13.1 Hypopituitarism, Pituitary Apoplexy & Hyperprolactinaemia

The pituitary gland (hypophysis) sits within the sella turcica of the sphenoid bone, immediately inferior to the optic chiasm. Mastery of the hypothalamic-pituitary-end organ axes, dynamic endocrine testing, hormonal hypersecretion syndromes, and water balance disorders is vital for MRCP(UK) Part 1.

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1. Hypopituitarism & Pituitary Apoplexy

Functional Anatomy & Vascular Supply

The pituitary comprises two embryologically distinct lobes:

• Anterior Pituitary (Adenohypophysis): Derived from oral ectoderm (Rathke's pouch). Lacks a direct arterial blood supply; instead, hypothalamic releasing and inhibiting hormones are delivered via the hypothalamic-hypophyseal portal venous system originating from the superior hypophyseal artery.
• Posterior Pituitary (Neurohypophysis): Derived from neural ectoderm. Receives direct arterial blood from the inferior hypophyseal arteries. Stores and secretes oxytocin and arginine vasopressin (AVP/ADH), which are synthesized in the paraventricular and supraoptic hypothalamic nuclei and transported down unmyelinated axons.

Etiologies of Hypopituitarism

Hypopituitarism denotes deficiency of one or more pituitary hormones. Primary pituitary causes must be distinguished from hypothalamic lesions:

1. Non-Functioning Pituitary Adenomas (~50%): Macroadenomas ($\ge 10\text{ mm}$) compress normal functional pituitary tissue and compromise portal blood flow.
2. Pituitary Surgery and Radiotherapy: Radiation-induced hypopituitarism develops insidiously over 2 to 10 years.
3. Sheehan's Syndrome (Postpartum Pituitary Necrosis): During pregnancy, the anterior pituitary undergoes physiological lactotroph hyperplasia without a corresponding increase in blood supply. Catastrophic obstetric haemorrhage and profound hypovolaemic shock lead to arterial vasospasm, ischaemic infarction, and necrosis of the anterior gland. Classically presents postpartum with failure of lactation (agalactorrhoea), failure of menses resumption, profound lethargy, and secondary adrenal insufficiency.
4. Pituitary Apoplexy: Acute haemorrhage or infarction into a pre-existing (often undiagnosed) pituitary macroadenoma. Precipitating triggers include major surgery, cardiac bypass, dynamic pituitary function testing, and anticoagulation. Clinical triad: sudden-onset severe 'thunderclap' headache, visual disturbances (bitemporal hemianopia or visual loss), and cranial nerve palsies (CN III, IV, VI) due to lateral expansion into the cavernous sinus. Acute secondary hypocortisolemia precipitates life-threatening cardiovascular collapse. Immediate management: Urgent blood draw for baseline endocrine profile, followed immediately by intravenous hydrocortisone (100 mg bolus), fluid resuscitation, and emergency neurosurgical decompression if visual acuity or consciousness is compromised.
5. Lymphocytic Hypophysitis: Autoimmune lymphocytic infiltration of the pituitary gland and stalk, classically occurring in women during late pregnancy or the immediate postpartum period. MRI shows symmetric enlargement of the gland with homogeneous gadolinium enhancement and thickened pituitary stalk.
6. Craniopharyngioma: Benign, dysontogenetic suprasellar tumors arising from remnants of Rathke's pouch. Exhibits a bimodal age incidence (peaks at 5–14 years and 50–75 years). Histologically composed of squamous epithelium and cystic spaces filled with cholesterol-rich 'machinery oil' fluid; typically demonstrates suprasellar calcification on skull radiography or CT (present in $> 80%$ of children and $> 50%$ of adults). Compresses the optic chiasm (inferior bitemporal quadrantanopia progressing to bitemporal hemianopia) and hypothalamic-pituitary stalk, frequently provoking central diabetes insipidus and hypopituitarism.

Order of Anterior Pituitary Hormonal Loss

In progressive compressive or infiltrative lesions, anterior pituitary hormone secretion fails in a characteristic, highly reproducible sequence: $\text{GH} \longrightarrow \text{LH / FSH} \longrightarrow \text{TSH} \longrightarrow \text{ACTH}$

• Growth Hormone (GH): First to decline. In adults, manifests as decreased lean muscle mass, central adiposity, reduced bone density, and impaired psychological quality of life.
• Gonadotropins (LH / FSH): Causes hypogonadotrophic hypogonadism (oligomenorrhoea/amenorrhoea and vaginal dryness in premenopausal women; loss of libido, erectile dysfunction, and testicular atrophy in men).
• TSH: Secondary (central) hypothyroidism with fatigue, cold intolerance, and weight gain. Serum free T4 is low, but serum TSH is inappropriately normal or low.
• ACTH: Last to decline. Causes secondary adrenal insufficiency. Because the renin-angiotensin-aldosterone axis is regulated by renal perfusion and serum potassium, aldosterone secretion is entirely preserved. Thus, patients do not suffer hyperkalaemia, and hyperpigmentation is absent because ACTH and POMC are low.

MRCP Rule: Hormone Replacement Order: When initiating hormone replacement in panhypopituitarism, hydrocortisone must ALWAYS precede levothyroxine. Administering levothyroxine alone accelerates the hepatic clearance of endogenous cortisol, precipitating an acute, fatal Addisonian crisis.

Dynamic Endocrine Tests

• Insulin Tolerance Test (ITT): The international gold standard for assessing both the hypothalamic-pituitary-adrenal (HPA) axis and GH reserve simultaneously. Intravenous soluble insulin ($0.10\text{–}0.15\text{ U/kg}$) is administered to induce profound symptomatic hypoglycaemia (blood glucose $< 2.2\text{ mmol/L}$). Adequate stress responses require a peak serum cortisol $> 450\text{–}500\text{ nmol/L}$ and peak GH $> 5\text{–}7\text{ mcg/L}$ ($> 15\text{–}20\text{ mU/L}$). Absolute contraindications: Ischaemic heart disease, epilepsy, severe cerebrovascular disease, and frail elderly patients.
• Short Synacthen Test (SST): $250\text{ mcg}$ tetracosactide (synthetic ACTH 1–24) IM or IV. Measures adrenal cortisol output at 0 and 30 minutes (normal peak $> 450\text{–}500\text{ nmol/L}$). Note: SST may be falsely normal in acute pituitary injury ($< 2\text{–}4\text{ weeks}$) because the adrenal cortex has not yet had sufficient time to undergo secondary atrophy.

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2. Hyperprolactinaemia & Prolactinomas

Physiological Regulation

Prolactin is unique among anterior pituitary hormones: its primary hypothalamic control is tonic inhibition mediated by dopamine acting on dopamine D2 receptors located on lactotroph cells. TRH, vasoactive intestinal peptide (VIP), and oestrogens act as physiological secretagogues.

Differential Diagnosis of Hyperprolactinaemia

Evaluating hyperprolactinaemia requires correlating serum prolactin concentrations with the clinical context:

• Physiological: Pregnancy ($> 5000\text{ mU/L}$), lactation, intense physical exercise, severe systemic stress, venepuncture stress.
• Pharmacological (Dopamine Antagonists): By far the most common non-physiological cause. Levels usually range between $1000\text{ and }4000\text{ mU/L}$:
  • Antipsychotics: Typical neuroleptics (haloperidol, chlorpromazine) and atypical agents (especially risperidone and amisulpride).
  • Antiemetics / Prokinetics: Metoclopramide, domperidone.
  • Antidepressants: SSRIs, SNRIs, tricyclic antidepressants, and MAOIs.
  • Antihypertensives: Methyldopa, verapamil.
  • Opioids and H2-receptor antagonists.
• Stalk Disconnection Effect: Any suprasellar mass, non-functioning pituitary macroadenoma, or infundibular infiltration (e.g. sarcoidosis, histiocytosis) compressing the pituitary stalk disrupts the transport of inhibitory dopamine from the hypothalamus to the adenohypophysis. Prolactin levels are mildly to moderately elevated, almost universally $< 2000\text{ mU/L}$ (rarely up to $3000\text{ mU/L}$).
• Prolactinomas (Lactotroph Adenomas):
  • Microprolactinoma ($< 10\text{ mm}$): Prolactin levels typically $2000\text{–}5000\text{ mU/L}$. Far more common in premenopausal women (presenting early with oligomenorrhoea and galactorrhoea).
  • Macroprolactinoma ($\ge 10\text{ mm}$): Prolactin levels correlate with tumor volume and are characteristically $> 5000\text{ mU/L}$, frequently exceeding $10,000\text{–}20,000\text{ mU/L}$. More common in men, presenting late with mass effects (headache, bitemporal upper quadrantanopia/hemianopia, hypopituitarism).
• Systemic Conditions:
  • Primary Hypothyroidism: Elevated hypothalamic TRH stimulates lactotroph TRH receptors, causing mild hyperprolactinaemia ($1000\text{–}2500\text{ mU/L}$). Always measure serum TSH before performing pituitary MRI!
  • Chronic Kidney Disease: Impaired renal clearance of prolactin.
  • Macroprolactinaemia: Biologically inactive complexes of monomeric prolactin with IgG autoantibodies. Detected via polyethylene glycol (PEG) precipitation; prevents unnecessary neuroimaging or dopamine agonist therapy.
  • 'Hook Effect': In massive macroprolactinomas with prolactin $> 50,000\text{ mU/L}$, antigen excess saturates both capture and detection antibodies in two-site immunometric assays, yielding a falsely low reading (e.g. $1000\text{ mU/L}$). Performing serial serum dilutions unmasks the true astronomical concentration.

Clinical Features & Medical Management

Clinical features include galactorrhoea (milky breast secretion), secondary amenorrhoea/oligomenorrhoea, subfertility, and accelerated osteopenia/osteoporosis secondary to hypogonadotrophic hypogonadism. In men, manifestations include decreased libido, erectile dysfunction, gynaecomastia, and visual loss.

• First-Line Therapy: Medical management with oral dopamine D2 receptor agonists is first-line for both micro- and macroprolactinomas:
  • Cabergoline: Preferred agent of choice. Administered once or twice weekly. Significantly superior to bromocriptine in achieving prolactin normalisation ($> 85%$) and tumor shrinkage ($> 80%$), with superior gastrointestinal tolerability. Potential adverse effects include nausea, orthostatic hypotension, impulse control disorders (pathological gambling, hypersexuality), and psychiatric symptoms. At the high doses used in Parkinson's disease, cabergoline is associated with 5-HT2B receptor-mediated cardiac valvulopathy; baseline echocardiography is standard practice.
  • Bromocriptine: Short-acting daily oral agent; alternative if pregnancy is actively planned, though cabergoline safety in pregnancy is well established.
• Surgical Indications: Transsphenoidal hypophysectomy is reserved for dopamine agonist resistance, intractable drug intolerance, or acute apoplexy with progressive visual deterioration.

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