state, or compression of neighbouring structures ^[13].

If the patient is asymptomatic (regular menses, no galactorrhoea, no desire for fertility, normal BMD) and PRL is only mildly elevated → observation with periodic PRL monitoring is acceptable.
Many microprolactinomas remain stable or even regress spontaneously.
Intervene if: symptoms develop, PRL rises significantly, or tumour enlarges on MRI.

The main concern of hyperprolactinaemia (hypogonadism) is less relevant after menopause (ovaries no longer producing significant oestrogen regardless).
DA agonists can be stopped at menopause ^[2] for microprolactinomas if there is no macroadenoma mass effect.
Continue surveillance if macroadenoma (for mass effect).

Parameter	Frequency	Purpose
Serum prolactin	Every 6–8 weeks initially, then 6-monthly once stable	Assess biochemical response to DA agonist
MRI pituitary	3–6 months after starting DA (macroadenoma); then annually	Assess tumour shrinkage; detect regrowth
Visual field perimetry	Baseline + with each MRI (if suprasellar extension)	Detect optic chiasm decompression or new compression
DEXA scan	Every 1–2 years if hypogonadal	Monitor bone mineral density
Menstrual history / symptoms	Each visit	Assess restoration of gonadal function
Echocardiography	Consider if on high-dose cabergoline long-term	Screen for cardiac valve fibrosis
Serum Na, urine osmolality	Daily post-surgery; then as needed	Detect DI/SIADH post-operatively

Cause	First-Line Management	Second-Line	Key Points
Drug-induced	Withdraw/substitute offending drug	Add-back sex hormones if drug cannot be changed	Liaise with psychiatry for antipsychotics
Primary hypothyroidism	Thyroxine replacement	—	PRL normalises with adequate T4
CKD	Treat underlying CKD / dialysis	DA agonist if symptomatic
Microprolactinoma	DA agonist (cabergoline)	TSS	Taper after 2 years normal PRL ^[2]
Macroprolactinoma	DA agonist (cabergoline)	TSS ± RT	Continue indefinitely / until menopause ^[2]
Non-functioning adenoma (stalk effect)	Transsphenoidal surgery	Observation if small + asymptomatic	DA normalises PRL but does NOT shrink tumour ^[6]
Pregnancy planning	Bromocriptine	TSS pre-conception for macroprolactinoma	Advise contraception until planning ^[2]
Pituitary apoplexy	IV hydrocortisone + urgent TSS	—	Neurosurgical emergency ^[13]
Idiopathic / asymptomatic	Observation	DA agonist if becomes symptomatic	Monitor PRL periodically

High Yield Summary — Management of Hyperprolactinaemia

General Principle: Treat the underlying cause. The aim is to prevent long-term consequences of hypogonadism ^[2].

Prolactinoma — First-line = Dopamine agonist ^[2]:

Cabergoline preferred (higher efficacy, fewer S/E, less frequent dosing) ^[2]
Bromocriptine preferred in pregnancy ^[2]
Indications: Symptomatic; PRL > 10,000; macroadenoma on MRI; microadenoma + hyperPRL ^[2]
Duration: Micro → taper after 2 yr normal PRL. Macro → continue indefinitely/menopause ^[2]
S/E: N/V, postural hypotension, constipation, psychosis, retroperitoneal/cardiac valve fibrosis ^[2]
Advise contraception — fertility returns rapidly ^[2]

Prolactinoma — Second-line = Transsphenoidal surgery ^[2]:

Indications: DA-resistant; failure to shrink tumour; pituitary apoplexy; planning pregnancy; intolerance ^[2]
Post-op complications: Hypopituitarism, DI→SIADH→DI triphasic response, CSF rhinorrhoea ^[2]^[13]

Non-functioning adenoma (stalk effect) — First-line = Surgery ^[6]:

DA normalises PRL but does NOT shrink tumour ^[6]
Post-op: reassess all pituitary axes; watch for DI, cortisol/GH deficiency ^[6]

Drug-induced: Withdraw/substitute drug. Liaise psychiatry for antipsychotics.

Hypothyroidism: Thyroxine replacement normalises PRL.

Active Recall — Management of Hyperprolactinaemia

References

^[2] Senior notes: Maksim Medicine Notes.pdf (Endocrinology section, p107–108) ^[6] Lecture slides: GC 067. I keep on bumping into people on my side.pdf (p24 — clinical case management) ^[9] Senior notes: Block A - I keep on bumping into people on my side_ pituitary tumours; hypopituitarism.pdf (p10 — diagnosis and treatment of pituitary tumours) ^[12] Senior notes: Ryan Ho Psychiatry.pdf (p46 — antipsychotics and tuberoinfundibular pathway) ^[13] Senior notes: Ryan Ho Neurology.pdf (p166 — pituitary adenoma management and complications, pituitary apoplexy)

Complications of Hyperprolactinaemia

Complications of hyperprolactinaemia arise from three distinct sources:

Consequences of the hormonal disturbance itself (chronic hyperprolactinaemia → hypogonadism)
Consequences of the underlying mass (if a pituitary adenoma is the cause)
Complications of treatment (dopamine agonist side effects, surgical complications)

Understanding these from first principles requires recalling that the dominant clinical effect of hyperprolactinaemia is hypogonadotrophic hypogonadism due to inhibition of GnRH secretion ^[2]^[3], and that pituitary tumours are space-occupying lesions within the rigid bony sella turcica.

1. Complications of Chronic Hyperprolactinaemia (Hormonal)

Aspect	Detail
Mechanism	Chronic hypogonadism → oestrogen deficiency (females) / testosterone deficiency (males) → ↑osteoclast activity → accelerated bone resorption → ↓BMD → osteoporosis ^[2]
Why this matters	Hyperprolactinaemia-induced hypogonadism can persist for years (especially in men who present late with macroprolactinomas). Prolonged untreated oestrogen/testosterone deficiency has the same skeletal consequences as premature menopause or surgical castration.
Sites at risk	Lumbar spine and femoral neck (predominantly trabecular bone, which is more metabolically active and thus more vulnerable to oestrogen/testosterone deficiency)
Clinical consequence	Fragility fractures — vertebral compression fractures, hip fractures, distal radius fractures
Monitoring	↓BMD on DEXA scan ^[2] — should be performed in any patient with prolonged hyperprolactinaemia (> 6–12 months) and hypogonadism
Reversibility	Partially reversible: BMD improves when prolactin is normalised and gonadal function is restored, but may not return to baseline if prolonged

Osteoporosis in Young Patients

Osteoporosis from hyperprolactinaemia is particularly concerning because it affects young, premenopausal women and young men — populations who would normally have peak bone mass. Missing the diagnosis means years of silent bone loss during what should be the bone-building years.

Aspect	Detail
In females	↑Prolactin → ↓GnRH → ↓LH/FSH → anovulation → infertility ^[2]^[3]. Without the mid-cycle LH surge, ovulation cannot occur. Even if some follicular development happens, the corpus luteum may be inadequate (luteal phase defect).
In males	↓LH → ↓testosterone → impaired spermatogenesis (testosterone is essential for Sertoli cell function in the seminiferous tubules). ↓FSH → further impaired spermatogenesis directly.
Reversibility	Fertility typically returns once prolactin is normalised ^[2] — this is why contraception counselling is important when starting dopamine agonists (see below)

Aspect	Detail
In females	↓Oestrogen → vaginal dryness, dyspareunia, ↓libido — mimics climacteric (menopausal) symptoms ^[2]
In males	↓Testosterone → ↓libido, erectile dysfunction, ↓shaving frequency, lethargy ^[2]^[3]. Prolactin may also directly impair erectile physiology independent of testosterone.
Impact	Significant effect on quality of life, relationships, and psychological wellbeing

Aspect	Detail
Mechanism	Chronic oestrogen deficiency (females) → loss of cardioprotective effect of oestrogen → accelerated atherosclerosis. Testosterone deficiency (males) → unfavourable metabolic profile (↑visceral fat, ↑insulin resistance).
Evidence	Observational data suggest increased cardiovascular risk in patients with prolonged untreated hyperprolactinaemia-induced hypogonadism, though this is less well-established than osteoporosis

Aspect	Detail
Mechanism	Hypogonadism → fatigue, low mood, anxiety, ↓cognitive function, ↓motivation. Galactorrhoea → embarrassment and psychosocial distress. Infertility → significant emotional burden.
In men	Symptoms are often insidious — patients may attribute fatigue and ↓libido to "ageing" or "stress" and not seek help for years

2. Complications from Pituitary Tumour Mass Effect

These complications arise when the underlying cause is a pituitary adenoma (especially a macroadenoma).

Aspect	Detail
Mechanism	Suprasellar extension of the adenoma compresses the optic chiasm ^[1]^[2] → the nasal retinal fibres (carrying temporal visual field information) cross at the chiasm and are vulnerable to compression from below
Pattern	Bitemporal hemianopia — loss of temporal visual fields bilaterally. Initially may be an upper temporal quadrantanopia (because the inferior chiasmal fibres, carrying superior temporal field, are compressed first from below).
Clinical presentation	"I keep on bumping into people on my side" ^[1] — patients lose peripheral vision and collide with objects/people in their temporal visual fields
Progression	If untreated → progressive visual loss → eventually complete blindness
Reversibility	Often partially or fully reversible if the tumour is treated (shrunk by DA agonist or removed surgically) before optic nerve atrophy develops. If optic atrophy has already occurred (pale disc on fundoscopy), recovery is limited.

Aspect	Detail
Mechanism	Large adenoma compresses the remaining normal pituitary gland → progressive loss of other anterior pituitary hormones. The classical order of loss (in approximate descending sensitivity) is: GH → LH/FSH → TSH → ACTH
Clinical consequences
— GH deficiency	↓Muscle mass, ↑visceral fat, fatigue, ↓BMD (in adults); growth failure (in children)
— LH/FSH deficiency	Adds to hypogonadism already caused by hyperprolactinaemia
— TSH deficiency	Secondary (central) hypothyroidism — note: TSH may be inappropriately "normal" despite low fT4 ^[9] (the pituitary cannot mount an adequate TSH response, so you cannot rely on TSH alone as you would in primary hypothyroidism)
— ACTH deficiency	Secondary adrenal insufficiency — this is the most life-threatening deficiency. Cortisol deficiency → inability to mount stress response → risk of adrenal crisis (hypotension, shock, death) during illness or surgery. Note: no hyperpigmentation (unlike primary Addison's, because ACTH is low, not high).

Secondary Hypothyroidism — The 'Inappropriately Normal TSH' Trap

In secondary (central) hypothyroidism from pituitary compression, TSH is not elevated despite low fT4 ^[9]. This is because the pituitary itself is damaged and cannot produce adequate TSH. If you only look at TSH (as in primary hypothyroidism screening), you will miss this diagnosis. Always check fT4 alongside TSH in any patient with a pituitary mass.

Aspect	Detail
Mechanism	Lateral extension of the adenoma into the cavernous sinus → compresses CN III (oculomotor), CN IV (trochlear), CN V1/V2 (trigeminal), CN VI (abducens)
Clinical features	Diplopia (CN III, IV, VI), ptosis + "down-and-out" eye + dilated pupil (CN III), facial numbness (CN V)

Aspect	Detail
Definition	Haemorrhagic infarction of a pituitary tumour ^[13] — a neurosurgical emergency
Precipitants	Can occur spontaneously or be precipitated by anticoagulation, head trauma, surgery, pregnancy, or pituitary function testing
Presentation	Sudden excruciating headache + diplopia (CN III) + acute hypopituitarism (especially adrenal crisis) + visual field defects + altered consciousness ^[13]
Why it's dangerous	Acute ACTH deficiency → cortisol collapse → cardiovascular shock. Rapid expansion of the haemorrhagic mass → compression of optic chiasm and cranial nerves → acute visual loss.
Management	Immediate IV hydrocortisone + urgent surgical decompression under steroid cover ^[13]

Aspect	Detail
Mechanism	Tumour erosion through the floor of the sella turcica into the sphenoid sinus → dural breach → CSF rhinorrhoea
Risk	Ascending meningitis (bacteria from nasal flora enter the subarachnoid space)
Diagnosis	Test nasal fluid for beta-2 transferrin ^[2] (specific marker for CSF)

Very large tumours with significant suprasellar extension can obstruct the third ventricle → obstructive hydrocephalus → ↑ICP → headache, nausea/vomiting, papilloedema, altered consciousness

3. Complications of Treatment

Complication	Mechanism	Detail
Nausea and vomiting ^[2]	DA stimulation of the chemoreceptor trigger zone (CTZ in the area postrema)	Most common S/E; minimise by starting low dose, taking with food, and gradual titration
Postural hypotension ^[2]	DA-mediated peripheral vasodilation + ↓sympathetic tone	Can cause dizziness, syncope; counsel patients to rise slowly
Constipation ^[2]	DA effect on GI motility	Common; manage with dietary fibre, laxatives
Psychosis / impulse control disorders ^[2]	DA stimulation of mesolimbic pathway (the "reward" pathway)	Particularly relevant when prescribing to patients already on antipsychotics for psychotic illness — DA agonist directly opposes the antipsychotic effect. Impulse control disorders (gambling, hypersexuality) are well-described with DA agonists in Parkinson's disease.
Retroperitoneal fibrosis ^[2]	Ergot-derived DA agonists can cause serosal fibrotic reactions	Rare; more historical concern with older agents like methysergide
Cardiac valve fibrosis (especially tricuspid regurgitation) ^[2]	Activation of 5-HT2B receptors on cardiac valves → fibroblast proliferation → valve thickening and regurgitation	More relevant with high-dose cabergoline (as used in Parkinson's disease). At prolactinoma doses (typically ≤ 2 mg/week), the risk is low but not zero. Echocardiographic monitoring is recommended if on ≥ 2 mg/week or long-term therapy.
Unplanned pregnancy	Normalisation of prolactin restores GnRH pulsatility → ovulation resumes → fertility returns	Advise contraception as needed — fertility might return after PRL normalises ^[2]
CSF rhinorrhoea (rare)	Rapid tumour shrinkage in a macroprolactinoma that has eroded the sella floor → the tumour was "plugging" the defect → shrinkage reveals the dural/bony breach	Rare but important; may require surgical repair

DA Agonist + Antipsychotic = Pharmacological Conflict

DA agonists (to treat hyperprolactinaemia) directly oppose D2-blocking antipsychotics (to treat psychosis). Starting a DA agonist in a patient on antipsychotics risks destabilising their psychiatric condition. Conversely, the antipsychotic is the cause of the hyperprolactinaemia in the first place. This clinical conundrum requires close liaison between endocrinology and psychiatry — often the best approach is to switch to a prolactin-sparing antipsychotic (aripiprazole, quetiapine) rather than add a DA agonist.

Complication	Mechanism	Management
Hypopituitarism ^[2]	Surgical damage to normal pituitary tissue	High-dose IV hydrocortisone from the day of surgery ^[2]; lifelong hormone replacement as needed
DI → SIADH → DI (triphasic response) ^[2]	Phase 1: stalk damage → ↓vasopressin → DI. Phase 2: uncontrolled release of stored vasopressin → SIADH. Phase 3: permanent DI.	Monitor I/O, serum Na, urine osmolality daily ^[2]. DDAVP for DI; fluid restriction for SIADH.
CSF rhinorrhoea ^[2]	Dural breach during surgical approach through sphenoid sinus	Test fluid for beta-2 transferrin ^[2]. May need lumbar drain or surgical repair.
Diplopia / visual loss ^[2]	Damage to optic chiasm or oculomotor nerves during dissection	May be permanent
Meningitis	Ascending infection via CSF leak	Antibiotics; surgical repair of leak
Vascular injury / CVA ^[13]	Internal carotid artery injury (runs adjacent to sphenoid sinus)	Rare but catastrophic
Intracranial haemorrhage ^[13]	Intra/post-operative bleed	Neurosurgical management
ENT symptoms ^[13]	Nasal congestion, crusting, sinusitis from transnasal approach	Conservative management

GC 067 Case ^[6]: The post-operative course demonstrated two key complications: diabetes insipidus (requiring oral DDAVP) and pituitary insufficiency (ITT showed subnormal peak cortisol and GH → required hydrocortisone 10 mg OM). This case is a classic teaching example of post-TSS complications.

Complication	Mechanism	Detail
Delayed hypopituitarism	Progressive radiation damage to normal pituitary cells	May develop months to years after RT; requires lifelong annual pituitary axis screening
Optic neuropathy	Radiation damage to optic nerves/chiasm	Risk minimised with modern stereotactic techniques but not zero
Secondary brain tumours	Radiation-induced neoplasia	Very rare; long latency (> 10 years)
Cerebrovascular disease	Radiation vasculopathy of cerebral vessels	Increased stroke risk decades later

From the 2023 Fourth Summative MCQ ^[14]: A 32-year-old woman with inability to produce milk for her newborn and failure of menstruation to resume after severe post-partum haemorrhage from placenta previa. The question asks what other endocrine problem may have resulted.

Mechanism: Severe post-partum haemorrhage → hypovolaemic shock → ischaemic necrosis of the pituitary gland (Sheehan syndrome). The pituitary is particularly vulnerable during pregnancy because it has doubled in size (lactotroph hyperplasia from oestrogen) and thus has increased metabolic demand, yet its blood supply via portal vessels remains fixed.
Clinical features: Inability to lactate (prolactin deficiency, NOT hyperprolactinaemia), failure of menses to resume (gonadotrophin deficiency), fatigue (ACTH/cortisol deficiency), cold intolerance (TSH/T4 deficiency).
Answer to the MCQ: Arginine vasopressin deficiency (choice A) — the posterior pituitary/stalk can also be affected, causing central diabetes insipidus. This is distinct from hyperprolactinaemia (choice D) — Sheehan syndrome causes hypoprolactinaemia, not hyper.

Sheehan Syndrome — The Opposite of Hyperprolactinaemia

Do not confuse the consequences of Sheehan syndrome with hyperprolactinaemia. Sheehan syndrome causes pan-hypopituitarism including prolactin deficiency (cannot lactate) — the exact opposite of hyperprolactinaemia. The 2023 past paper tests this distinction ^[14].

While not directly a complication of hyperprolactinaemia, it is worth understanding in the context of pituitary tumour biology:

After bilateral adrenalectomy for Cushing's disease, the corticotroph adenoma may enlarge aggressively (loss of cortisol negative feedback → ↑ACTH drive → tumour growth) → Nelson syndrome
The expanding tumour can cause hyperprolactinaemia (stalk effect), visual field defects, and hyperpigmentation (from very high ACTH/MSH)

Category	Complication	Mechanism	Key Points
Hormonal	Osteoporosis	Chronic hypogonadism → ↓oestrogen/testosterone → ↑bone resorption	Monitor with DEXA; partially reversible
	Infertility	↓GnRH → anovulation / impaired spermatogenesis	Reversible with PRL normalisation
	Sexual dysfunction	↓Sex hormones + direct PRL effect	Major QoL impact
	Cardiovascular risk	Loss of oestrogen cardioprotection; metabolic derangement	Less well-established
	Psychological	Hypogonadism + galactorrhoea + infertility	Depression, anxiety, low self-esteem
Mass effect	Bitemporal hemianopia	Optic chiasm compression	Often reversible if treated early
	Hypopituitarism	Compression of normal pituitary	GH → LH/FSH → TSH → ACTH (order of loss)
	CN palsies	Cavernous sinus invasion	CN III, IV, V, VI
	Pituitary apoplexy	Haemorrhagic infarction of tumour	Neurosurgical emergency; IV hydrocortisone
	CSF rhinorrhoea	Sella floor erosion	Beta-2 transferrin to confirm
Treatment	DA agonist S/E	Various (see above)	N/V, postural hypotension, cardiac valve fibrosis, psychosis, unplanned pregnancy
	Post-TSS complications	Surgical damage	Hypopituitarism, DI→SIADH→DI, CSF leak, diplopia ^[2]
	Post-RT complications	Radiation damage	Delayed hypopituitarism, optic neuropathy

High Yield Summary — Complications of Hyperprolactinaemia

Hormonal Complications (from chronic hypogonadism):

Osteoporosis — oestrogen/testosterone deficiency → ↑bone resorption → ↓BMD ^[2]
Infertility — anovulation (F), impaired spermatogenesis (M) — reversible with treatment
Sexual dysfunction — ↓libido, ED, vaginal dryness, climacteric symptoms

Mass Effect Complications (from pituitary adenoma):

Bitemporal hemianopia — optic chiasm compression
Hypopituitarism — compression of normal pituitary (order: GH → LH/FSH → TSH → ACTH)
Pituitary apoplexy — haemorrhagic infarction; emergency; IV hydrocortisone + surgery ^[13]
CN palsies — cavernous sinus invasion
CSF rhinorrhoea — sella floor erosion; test for beta-2 transferrin ^[2]

Treatment Complications:

DA agonists: N/V, postural hypotension, cardiac valve fibrosis (cabergoline), psychosis, retroperitoneal fibrosis, unplanned pregnancy ^[2]
TSS: Hypopituitarism (give IV hydrocortisone day of surgery), DI→SIADH→DI (monitor I/O, Na, urine osmolality daily), CSF rhinorrhoea, diplopia ^[2]
RT: Delayed hypopituitarism (lifelong monitoring), optic neuropathy

Exam Pearl: Sheehan syndrome causes prolactin deficiency (not hyperprolactinaemia) — pan-hypopituitarism from post-partum pituitary necrosis. Tested in 2023 past paper ^[14].

Active Recall — Complications of Hyperprolactinaemia

References

^[1] Lecture slides: GC 067. I keep on bumping into people on my side.pdf ^[2] Senior notes: Maksim Medicine Notes.pdf (Endocrinology section, p107–108) ^[3] Senior notes: Ryan Ho Endocrine.pdf (Section 5.2.2, p110) ^[6] Lecture slides: GC 067. I keep on bumping into people on my side.pdf (p24 — clinical case, post-operative complications) ^[9] Senior notes: Block A - Introduction to Endocrine investigations.pdf (p9 — screening for co-secretion, secondary hypothyroidism concept) ^[13] Senior notes: Ryan Ho Neurology.pdf (p166 — pituitary apoplexy, TSS complications) ^[14] Past papers: 2023 Fourth Summative MCQ.pdf (p15 — Question 38, Sheehan syndrome)

High Yield Summary

Definition: Sustained elevation of serum prolactin (> 500 mU/L).

Key Physiology: Prolactin is uniquely under tonic dopaminergic inhibition via D2 receptors on lactotrophs. TRH and oestrogen are stimulatory.

Aetiology (SAQ favourite):

Physiological: Pregnancy, lactation, stress, chest wall stimulation (herpes zoster!), sleep
Pharmacological: D2 antagonists (antipsychotics, metoclopramide, domperidone), dopamine-depleting (methyldopa), oestrogens, verapamil, H2 blockers
Pituitary: Prolactinoma (micro < 10 mm, macro ≥ 10 mm), non-functioning adenoma (stalk effect), mixed GH/PRL adenoma
Hypothalamic/Stalk: Craniopharyngioma, radiotherapy, trauma, infiltrative disease (sarcoidosis)
Systemic: Primary hypothyroidism (↑TRH), CKD (↓dopamine, ↓clearance), liver cirrhosis, PCOS

Prolactin Levels and Causes:

< 500: Normal
500–1,000: Stress, drugs
1,000–5,000: Drugs, microprolactinoma, stalk effect
5,000: Macroprolactinoma
100,000: Hook effect risk (false negative!)

Clinical Features:

Hypogonadotrophic hypogonadism (amenorrhoea, ↓libido, ED, infertility, ↓BMD, climacteric symptoms)
Galactorrhoea (more common in females)
Mass effects (bitemporal hemianopia, headache, CN palsies, hypopituitarism)
Concomitant acromegaly (shared Pit-1 lineage)

Critical Distinction: Stalk effect (PRL < 5,000, large non-functioning adenoma) vs. macroprolactinoma (PRL > 5,000) → completely different management!

Macroprolactin: PRL-IgG complex, NOT physiologically active, can cause assay interference → PEG precipitation to exclude.

High Yield Summary — DDx of Hyperprolactinaemia

Always exclude pregnancy first (urine βhCG) ^[7]
Always repeat the test if mildly elevated (exclude stress) ^[7]
Always exclude macroprolactin (PEG precipitation)
Drug history — most common non-physiological cause ^[2]^[3]^[6]
TFT — must exclude primary hypothyroidism ^[7]
RFT, LFT — exclude CKD, cirrhosis
MRI pituitary if PRL remains elevated after above exclusions
Correlate PRL level with tumour size — the critical step:
- PRL matches size → prolactinoma → DA agonist
- PRL disproportionately low for size → stalk effect → surgery ^[6]
- Very large mass + unexpectedly low PRL → request serial dilution for hook effect
Non-functioning adenoma with stalk effect: PRL normalises on DA agonist but tumour does NOT shrink ^[6]; tumour stains negative for all pituitary hormones ^[6]
Check IGF-1 to exclude co-existing GH excess (mixed adenoma, Pit-1 lineage) ^[2]

High Yield Summary — Diagnostics of Hyperprolactinaemia

Diagnostic Approach — The 7 Steps:

Urine pregnancy test — always first in reproductive-age women ^[7]
Serum prolactin — fasting, morning, rested; repeat if mildly elevated ^[7]^[9]
Exclude macroprolactin — PEG precipitation (PWH auto-excludes) ^[2]
Drug history — most common non-physiological cause
TFT, RFT, LFT — exclude hypothyroidism, CKD, cirrhosis ^[7]
MRI pituitary (contrast) — only after biochemical workup ^[9]; indicated if PRL > 1,000, symptomatic, or evidence of pituitary insufficiency ^[2]
Screen all pituitary axes — IGF-1, ACTH/cortisol, TSH/fT4, LH/FSH/sex hormones ^[2]

Key Principles:

Biochemistry before imaging ^[9]
Correlate PRL level with tumour size ^[6]^[9]
Prolactinoma diagnosis is a therapeutic diagnosis — confirmed by tumour shrinkage on DA agonist ^[9]
Stalk effect: PRL < 5,000 with large mass; PRL normalises on DA but tumour does NOT shrink ^[6]
Hook effect: Very large mass + unexpectedly low PRL → serial dilution ^[2]^[7]
Post-surgical assessment: Re-evaluate all axes; watch for DI and cortisol/GH deficiency ^[6]

High Yield Summary — Management of Hyperprolactinaemia

General Principle: Treat the underlying cause. The aim is to prevent long-term consequences of hypogonadism ^[2].

Prolactinoma — First-line = Dopamine agonist ^[2]:

Cabergoline preferred (higher efficacy, fewer S/E, less frequent dosing) ^[2]
Bromocriptine preferred in pregnancy ^[2]
Indications: Symptomatic; PRL > 10,000; macroadenoma on MRI; microadenoma + hyperPRL ^[2]
Duration: Micro → taper after 2 yr normal PRL. Macro → continue indefinitely/menopause ^[2]
S/E: N/V, postural hypotension, constipation, psychosis, retroperitoneal/cardiac valve fibrosis ^[2]
Advise contraception — fertility returns rapidly ^[2]

Prolactinoma — Second-line = Transsphenoidal surgery ^[2]:

Indications: DA-resistant; failure to shrink tumour; pituitary apoplexy; planning pregnancy; intolerance ^[2]
Post-op complications: Hypopituitarism, DI→SIADH→DI triphasic response, CSF rhinorrhoea ^[2]^[13]

Non-functioning adenoma (stalk effect) — First-line = Surgery ^[6]:

DA normalises PRL but does NOT shrink tumour ^[6]
Post-op: reassess all pituitary axes; watch for DI, cortisol/GH deficiency ^[6]

Drug-induced: Withdraw/substitute drug. Liaise psychiatry for antipsychotics.

Hypothyroidism: Thyroxine replacement normalises PRL.

High Yield Summary — Complications of Hyperprolactinaemia

Hormonal Complications (from chronic hypogonadism):

Osteoporosis — oestrogen/testosterone deficiency → ↑bone resorption → ↓BMD ^[2]
Infertility — anovulation (F), impaired spermatogenesis (M) — reversible with treatment
Sexual dysfunction — ↓libido, ED, vaginal dryness, climacteric symptoms

Mass Effect Complications (from pituitary adenoma):

Bitemporal hemianopia — optic chiasm compression
Hypopituitarism — compression of normal pituitary (order: GH → LH/FSH → TSH → ACTH)
Pituitary apoplexy — haemorrhagic infarction; emergency; IV hydrocortisone + surgery ^[13]
CN palsies — cavernous sinus invasion
CSF rhinorrhoea — sella floor erosion; test for beta-2 transferrin ^[2]

Treatment Complications:

DA agonists: N/V, postural hypotension, cardiac valve fibrosis (cabergoline), psychosis, retroperitoneal fibrosis, unplanned pregnancy ^[2]
TSS: Hypopituitarism (give IV hydrocortisone day of surgery), DI→SIADH→DI (monitor I/O, Na, urine osmolality daily), CSF rhinorrhoea, diplopia ^[2]
RT: Delayed hypopituitarism (lifelong monitoring), optic neuropathy

Exam Pearl: Sheehan syndrome causes prolactin deficiency (not hyperprolactinaemia) — pan-hypopituitarism from post-partum pituitary necrosis. Tested in 2023 past paper ^[14].

Hyperprolactinaemia

1. Definition

2. Epidemiology & Risk Factors

3. Anatomy & Physiology of Prolactin Regulation

3.1 The Hypothalamic-Pituitary Axis for Prolactin

3.2 Prolactin Actions

4. Aetiology

4.1 Physiological Causes

4.2 Pharmacological Causes (Drug-Induced)

4.3 Pathological Causes

A. Pituitary Causes

B. Hypothalamic / Suprasellar Causes

C. Systemic / Other Pathological Causes

5. Pathophysiology — How Elevated Prolactin Causes Disease

5.1 Direct Prolactin Effect on Breast Tissue

5.2 Inhibition of the HPG Axis → Hypogonadotrophic Hypogonadism

5.3 Mass Effect (if Cause is a Pituitary Adenoma)

6. Classification

6.1 By Prolactin Level

6.2 Macroprolactin

6.3 By Tumour Size (if Prolactinoma)

7. Clinical Features

7.1 Symptoms

A. Symptoms Due to Hyperprolactinaemia Itself (Hormonal Effects)

B. Symptoms Due to Mass Effect (if Pituitary Adenoma)

C. Symptoms Related to Underlying Cause

7.2 Signs

A. Signs of Hyperprolactinaemia

B. Signs of Mass Effect (if Pituitary Tumour)

C. Signs Related to Other Pituitary Hormone Deficiencies

D. Signs Related to Underlying Cause

8. Important Concepts & Special Situations

8.1 The "Stalk Effect" (Disconnection Hyperprolactinaemia)

8.2 Prolactinoma and Pregnancy

8.3 Hyperprolactinaemia and Bromocriptine in Lupus/Raynaud's

8.4 Lithium and Endocrine Side Effects

9. Summary of Pathophysiology → Clinical Feature Connections

Active Recall - Hyperprolactinaemia (Definition, Aetiology, Pathophysiology, Clinical Features)

References

Why a Systematic DDx Matters

Approach to the Differential Diagnosis

Systematic Differential Diagnosis

1. Physiological Causes

2. Pharmacological (Drug-Induced) Causes

3. Pathological Causes — Pituitary

A. Prolactinoma

B. Non-Functioning Pituitary Adenoma (Stalk Effect / Disconnection Hyperprolactinaemia)

C. Mixed GH/Prolactin-Secreting Adenoma

D. Other Pituitary Tumours Causing Stalk Effect

4. Pathological Causes — Hypothalamic / Stalk

5. Pathological Causes — Systemic

6. Macroprolactinaemia (Assay Artefact)

7. Idiopathic / Familial Hyperprolactinaemia

Clinical Approach to Differentiating Causes — A Stepwise Algorithm

Key Differentiating Features — Summary Table

Differential Diagnosis of Galactorrhoea (a Related but Distinct DDx)

Differential Diagnosis of Amenorrhoea (Overlapping DDx)

Active Recall — Differential Diagnosis of Hyperprolactinaemia

Why There Are No "Formal Diagnostic Criteria" Per Se

1. Biochemical Diagnostic Thresholds

Key Diagnostic Principles (from Endocrine Investigations Teaching) [9]

2. The Diagnostic Algorithm

3. Investigation Modalities — Detailed Breakdown

3.1 First-Line: Serum Prolactin

3.2 Urine Pregnancy Test

3.3 Thyroid Function Tests (TFT)

3.4 Renal Function Tests (RFT) and Liver Function Tests (LFT)

3.5 Macroprolactin Screening (PEG Precipitation)

3.6 MRI Pituitary (Contrast-Enhanced)

3.7 Screening Other Pituitary Axes

3.8 Insulin Tolerance Test (ITT)

3.9 Visual Field Testing

3.10 DEXA Scan (Bone Mineral Density)

4. Diagnosing the Underlying Cause — Specific Patterns

4.1 Prolactinoma Diagnosis

4.2 Stalk Effect / Non-Functioning Adenoma

4.3 Drug-Induced Hyperprolactinaemia

4.4 Primary Hypothyroidism

5. Summary Table: Investigations for Hyperprolactinaemia

Active Recall — Diagnosis and Investigation of Hyperprolactinaemia